METHODS AND SYSTEMS FOR CLASSIFICATION AND TREATMENT OF SMALL CELL LUNG CANCER

Information

  • Patent Application
  • 20230405117
  • Publication Number
    20230405117
  • Date Filed
    November 05, 2021
    3 years ago
  • Date Published
    December 21, 2023
    a year ago
Abstract
Aspects of the present disclosure are directed to methods for classification and treatment of small cell lung cancer (SCLC). Certain aspects pertain to treatment of a subject having SCLC using a targeting agent for a cell surface protein, where a targeting agent is selected based on a subtype classification of the SCLC. Disclosed are methods for identifying a subject as having an SCLC subtype (e.g., SCLC-A, SCLC-N, SCLC-P, SCLC-I) and administering a targeting agent configured to target a cell surface protein associated with the identified SCLC subtype. Also disclosed are compositions comprising targeting agents for treatment of SCLC.
Description
BACKGROUND
I. Field of the Invention

Aspects of this invention relate to at least the fields of cancer biology and medicine.


II. Background

Small cell lung cancer (SCLC) is a highly aggressive form of lung cancer for which there exist a very limited number of therapeutics and minimal improvements made over the past 30 years1-3. As a result, the 5-year survival rate is less than 7% across all stages of SCLC2,3. The National Cancer Institute has declared SCLC to be a recalcitrant malignancy with urgent need for a deeper mechanistic understanding of resistance development and identification and targeting of unique vulnerabilities4,5.


SCLC has previously been considered and managed as a homogenous disease, with nearly ubiquitous loss of tumor protein 53 (TP53) and RB Transcriptional Corepressor 1 (RBI) expression resulting in high rates of mutation (tumor mutational burden, or TMB)6. Unfortunately, neither of these ubiquitous mutations are targetable by currently available therapeutics. The current standard of care (SOC) for patients is platinum-based chemotherapy often in combination with immunotherapy7,8. Chemotherapy alone usually results in a response, but is followed by rapid relapse of resistant disease, and the addition of immunotherapy results in only modest improvements in survival9,10. Second-line treatment consisted solely of topotecan until mid-2020, at which time lurbinectedin was approved for patients with relapsed SCLC11,12. However, both of these treatments have only modest success against relapsed disease13. The treatment of SCLC as a single disease ignores a potentially striking avenue for therapeutic development. Current treatment does not consider disease heterogeneity, which could explain the disappointing results from clinical trials and SOC in unselected populations. In contrast to SCLC, NSCLC has seen striking advances in patient care and survival by targeting specific tumor vulnerabilities, as exemplified by treatment of EGFR-mutant patients14,15. Similarly, exploiting different genetic and proteomic vulnerabilities within SCLC tumors could allow for the development of novel, targeted therapeutic reagents based on the tumor's unique signature. Shifting SCLC treatment from a “one-treatment-fits-all” to a more tailored approach will allow for targeted therapeutic reagents to be developed specific to tumor vulnerabilities, providing more effective care and ultimately improving overall survival rates among patients.


SCLC has been surprisingly unresponsive to immune checkpoint blockade (ICB), especially when compared to other cancers with similarly high TMB levels20-22. For example, the addition of the anti-PD-L1 compounds atezolizumab or durvalumab to chemotherapy showed median improvement of only one month compared with chemotherapy alone9,10. There is a need in the art for new and improved methods and compositions for treatment of patients with SCLC, including targeted and immune-based therapeutics.


SUMMARY

The present disclosure fulfils certain needs in the field of cancer medicine by the identification of novel, targetable, surface-expressed targets within each SCLC subtype (SCLC-A, SCLC-N, SCLC-P, and SCLC-I). Identified herein are numerous differentially expressed surface proteins between the four subtypes of SCLC for therapeutic targeting. Embodiments of the disclosure are directed to methods for treatment of a subject determined to have SCLC-A, SCLC-N, SCLC-P, or SCLC-I using a targeting agent configured to target one or more surface proteins associated with the subject's SCLC subtype.


Embodiments of the present disclosure include methods for detecting SCLC, methods for treating SCLC, methods for classifying a subject with SCLC, methods for identifying an SCLC subtype, methods for treating a subject having SCLC-A, methods for treating a subject having SCLC-N, methods for treating a subject having SCLC-P, methods for treating a subject having SCLC-I, methods for targeting a surface marker associated with SCLC-A, methods for targeting a surface marker associated with SCLC-N, methods for targeting a surface marker associated with SCLC-P, and methods for targeting a surface marker associated with SCLC-I. Methods of the disclosure can include at least 1, 2, 3, 4 or more of the following steps: classifying a subject as having SCLC-A, classifying a subject as having SCLC-N, classifying a subject as having SCLC-P, classifying a subject as having SCLC-I, sequencing DNA from a tumor sample from a subject, measuring an expression level of ASCU in a biological sample from a subject, measuring an expression level of NEUROD1 in a biological sample from a subject, measuring an expression level of POU2F3 in a biological sample from a subject, measuring methylation levels of one or more methylation sites from a nucleic acid sample from a subject, and administering a targeting agent to a subject.


Disclosed herein, in some embodiments, is a method for treating a subject for small cell lung cancer (SCLC), the method comprising administering a targeting agent capable of specifically binding to one or more of the proteins of Table 1, Table 2, or Table 3 to a subject determined to have SCLC-A. In some embodiments, the one or more proteins are one or more proteins of Table 1. In some embodiments, the one or more proteins are one or more proteins of Table 2. In some embodiments, the one or more proteins are one or more proteins of Table 3. In some embodiments, the targeting agent is capable of specifically binding to DLL3. In some embodiments, the targeting agent is capable of specifically binding to CEACAM5. In some embodiments, the targeting agent is capable of specifically binding to SCNN1A. In some embodiments, the subject was determined to have SCLC-A by detecting expression of ASCL1 from cancer cells from the subject.


Disclosed herein, in some embodiments, is a method for treating a subject for small cell lung cancer (SCLC), the method comprising administering a targeting agent capable of specifically binding to one or more of the proteins of Table 4, Table 5, or Table 6 to a subject determined to have SCLC-N. In some embodiments, the one or more proteins are one or more proteins of Table 4. In some embodiments, the one or more proteins are one or more proteins of Table 5. In some embodiments, the one or more proteins are one or more proteins of Table 6. In some embodiments, the targeting agent is capable of specifically binding to SSTR2. In some embodiments, the targeting agent is capable of specifically binding to SEMA6D. In some embodiments, the targeting agent is capable of specifically binding to SGCD. In some embodiments, the subject was determined to have SCLC-N by detecting expression of NEUROD1 from cancer cells from the subject.


Disclosed herein, in some embodiments, is a method for treating a subject for small cell lung cancer (SCLC), the method comprising administering a targeting agent capable of specifically binding to one or more of the proteins of Table 7, Table 8, or Table 9 to a subject determined to have SCLC-P. In some embodiments, the one or more proteins are one or more proteins of Table 7. In some embodiments, the one or more proteins are one or more proteins of Table 8. In some embodiments, the one or more proteins are one or more proteins of Table 9. In some embodiments, the targeting agent is capable of specifically binding to MICA. In some embodiments, the targeting agent is capable of specifically binding to TMEM87A. In some embodiments, the targeting agent is capable of specifically binding to ART3. In some embodiments, the subject was determined to have SCLC-P by detecting expression of POU2F3 from cancer cells from the subject.


Disclosed herein, in some embodiments, is a method for treating a subject for small cell lung cancer (SCLC), the method comprising administering a targeting agent capable of specifically binding to one or more of the proteins of Table 10, Table 11, or Table 12 to a subject determined to have SCLC-I. In some embodiments, the one or more proteins are one or more proteins of Table 10. In some embodiments, the one or more proteins are one or more proteins of Table 11. In some embodiments, the one or more proteins are one or more proteins of Table 12. In some embodiments, the targeting agent is capable of specifically binding to SLAMF8. In some embodiments, the targeting agent is capable of specifically binding to MRC2. In some embodiments, the targeting agent is capable of specifically binding to PIEZO1. In some embodiments, the subject was determined to have SCLC-I by determining cancer cells from the subject not to express any of ASCL1, NEUROD1, or POU2F3.


In some embodiments, the targeting agent comprises an antibody or fragment thereof. In some embodiments, the targeting agent is a bispecific T-cell engager. In some embodiments, a cell comprising the targeting agent is administered to the subject. In some embodiments, the cell is an immune cell. In some embodiments, the immune cell is a T cell. In some embodiments, the targeting agent is a chimeric antigen receptor. In some embodiments, the targeting agent is a T cell receptor. In some embodiments, the targeting agent is operatively linked to a therapeutic agent. In some embodiments, the therapeutic agent is a chemotherapeutic. In some embodiments, the therapeutic agent is a toxin. In some embodiments, the therapeutic agent is a therapeutic nucleic acid. In some embodiments, the targeting agent is an antibody-drug conjugate. In some embodiments, the targeting agent is an antibody-oligonucleotide conjugate.


Disclosed here, in some embodiments, is a method for treating a subject for SCLC, the method comprising administering a DLL3-binding protein to a subject determined to have SCLC-A.


Disclosed here, in some embodiments, is a method for treating a subject for SCLC, the method comprising administering a CEACAM5-binding protein to a subject determined to have SCLC-A.


Disclosed here, in some embodiments, is a method for treating a subject for SCLC, the method comprising administering a SCNN1A-binding protein to a subject determined to have SCLC-A.


Disclosed here, in some embodiments, is a method for treating a subject for SCLC, the method comprising administering a SSTR2-binding protein to a subject determined to have SCLC-N.


Disclosed here, in some embodiments, is a method for treating a subject for SCLC, the method comprising administering a SEMA6D-binding protein to a subject determined to have SCLC-N.


Disclosed here, in some embodiments, is a method for treating a subject for SCLC, the method comprising administering a SGCD-binding protein to a subject determined to have SCLC-N.


Disclosed here, in some embodiments, is a method for treating a subject for SCLC, the method comprising administering a MICA-binding protein to a subject determined to have SCLC-P.


Disclosed here, in some embodiments, is a method for treating a subject for SCLC, the method comprising administering a TMEM87A-binding protein to a subject determined to have SCLC-P.


Disclosed here, in some embodiments, is a method for treating a subject for SCLC, the method comprising administering a ART3-binding protein to a subject determined to have SCLC-P.


Disclosed here, in some embodiments, is a method for treating a subject for SCLC, the method comprising administering a SLAMF8-binding protein to a subject determined to have SCLC-I.


Disclosed here, in some embodiments, is a method for treating a subject for SCLC, the method comprising administering a MRC2-binding protein to a subject determined to have SCLC-I.


Disclosed here, in some embodiments, is a method for treating a subject for SCLC, the method comprising administering a PIEZO1-binding protein to a subject determined to have SCLC-I.


Throughout this application, the term “about” is used to indicate that a value includes the inherent variation of error for the measurement or quantitation method.


The use of the word “a” or “an” when used in conjunction with the term “comprising” may mean “one,” but it is also consistent with the meaning of “one or more,” “at least one,” and “one or more than one.”


The phrase “and/or” means “and” or “or”. To illustrate, A, B, and/or C includes: A alone, B alone, C alone, a combination of A and B, a combination of A and C, a combination of B and C, or a combination of A, B, and C. In other words, “and/or” operates as an inclusive or.


The words “comprising” (and any form of comprising, such as “comprise” and “comprises”), “having” (and any form of having, such as “have” and “has”), “including” (and any form of including, such as “includes” and “include”) or “containing” (and any form of containing, such as “contains” and “contain”) are inclusive or open-ended and do not exclude additional, unrecited elements or method steps.


The compositions and methods for their use can “comprise,” “consist essentially of,” or “consist of” any of the ingredients or steps disclosed throughout the specification. Compositions and methods “consisting essentially of” any of the ingredients or steps disclosed limits the scope of the claim to the specified materials or steps which do not materially affect the basic and novel characteristic of the claimed invention. As used in this specification and claim(s), the words “comprising” (and any form of comprising, such as “comprise” and “comprises”), “having” (and any form of having, such as “have” and “has”), “including” (and any form of including, such as “includes” and “include”) or “containing” (and any form of containing, such as “contains” and “contain”) are inclusive or open-ended and do not exclude additional, unrecited elements or method steps. It is contemplated that embodiments described herein in the context of the term “comprising” may also be implemented in the context of the term “consisting of” or “consisting essentially of.”


“Individual, “subject,” and “patient” are used interchangeably and can refer to a human or non-human.


It is specifically contemplated that any limitation discussed with respect to one embodiment of the invention may apply to any other embodiment of the invention. Furthermore, any composition of the invention may be used in any method of the invention, and any method of the invention may be used to produce or to utilize any composition of the invention. Aspects of an embodiment set forth in the Examples are also embodiments that may be implemented in the context of embodiments discussed elsewhere in a different Example or elsewhere in the application, such as in the Summary, Detailed Description, Claims, and Brief Description of the Drawings.


Any method in the context of a therapeutic, diagnostic, or physiologic purpose or effect may also be described in “use” claim language such as “Use of” any compound, composition, or agent discussed herein for achieving or implementing a described therapeutic, diagnostic, or physiologic purpose or effect.


Other objects, features and advantages of the present invention will become apparent from the following detailed description. It should be understood, however, that the detailed description and the specific examples, while indicating specific embodiments of the invention, are given by way of illustration only, since various changes and modifications within the spirit and scope of the invention will become apparent to those skilled in the art from this detailed description.





BRIEF DESCRIPTION OF THE DRAWINGS

The following drawings form part of the present specification and are included to further demonstrate certain aspects of the present invention. The invention may be better understood by reference to one or more of these drawings in combination with the detailed description of specific embodiments presented herein.



FIG. 1 shows differential gene expression from RNASeq data (Cell Line, George) and microarray data (Sato) of surfaceome proteins across all four SCLC subtypes.



FIGS. 2A-2D shows example hits for SCLC-A (FIG. 2A), SCLC-N (FIG. 2B), SCLC-P (FIG. 2C), and SCLC-I (FIG. 2D). Shown is the analysis from the George et al dataset; an identical analysis was performed for the cell line and Sato datasets



FIGS. 3A-3D show mean expression of the cell surface protein encoding gene SSTR2 in multiple datasets (FIGS. 3A-3C) along with flow cytometry analysis of proportion of analyzed cells that express SSTR2 protein in subtyped cell lines (FIG. 3D).



FIGS. 4A-4C show differential mean expression between subtypes of genes encoding MICA for the George et al. tumor mRNA (FIG. 4A), cell line mRNA (FIG. 4B), and Sato et al. tumor mRNA (FIG. 4C).



FIGS. 5A-5C show differential mean expression between subtypes of genes encoding CEACAM5 for the George et al. tumor mRNA (FIG. 5A), cell line mRNA (FIG. 5B), and Sato et al. tumor mRNA (FIG. 5C).



FIGS. 6A and 6B show western blot analysis of cell lines of each of the four SCLC subtypes. (FIG. 6A) shows analysis of SSTR2 expression. A ratio of band intensity of SSTR2 to GAPDH, arbitrarily normalized to the first lane (H82), is shown below the membrane. (FIG. 6B) shows analysis of CEACAM5 and MICA expression.





DETAILED DESCRIPTION OF THE INVENTION

Using mRNA gene expression patterns, tumors from SCLC patients can be classified into four major subtypes of SCLC. Three of them are defined by differential expression of the transcription factors ASCL1 (SCLC-A), NEUROD1 (SCLC-N), and POU2F3 (SCLC-P), and a fourth group is characterized for having high expression of inflammatory-related genes (SCLC-I). Importantly, these subtypes have distinct therapeutic vulnerabilities and show differential response patterns to standard of care and investigation agents. Certain methods for such classification and treatment of SCLC are described in U.S. Patent Application Publication No. US 2021/0062274, incorporated by reference herein in its entirety.


The present disclosure is based, at least in part, on the identification of surface markers (also “cell surface proteins” or “surface proteins”) associated with (i.e., preferentially expressed in) each of the four SCLC subtypes. These associated surface markers may be used to select targeting agents (e.g., antibodies, antibody fragments, CAR T cells, etc.) for use in treatment of each subtype. For example, a targeting agent configured to bind to a surface marker associated with SCLC-A may be used to treat a subject who has been identified to have the SCLC-A subtype. Similarly, a targeting agent configured to bind to a surface marker associated with SCLC-N, SCLC-P, or SCLC-I may be used to treat a subject who has been identified to have the SCLC-N, SCLC-P, or SCLC-I subtype, respectively.


Certain aspects of the disclosure are directed to methods for treatment of a subject with SCLC comprising administering a targeting agent configured to bind to a surface protein of Table 1, Table 2, and/or Table 3, where the subject was determined to have SCLC-A. In some embodiments, the targeting agent is a DLL3-binding protein. In some embodiments, the targeting agent is a CEACAM5-binding protein. In some embodiments, the targeting agent is a SCNN1A-binding protein.


Further aspects of the disclosure are directed to methods for treatment of a subject with SCLC comprising administering a targeting agent configured to bind to a surface protein of Table 4, Table 5, and/or Table 6, where the subject was determined to have SCLC-N. In some embodiments, the targeting agent is a SSTR2-binding protein. In some embodiments, the targeting agent is a SEMA6D-binding protein. In some embodiments, the targeting agent is a SGCD-binding protein.


Further aspects of the disclosure are directed to methods for treatment of a subject with SCLC comprising administering a targeting agent configured to bind to a surface protein of Table 7, Table 8, and/or Table 9, where the subject was determined to have SCLC-P. In some embodiments, the targeting agent is a MICA-binding protein. In some embodiments, the targeting agent is a TMEM87-binding protein. In some embodiments, the targeting agent is a ART3-binding protein.


Further aspects of the disclosure are directed to methods for treatment of a subject with SCLC comprising administering a targeting agent configured to bind to a surface protein of Table 10, Table 11, and/or Table 12, where the subject was determined to have SCLC-I. In some embodiments, the targeting agent is a SLAMF8-binding protein. In some embodiments, the targeting agent is a MRC2-binding protein. In some embodiments, the targeting agent is a PIEZO1-binding protein.


I. Treatment Methods

Aspects of the present disclosure include methods of treating a patient with small cell lung cancer (SCLC). Certain aspects are directed to methods for treatment of a subject for SCLC, where the treatment is selected based on the SCLC subtype of the subject. As described herein, a subject may have SCLC, where the SCLC can be classified as one of four subtypes: SCLC-A, SCLC-N, SCLC-P, or SCLC-I. In some embodiments, the treatment is a treatment with a targeting agent disclosed herein, wherein the targeting agent is configured to bind to a surface protein identified with an SCLC subtype.


In some embodiments, the subject is identified as having an SCLC subtype based on the expression or methylation status of ASCU, NEUROD1, and POU2F3 in nucleic acid from cancer tissue from the subject. SCLC-A may be identified based on expression of ASCU and lack of expression of NEUROD1 or POU2F3. SCLC-N may be identified based on expression of NEUROD1 and lack of expression of either ASCU or POU2F3. SCLC-P may be identified based on expression of POU2F3 and lack of expression of either ASCU or NEUROD1. SCLC-I may be identified based on lack of expression of any of ASCL1, NEUROD1, and POU2F3.


A treatment for the subject may be determined based on the subtype determination. Such treatment may also be in combination with another therapeutic regime, such as chemotherapy or immunotherapy. In addition, the treatment may be in combination due to a subject's cancer falling into more than one subtype, such as, for example, if one portion of the cancer cells fall into the SCLC-A subtype (e.g., express ASCL1) and another portion of the cancer cells fall into the SCLC-N subtype (e.g., express NEUROD1). The type and/or subtype of a given cancer may change over time, and in some embodiments the present methods regarding identifying the type and/or subtype and selecting an appropriate treatment are performed more than once, such as repeating the methods after a patient develops resistance to a selected therapy, or after a predetermined period of time, and modifying the therapy accordingly.


In some embodiments, a subject is or was determined to have a cancer of the SCLC-A subtype. In some embodiments, the subject is administered a B-cell lymphoma 2 (BCL-2) inhibitor. A BCL-2 inhibitor may describe any agent, molecule, or compound capable of inhibiting the activity of a BCL-2 family protein. Examples of BCL-2 inhibitors include ABT-737, ABT-263 (navitoclax), ABT-199 (venetoclax), GX15-070 (obatoclax), HA14-1, TW-37, AT101, and BI-97C1 (sabutoclax). In some embodiments, the BCL-2 inhibitor is ABT-737 or navitoclax. In some embodiments, the subject is administered a DLL3-targeted therapeutic. A DLL3-targeted therapeutic may describe any agent, molecule, or compound capable of binding to a DLL3 protein. In some embodiments, the DLL3-targeted therapeutic is an anti-DLL3 antibody or fragment thereof. In some embodiments, the DLL3-targeted therapeutic is rovalpituzumab. In some embodiments, the DLL3-targeted therapeutic is an antibody-drug conjugate. In some embodiments, the DLL3-targeted therapeutic is rovalpituzumab tesirine. In some embodiments, the subject having a cancer of the SCLC-A subtype is administered a targeting agent configured to bind to one or more of the proteins of Table 1, Table 2, and/or Table 3. In some embodiments, the subject is administered a targeting agent configured to bind to one or more of the proteins of Table 1. In some embodiments, the subject is administered a targeting agent configured to bind to one or more of the proteins of Table 2. In some embodiments, the subject is administered a targeting agent configured to bind to one or more of the proteins of Table 3. In some embodiments, the subject is administered a targeting agent configured to bind to DLL3 (e.g., a DLL3-binding protein). In some embodiments, the subject is administered a targeting agent configured to bind to CEACAM5 (e.g., a CEACAM5-binding protein). In some embodiments, the subject is administered a targeting agent configured to bind to SCNN1A (e.g., a SCNN1A-binding protein).


In some embodiments, a subject is or was determined to have a cancer of the SCLC-N subtype. In some embodiments, the subject is administered an Aurora kinase (AURK) inhibitor, a JAK inhibitor, or a c-Met inhibitor. In some embodiments, the subject is administered an AURK inhibitor. Examples of AURK inhibitors include alisertib, ZM447439, hesperidin, ilorasertib, VX-680, CCT 137690, lestaurtinib, NU 6140, PF 03814735, SNS 314 mesylate, TC-A 2317 hydrochloride, TAK-901, AMG-900, AS-703569, AT-9283, CYC-116, SCH-1473759, and TC-S 7010. In some embodiments, the AURK inhibitor is CYC-116, alisertib, or AS-703569. Examples of JAK inhibitors include ruxolitinib, tofacitinib, oclacitinib, baricitinib, peficitinib, fedratinib, upadacitinib, filgotinib, cerdulatinib, gandotinib, lestaurtinib, momelotinib, pacritinib, and PF-04975842. Examples of c-Met inhibitors include BMS-777607, cabozantinib, MK-2461, AMG-458, JNJ-38877605, PF-04217903, and GSK-1363089. Other drugs to which subjects having a cancer of the SCLC-N subtype may be sensitive include PF-562271, VS-507, KW-2449, pimozide, CB-64D, AC-220, omacetaxine mepasuccinate, XL-888, XL-880, ifosfamide, SL-0101, GW-5074, letrozole, CYC-202, and BIM-46187. In some embodiments, the subject having a cancer of the SCLC-N subtype is administered a targeting agent configured to bind to one or more of the proteins of Table 4, Table 5, and/or Table 6. In some embodiments, the subject is administered a targeting agent configured to bind to one or more of the proteins of Table 4. In some embodiments, the subject is administered a targeting agent configured to bind to one or more of the proteins of Table 5. In some embodiments, the subject is administered a targeting agent configured to bind to one or more of the proteins of Table 6. In some embodiments, the subject is administered a targeting agent configured to bind to SSTR2 (e.g., a SSTR2-binding protein). In some embodiments, the subject is administered a targeting agent configured to bind to SEMA6D (e.g., a SEMA6D-binding protein). In some embodiments, the subject is administered a targeting agent configured to bind to SGCD (e.g., a SGCD-binding protein).


In some embodiments, a subject is or was determined to have a cancer of the SCLC-P subtype. In some embodiments, the subject is administered a PARP inhibitor, an AKT inhibitor, a Sky inhibitor, a JAK inhibitor, a SRC inhibitor, a BET inhibitor, an ERK inhibitor, an mTor inhibitor, an HSP90 inhibitor, a PI3K inhibitor, a CDK inhibitor, a topoisomerase inhibitor, a nucleoside analogue, an anti-metabolite, or a platinum-containing chemotherapeutic agent. Examples of PARP inhibitors include olaparib, rucaparib, niraparib, talazoparib, veliparib, pamiparib, CEP 9722, E7016, iniparib, AZD2461, and 3-aminobenzamide. In some embodiments, the PARP inhibitor is talazoparib, olaparib, niraparib, AZD-2461, or rucaparib. Examples of AKT inhibitors include CCT-128930, GSK690693, MK 2206, SC79, capivasertib, ipatasertib, borussertib, uprosertib, perifosine, AZD-5363, and A-443654. Examples of Syk inhibitors include R-406, R-788 (fostamatinib), BAY 61-3606, and nilvadipine. Examples of JAK inhibitors include ruxolitinib, tofacitinib, oclacitinib, baricitinib, peficitinib, fedratinib, upadacitinib, filgotinib, cerdulatinib, gandotinib, lestaurtinib, momelotinib, pacritinib, AZD-1480, XL-019, SB-1578, WL-1034, and PF-04975842. Examples of SRC inhibitors include dasatinib, AZD-0530, KX2-391, bosutinib, saracatinib, and quercetin. Examples of BET inhibitors include GSK1210151A, GSK525762, (+)-JQ1, OTX-015, TEN-010, CPI-203, CPI-0610, LY294002, AZD5153, MT-1, and MS645. Examples of ERK inhibitors include SC-1 (pluripotin), AX 15836, BIX 02189, ERK5-IN-1, FR 180204, TCS ERK 11e, TMCB, and XMD 8-92. Examples of CDK inhibitors include R-547, palbociclib, LY-2835219, CYC-202, ribociclib, abemaciclib, and trilaciclib. Examples of mTor inhibitors include PF-04212384, OSI-027, rapamycin, AZD-2014, RG-7603, BGT-226, PI-103, GS K-2126458, everolimus, temsirolimus, ridaforolimus, sirolimus, dactolisib, and sapanisertib. Examples of anti-metabolites and nucleoside analogues include teriflunomide, pemetrexed, ONX-0801, fluorouracil, cladribine, methotrexate, mercaptopurine, gemcitabine, capecitabine, hydroxyurea, fludarabine, 2-fluoroadenosine, pralatrexate, nelarabine, cladribine, clofarabine, decitabine, azacitidine, cytarabine, floxuridine, and thioguanine. In some embodiments, the anti-metabolite is pemetrexed, methotrexate, or pralatrexate. In some embodiments, the nucleoside analog is floxuridine, cytarabine, clofarabine, or fludarabine. Examples of platinum-containing chemotherapeutic agents include cisplatin, carboplatin, oxaliplatin, nedaplatin, picoplatin, and satraplatin. In some embodiments, the platinum-containing chemotherapeutic agent is cisplatin, carboplatin, oxaliplatin, nedaplatin, picoplatin, or satraplatin. Other drugs to which patients having a cancer of the SCLC-P subtype may be sensitive include ENMD-2076, HPI-1, CP-868596, TL-32711, FGF inhibitor, AS-703569, vandetanib, CYC-116, KW-2499, GSK-2334470, BMS-582664, AEG-40730, ICG-001, CB-64D, SCH-1473759, MK-2461, CH-5132799, dovitinib, AM-2282, PP-242, ZSTK-474, crizotinib, apitolisib, AT-9283, MPC-3100, alisertib, LOR-253, INK-128, AZD-8055, omacetaxine mepasuccinate, everolimus, XL-888, XL-880, PF-04929113, PF-4942847, dactolisib, PF-04691502, TAK-901, CUDC-305, tretinoin, GSK-461364, BAY-80-6946, danorubicin, doxorubicin, valrubicin, YK-4-279, PF-4176340, BKM-120, APO-866, EB-1627, axitinib, XR-5944, XR-5000, BX-912, mitoxantrone, LY-294002, ixabepilone, GDC-0941, BMS-536924, 3-AP, thiotepa, belinostat, and ABT-348. In some embodiments, the subject having a cancer of the SCLC-P subtype is administered a targeting agent configured to bind to one or more of the proteins of Table 7, Table 8, and/or Table 9. In some embodiments, the subject is administered a targeting agent configured to bind to one or more of the proteins of Table 7. In some embodiments, the subject is administered a targeting agent configured to bind to one or more of the proteins of Table 8. In some embodiments, the subject is administered a targeting agent configured to bind to one or more of the proteins of Table 9. In some embodiments, the subject is administered a targeting agent configured to bind to MICA (e.g., a MICA-binding protein). In some embodiments, the subject is administered a targeting agent configured to bind to TMEM87A (e.g., a TMEM87A-binding protein). In some embodiments, the subject is administered a targeting agent configured to bind to ART3 (e.g., a ART3-binding protein).


In some embodiments, a subject is or was determined to have a cancer of the SCLC-I subtype. These cells may express immune checkpoint proteins, inflammatory markers, STING pathway proteins, CCL5, CXCL10, MHC proteins, CD274 (PD-L1), LAG3, C10orf54 (VISTA), ID01, CD38, and ICOS. In this case, the patient is selected for treatment with an immune checkpoint inhibitor, a BTK inhibitor, a Syk inhibitor, a multikinase inhibitor, an ERK inhibitor, an VEGFR inhibitor, a MEK inhibitor, a FGFR inhibitor. Examples of BTK inhibitors include ibrutinib, LCB 03-0110, LFM-A13, PCI 29732, PF 06465469, and terreic acid. Examples of Syk inhibitors include R-406, R-788 (fostamatinib), BAY 61-3606, and nilvadipine. Examples of multikinase inhibitors include LY-2801653, ENMD-2076, ponatinib, and pazopanib. Examples of ERK inhibitors include SC-1 (pluripotin), AX 15836, BIX 02189, ERK5-IN-1, FR 180204, TCS ERK 11e, TMCB, and XMD 8-92. Examples of VEGFR inhibitors include ASP-4130 (tivozanib), lenvatinib, RG-7167, sorafenib, sunitinib, bevacizumab, cabozantinib, regorafenib, nintedanib, and apatinib. Examples of MEK inhibitors include RO-5126766, AZD-8330, TAK-733, XL-518, PD-0325901, ARRY-162, trametinib, pimasertib, cobimetinib, binimetinib, and selumetinib. Examples of FGFR inhibitors include AZD-4547, PD-173074, LY-2874455, BGJ-398, ponatinib, nintedanib, dovitinib, danusertib, and brivanib. Other drugs to which patients having a cancer of the SCLC-I subtype may be sensitive include AZD-1480, AZD-0530, ASP-3026, fulvestrant, SCH-1473759, MK-2461, LY-2090314, PP-242, 17-AAG, BPR1J-097, INK-128, AZD-8055, omacetaxine mepasuccinate, everolimus, XL-888, XL-880, dactolisib, PF-04691502, OSI-027, rapamycin, CUDC-305, and bleomycin. In some embodiments, the subject having a cancer of the SCLC-I subtype is administered a targeting agent configured to bind to one or more of the proteins of Table 10 Table 11, and/or Table 12. In some embodiments, the subject is administered a targeting agent configured to bind to one or more of the proteins of Table 10. In some embodiments, the subject is administered a targeting agent configured to bind to one or more of the proteins of Table 11. In some embodiments, the subject is administered a targeting agent configured to bind to one or more of the proteins of Table 12. In some embodiments, the subject is administered a targeting agent configured to bind to SLAMF8 (e.g., a SLAMF8-binding protein). In some embodiments, the subject is administered a targeting agent configured to bind to MRC2 (e.g., a MRC2-binding protein). In some embodiments, the subject is administered a targeting agent configured to bind to PIEZO1 (e.g., a PIEZO1-binding protein).


II. Targeting Agents

Aspects of the present disclosure comprise targeting agents. A “targeting agent” of the present disclosure describes a molecule capable of specifically binding to a cell surface protein. In some embodiments, a targeting agent is an antigen-binding protein. An antigen-binding protein describes a protein capable of specifically binding to an antigen. Examples of antigen-binding proteins include antibodies, antibody fragments (e.g., scFv, Fab, etc.), antibody-like molecules (e.g., bispecific T-cell engagers), chimeric antigen receptors, and ligands (e.g., natural ligands, synthetic ligands). In some embodiments, a targeting agent comprises an antibody. Various agents capable of specifically binding to a cell surface protein are known in the art and are contemplated herein.


Targeting agents of the present disclosure include molecules comprising an antigen-binding protein and one or more additional components. In some embodiments, an antigen-binding protein is operatively linked (e.g., covalently linked, non-covalently linked) to one or more therapeutic agents. In some embodiments, the therapeutic agent is a chemotherapeutic. In some embodiments, the therapeutic agent is a toxin (e.g., MMAE, DM1, tesirine, etc.). In some embodiments, the therapeutic agent is a therapeutic nucleic acid (e.g., antisense oligonucleotide, small interfering RNA, small hairpin RNA, etc.). In some embodiments, a targeting molecule of the present disclosure is an antibody-drug conjugate (ADC). In some embodiments, a targeting molecule of the present disclosure is an antibody-oligonucleotide conjugate (AOC).


A targeting agent of the disclosure may be a molecule capable of specifically binding to one or more surface markers of any of Tables 1-12. In some embodiments, a targeting agent is capable of specifically binding to a surface marker of Table 1. In some embodiments, a targeting agent is capable of specifically binding to a surface marker of Table 2. In some embodiments, a targeting agent is capable of specifically binding to a surface marker of Table 3. In some embodiments, a targeting agent is capable of specifically binding to a surface marker of Table 4. In some embodiments, a targeting agent is capable of specifically binding to a surface marker of Table 5. In some embodiments, a targeting agent is capable of specifically binding to a surface marker of Table 6. In some embodiments, a targeting agent is capable of specifically binding to a surface marker of Table 7. In some embodiments, a targeting agent is capable of specifically binding to a surface marker of Table 8. In some embodiments, a targeting agent is capable of specifically binding to a surface marker of Table 9. In some embodiments, a targeting agent is capable of specifically binding to a surface marker of Table 10. In some embodiments, a targeting agent is capable of specifically binding to a surface marker of Table 11. In some embodiments, a targeting agent is capable of specifically binding to a surface marker of Table 12.


III. Cell Surface Proteins

As used herein, a “protein” or “polypeptide” refers to a molecule comprising at least five amino acid residues. As used herein, the term “wild-type” refers to the endogenous version of a molecule that occurs naturally in an organism. In some embodiments, wild-type versions of a protein or polypeptide are employed, however, in many embodiments of the disclosure, a modified protein or polypeptide is employed. The terms described above may be used interchangeably. A “modified protein” or “modified polypeptide” or a “variant” refers to a protein or polypeptide whose chemical structure, particularly its amino acid sequence, is altered with respect to the wild-type protein or polypeptide. In some embodiments, a modified/variant protein or polypeptide has at least one modified activity or function (recognizing that proteins or polypeptides may have multiple activities or functions). It is specifically contemplated that a modified/variant protein or polypeptide may be altered with respect to one activity or function yet retain a wild-type activity or function in other respects, such as immunogenicity.


Where a protein is specifically mentioned herein, it is in general a reference to a native (wild-type) or recombinant protein or, optionally, a protein in which any signal sequence has been removed. The protein may be isolated directly from the organism of which it is native, produced by recombinant DNA/exogenous expression methods, or produced by solid-phase peptide synthesis (SPPS) or other in vitro methods. In particular embodiments, there are isolated nucleic acid segments and recombinant vectors incorporating nucleic acid sequences that encode a polypeptide (e.g., an antibody or fragment thereof). The term “recombinant” may be used in conjunction with a polypeptide or the name of a specific polypeptide, and this generally refers to a polypeptide produced from a nucleic acid molecule that has been manipulated in vitro or that is a replication product of such a molecule.


As used herein, a “cell surface protein,” (also “surface protein” or “surface marker”) describes a protein which may be expressed on a surface (e.g., cell membrane) of a cell. A cell surface protein may be attached to a membrane of a cell. A cell surface protein may be embedded in a membrane of a cell. A cell surface protein may comprise one or more transmembrane regions. In some embodiments, cell surface proteins associated with (i.e. preferentially expressed in) SCLC subtypes are contemplated. Also contemplated are methods of targeting cell surface proteins for treatment of SCLC. A cell surface protein may be targeted, e.g., via an antibody or antibody fragment, for delivery of a therapeutic to SCLC cells. For example, a cell surface protein may be targeted using an antibody for delivery of a toxin or other therapeutic to SCLC cells expressing the cell surface protein. Examples of cell surface proteins which may be targeted using methods and compositions of the present disclosure include Delta Like Canonical Notch Ligand 3 (DLL3), CEA Cell Adhesion Molecule 5 (CEACAM5), Sodium Channel Epithelial 1 Subunit Alpha (SCNN1A), Somatostatin receptor type 2 (SSTR2), Semaphorin 6D (SEMAD6), Sarcoglycan Delta (SGCD), MHC Class I Polypeptide-Related Sequence A (MICA), Transmembrane Protein 87A (TMEM87A), ADP-Ribosyltransferase 3 (ARTS), SLAM Family Member 8 (SLAMF8), Mannose Receptor C Type 2 (MRC2), and Piezo Type Mechanosensitive Ion Channel Component 1 (PIEZO1).


A. DLL3


Delta Like Canonical Notch Ligand 3 (DLL3), also known as SCDO1, is an inhibitory Notch ligand highly expressed in neuroendocrine tumors. A complete mRNA sequence of human DLL3 has the Genbank accession number NM 016941. DLL3 expression is driven by ASCL1 and, accordingly, as demonstrated herein, DLL3 is preferentially expressed in SCLC-A. A novel antibody-drug conjugate (ADC) targeting DLL3, rovalpituzumab tesirine (Rova-T), showed activity in DLL3-expressing patient-derived xenograft (PDX) models. In clinical trials, clinical activity of Rova-T was observed in a subset of patients, but further clinical development was stopped due to ADC payload toxicity and lower-than-expected response rates in relapsed SCLC. Despite disappointing results with Rova-T, other DLL3 approaches appear promising and are being investigated, including DLL3 CAR-T (NCT03392064), the first CAR-T therapy trial for SCLC. Additionally, DLL3 is the target of bispecific T cell engager (BiTE) immuno-oncology therapy AMG 757 because the cessation of Rova-T appears to be a result of ADC toxicity effects and not DLL3-specific effects.


In some embodiments, disclosed are methods comprising administering to a subject with SCLC a DLL3-binding protein, where the subject was determined to have SCLC-A. Certain non-limiting examples of DLL3-binding proteins of the disclosure include anti-DLL3 antibodies, anti-DLL3 antibody fragments, anti-DLL3 antibody drug conjugates, anti-DLL3 bispecific T cell engagers (BiTEs), and anti-DLL3 chimeric antigen receptors. In some embodiments, the DLL3-binding protein is or comprises rovalpituzumab. In some embodiments, the DLL3-binding protein is rovalpituzumab tesirine. In some embodiments, the DLL3-binding protein is AMG 119. In some embodiments, the DLL3-binding protein is AMG 757.


B. CEACAM5


CEA Cell Adhesion Molecule 5 (CEACAM5), also known as CD66e, is a cell adhesion molecule overexpressed in gastrointestinal and breast cancers as well as in NSCLC. A complete mRNA sequence of human CEACAM5 has the Genbank accession number NM_001291484. CEACAM is the target of labetuzumab govitecan, an ADC in clinical investigation for patients with refractory metastatic colorectal cancer, as well as a CAR T-cell.


In some embodiments, disclosed are methods comprising administering to a subject with SCLC a CEACAM5-binding protein, where the subject was determined to have SCLC-A. Certain non-limiting examples of CEACAM5-binding proteins of the disclosure include anti-CEACAM5 antibodies, anti-CEACAM5 antibody fragments, anti-CEACAM5 antibody drug conjugates, anti-CEACAM5 bispecific T cell engagers (BiTEs), and anti-CEACAM5 chimeric antigen receptors. In some embodiments, the CEACAM5-binding protein is or comprises labetuzumab. In some embodiments, the CEACAM5-binding protein is labetuzumab govitecan.


C. SCNN1A


Sodium Channel Epithelial 1 Subunit Alpha (SCNN1A), also known as BESC2, is a nonvoltage-gated, amiloride-sensitive, sodium channels. A complete mRNA sequence of human SCNN1A has the Genbank accession number NM_001038.


In some embodiments, disclosed are methods comprising administering to a subject with SCLC a SCNN1A-binding protein, where the subject was determined to have SCLC-A. Certain non-limiting examples of CEACAM5-binding proteins of the disclosure include anti-SCNN1A antibodies, anti-SCNN1A antibody fragments, anti-SCNN1A antibody drug conjugates, anti-SCNN1A bispecific T cell engagers (BiTEs), and anti-SCNN1A chimeric antigen receptors.


D. SSTR2


Somatostatin receptor type 2 (SSTR2) is a seven transmembrane receptor. SSTR2 is a well-established target expressed in low- and intermediate-grade neuroendocrine tumors (NETs), in which somatostatin analogues, such as octreotide and lanreotide, which bind SSTR2, are routinely used therapeutically. SSTR2 is also the target of an ADC, PEN-221. A complete mRNA sequence of human SSTR2 has the Genbank accession number NM_001050.


In some embodiments, disclosed are methods comprising administering to a subject with SCLC a SSTR2-binding protein, where the subject was determined to have SCLC-N. Certain non-limiting examples of SSTR2-binding proteins of the disclosure include anti-SSTR2 antibodies, anti-SSTR2 antibody fragments, anti-SSTR2 antibody drug conjugates, anti-SSTR2 bispecific T cell engagers (BiTEs), and anti-SSTR2 chimeric antigen receptors. In some embodiments, the SSTR2-binding protein is PEN-221.


E. SEMAD6


Semaphorin 6D (SEMAD6) is a cell surface protein. A complete mRNA sequence of human SEMAD6 has the Genbank accession number NM_020858.


In some embodiments, disclosed are methods comprising administering to a subject with SCLC a SEMAD6-binding protein, where the subject was determined to have SCLC-N. Certain non-limiting examples of SEMAD6-binding proteins of the disclosure include anti-SEMAD6 antibodies, anti-SEMAD6 antibody fragments, anti-SEMAD6 antibody drug conjugates, anti-SEMAD6 bispecific T cell engagers (BiTEs), and anti-SEMAD6 chimeric antigen receptors.


F. SGCD


Sarcoglycan Delta (SGCD) is a component of the sarcoglycan complex. A complete mRNA sequence of human SGCD has the Genbank accession number NM_000337.


In some embodiments, disclosed are methods comprising administering to a subject with SCLC a SGCD-binding protein, where the subject was determined to have SCLC-N. Certain non-limiting examples of SGCD-binding proteins of the disclosure include anti-SGCD antibodies, anti-SGCD antibody fragments, anti-SGCD antibody drug conjugates, anti-SGCD bispecific T cell engagers (BiTEs), and anti-SGCD chimeric antigen receptors.


G. MICA


MHC Class I Polypeptide-Related Sequence A (MICA) is a cell surface protein. MICA normally acts as the ligand for Natural Killer Group 2 (NKG2D) receptor activation, however prolonged NKG2D activation can ultimately suppress Natural Killer (NK) cell and CD8+ T-cell activity, allowing for immune evasion. A complete mRNA sequence of human MICA has the Genbank accession number NM_000247.


In some embodiments, disclosed are methods comprising administering to a subject with SCLC a MICA-binding protein, where the subject was determined to have SCLC-P. Certain non-limiting examples of MICA-binding proteins of the disclosure include anti-MICA antibodies, anti-MICA antibody fragments, anti-MICA antibody drug conjugates, anti-MICA bispecific T cell engagers (BiTEs), and anti-MICA chimeric antigen receptors. In some embodiments, the MICA-binding protein is IPH43.


H. TMEM87A


Transmembrane Protein 87A (TMEM87A) is a cell surface protein. A complete mRNA sequence of human TMEM87A has the Genbank accession number NM_015497.


In some embodiments, disclosed are methods comprising administering to a subject with SCLC a TMEM87A-binding protein, where the subject was determined to have SCLC-P. Certain non-limiting examples of TMEM87A-binding proteins of the disclosure include anti-TMEM87A antibodies, anti-TMEM87A antibody fragments, anti-TMEM87A antibody drug conjugates, anti-TMEM87A bispecific T cell engagers (BiTEs), and anti-TMEM87A chimeric antigen receptors.


I. ART3


ADP-Ribosyltransferase 3 (ART3) is a cell surface protein. A complete mRNA sequence of human ART3 has the Genbank accession number NM_001130016.


In some embodiments, disclosed are methods comprising administering to a subject with SCLC a ART3-binding protein, where the subject was determined to have SCLC-P. Certain non-limiting examples of ART3-binding proteins of the disclosure include anti-ART3 antibodies, anti-ART3 antibody fragments, anti-ART3 antibody drug conjugates, anti-ART3 bispecific T cell engagers (BiTEs), and anti-ART3 chimeric antigen receptors.


J. SLAMF8


SLAM Family Member 8 (SLAMF8), also known as CD353, is a member of the CD2 family of cell surface proteins involved in lymphocyte activation. A complete mRNA sequence of human SLAMF8 has the Genbank accession number NM_020125.


In some embodiments, disclosed are methods comprising administering to a subject with SCLC a SLAMF8-binding protein, where the subject was determined to have SCLC-I. Certain non-limiting examples of SLAMF8-binding proteins of the disclosure include anti-SLAMF8 antibodies, anti-SLAMF8 antibody fragments, anti-SLAMF8 antibody drug conjugates, anti-SLAMF8 bispecific T cell engagers (BiTEs), and anti-SLAMF8 chimeric antigen receptors.


K. MRC2


Mannose Receptor C Type 2 (MRC2), also known as CD280, is a member of the mannose receptor family of proteins. A complete mRNA sequence of human MRC2 has the Genbank accession number NM_006039.


In some embodiments, disclosed are methods comprising administering to a subject with SCLC a MRC2-binding protein, where the subject was determined to have SCLC-I. Certain non-limiting examples of MRC2-binding proteins of the disclosure include anti-MRC2 antibodies, anti-MRC2 antibody fragments, anti-MRC2 antibody drug conjugates, anti-MRC2 bispecific T cell engagers (BiTEs), and anti-MRC2 chimeric antigen receptors.


L. PIEZO1


Piezo Type Mechanosensitive Ion Channel Component 1 (PIEZO1) is a mechanically-activated ion channel. A complete mRNA sequence of human PIEZO1 has the Genbank accession number NM_001142864.


In some embodiments, disclosed are methods comprising administering to a subject with SCLC a PIEZO1-binding protein, where the subject was determined to have SCLC-I. Certain non-limiting examples of PIEZO1-binding proteins of the disclosure include anti-PIEZO1 antibodies, anti-PIEZO1 antibody fragments, anti-PIEZO1 antibody drug conjugates, anti-PIEZO1 bispecific T cell engagers (BiTEs), and anti-PIEZO1 chimeric antigen receptors.


IV. Antibodies

Aspects of the disclosure relate to antibodies or fragments thereof. The term “antibody” refers to an intact immunoglobulin of any isotype, or a fragment thereof that can compete with the intact antibody for specific binding to the target antigen, and includes chimeric, humanized, fully human, and bispecific antibodies. As used herein, the terms “antibody” or “immunoglobulin” are used interchangeably and refer to any of several classes of structurally related proteins that function as part of the immune response of an animal, including IgG, IgD, IgE, IgA, IgM, and related proteins, as well as polypeptides comprising antibody CDR domains that retain antigen-binding activity.


The term “antigen” refers to a molecule or a portion of a molecule capable of being bound by a selective binding agent, such as an antibody. An antigen may possess one or more epitopes that are capable of interacting with different antibodies.


The term “epitope” includes any region or portion of molecule capable eliciting an immune response by binding to an immunoglobulin or to a T-cell receptor. Epitope determinants may include chemically active surface groups such as amino acids, sugar side chains, phosphoryl or sulfonyl groups, and may have specific three-dimensional structural characteristics and/or specific charge characteristics. Generally, antibodies specific for a particular target antigen will preferentially recognize an epitope on the target antigen within a complex mixture.


The epitope regions of a given polypeptide can be identified using many different epitope mapping techniques are well known in the art, including: x-ray crystallography, nuclear magnetic resonance spectroscopy, site-directed mutagenesis mapping, protein display arrays, see, e.g., Epitope Mapping Protocols, (Johan Rockberg and Johan Nilvebrant, Ed., 2018) Humana Press, New York, N.Y. Such techniques are known in the art and described in, e.g., U.S. Pat. No. 4,708,871; Geysen et al. Proc. Natl. Acad. Sci. USA 81:3998-4002 (1984); Geysen et al. Proc. Natl. Acad. Sci. USA 82:178-182 (1985); Geysen et al. Molec. Immunol. 23:709-715 (1986 See, e.g., Epitope Mapping Protocols, supra. Additionally, antigenic regions of proteins can also be predicted and identified using standard antigenicity and hydropathy plots.


An intact antibody is generally composed of two full-length heavy chains and two full-length light chains, but in some instances may include fewer chains, such as antibodies naturally occurring in camelids that may comprise only heavy chains. Antibodies as disclosed herein may be derived solely from a single source or may be “chimeric,” that is, different portions of the antibody may be derived from two different antibodies. For example, the variable or CDR regions may be derived from a rat or murine source, while the constant region is derived from a different animal source, such as a human. The antibodies or binding fragments may be produced in hybridomas, by recombinant DNA techniques, or by enzymatic or chemical cleavage of intact antibodies. Unless otherwise indicated, the term “antibody” includes derivatives, variants, fragments, and muteins thereof, examples of which are described below (Sela-Culang et al. Front Immunol. 2013; 4: 302; 2013)


The term “light chain” includes a full-length light chain and fragments thereof having sufficient variable region sequence to confer binding specificity. A full-length light chain has a molecular weight of around 25,000 Daltons and includes a variable region domain (abbreviated herein as VL), and a constant region domain (abbreviated herein as CL). There are two classifications of light chains, identified as kappa (κ) and lambda (λ). The term “VL fragment” means a fragment of the light chain of a monoclonal antibody that includes all or part of the light chain variable region, including CDRs. A VL fragment can further include light chain constant region sequences. The variable region domain of the light chain is at the amino-terminus of the polypeptide.


The term “heavy chain” includes a full-length heavy chain and fragments thereof having sufficient variable region sequence to confer binding specificity. A full-length heavy chain has a molecular weight of around 50,000 Daltons and includes a variable region domain (abbreviated herein as VH), and three constant region domains (abbreviated herein as CH1, CH2, and CH3). The term “VH fragment” means a fragment of the heavy chain of a monoclonal antibody that includes all or part of the heavy chain variable region, including CDRs. A VH fragment can further include heavy chain constant region sequences. The number of heavy chain constant region domains will depend on the isotype. The VH domain is at the amino-terminus of the polypeptide, and the CH domains are at the carboxy-terminus, with the CH3 being closest to the —COOH end. The isotype of an antibody can be IgM, IgD, IgG, IgA, or IgE and is defined by the heavy chains present of which there are five classifications: mu (t), delta (6), gamma (γ), alpha (a), or epsilon (c) chains, respectively. IgG has several subtypes, including, but not limited to, IgG1, IgG2, IgG3, and IgG4. IgM subtypes include IgM1 and IgM2. IgA subtypes include IgA1 and IgA2.


Antibodies can be whole immunoglobulins of any isotype or classification, chimeric antibodies, or hybrid antibodies with specificity to two or more antigens. They may also be fragments (e.g., F(ab′)2, Fab′, Fab, Fv, and the like), including hybrid fragments. An immunoglobulin also includes natural, synthetic, or genetically engineered proteins that act like an antibody by binding to specific antigens to form a complex. The term antibody includes genetically engineered or otherwise modified forms of immunoglobulins, such as the following:


The term “monomer” means an antibody containing only one Ig unit. Monomers are the basic functional units of antibodies. The term “dimer” means an antibody containing two Ig units attached to one another via constant domains of the antibody heavy chains (the Fc, or fragment crystallizable, region). The complex may be stabilized by a joining (J) chain protein. The term “multimer” means an antibody containing more than two Ig units attached to one another via constant domains of the antibody heavy chains (the Fc region). The complex may be stabilized by a joining (J) chain protein.


The term “bivalent antibody” means an antibody that comprises two antigen-binding sites. The two binding sites may have the same antigen specificities or they may be bispecific, meaning the two antigen-binding sites have different antigen specificities.


Bispecific antibodies are a class of antibodies that have two paratopes with different binding sites for two or more distinct epitopes. In some embodiments, bispecific antibodies can be biparatopic, wherein a bispecific antibody may specifically recognize a different epitope from the same antigen. In some embodiments, bispecific antibodies can be constructed from a pair of different single domain antibodies termed “nanobodies”. Single domain antibodies are sourced and modified from cartilaginous fish and camelids. Nanobodies can be joined together by a linker using techniques typical to a person skilled in the art; such methods for selection and joining of nanobodies are described in PCT Publication No. WO2015044386A1, No. WO2010037838A2, and Bever et al., Anal Chem. 86:7875-7882 (2014), each of which are specifically incorporated herein by reference in their entirety.


Bispecific antibodies can be constructed as: a whole IgG, Fab′2, Fab′PEG, a diabody, or alternatively as scFv. Diabodies and scFvs can be constructed without an Fc region, using only variable domains, potentially reducing the effects of anti-idiotypic reaction. Bispecific antibodies may be produced by a variety of methods including, but not limited to, fusion of hybridomas or linking of Fab′ fragments. See, e.g., Songsivilai and Lachmann, Clin. Exp. Immunol. 79:315-321 (1990); Kostelny et al., J. Immunol. 148:1547-1553 (1992), each of which are specifically incorporated by reference in their entirety.


In certain aspects, the antigen-binding domain may be multispecific or heterospecific by multimerizing with VH and VL region pairs that bind a different antigen. For example, the antibody may bind to, or interact with, (a) a cell surface antigen, (b) an Fc receptor on the surface of an effector cell, or (c) at least one other component. Accordingly, aspects may include, but are not limited to, bispecific, trispecific, tetraspecific, and other multispecific antibodies or antigen-binding fragments thereof that are directed to epitopes and to other targets, such as Fc receptors on effector cells.


In some embodiments, multispecific antibodies can be used and directly linked via a short flexible polypeptide chain, using routine methods known in the art. One such example is diabodies that are bivalent, bispecific antibodies in which the VH and VL domains are expressed on a single polypeptide chain, and utilize a linker that is too short to allow for pairing between domains on the same chain, thereby forcing the domains to pair with complementary domains of another chain creating two antigen binding sites. The linker functionality is applicable for embodiments of triabodies, tetrabodies, and higher order antibody multimers. (see, e.g., Hollinger et al., Proc Natl. Acad. Sci. USA 90:6444-6448 (1993); Polijak et al., Structure 2:1121-1123 (1994); Todorovska et al., J. Immunol. Methods 248:47-66 (2001)).


Bispecific diabodies, as opposed to bispecific whole antibodies, may also be advantageous because they can be readily constructed and expressed in E. coli. Diabodies (and other polypeptides such as antibody fragments) of appropriate binding specificities can be readily selected using phage display (WO94/13804) from libraries. If one arm of the diabody is kept constant, for instance, with a specificity directed against a protein, then a library can be made where the other arm is varied and an antibody of appropriate specificity selected. Bispecific whole antibodies may be made by alternative engineering methods as described in Ridgeway et al., (Protein Eng., 9:616-621, 1996) and Krah et al., (N Biotechnol. 39:167-173, 2017), each of which is hereby incorporated by reference in their entirety.


Heteroconjugate antibodies are composed of two covalently linked monoclonal antibodies with different specificities. See, e.g., U.S. Pat. No. 6,010,902, incorporated herein by reference in its entirety.


The part of the Fv fragment of an antibody molecule that binds with high specificity to the epitope of the antigen is referred to herein as the “paratope.” The paratope consists of the amino acid residues that make contact with the epitope of an antigen to facilitate antigen recognition. Each of the two Fv fragments of an antibody is composed of the two variable domains, VH and VL, in dimerized configuration. The primary structure of each of the variable domains includes three hypervariable loops separated by, and flanked by, Framework Regions (FR). The hypervariable loops are the regions of highest primary sequences variability among the antibody molecules from any mammal. The term hypervariable loop is sometimes used interchangeably with the term “Complementarity Determining Region (CDR).” The length of the hypervariable loops (or CDRs) varies between antibody molecules. The framework regions of all antibody molecules from a given mammal have high primary sequence similarity/consensus. The consensus of framework regions can be used by one skilled in the art to identify both the framework regions and the hypervariable loops (or CDRs) which are interspersed among the framework regions. The hypervariable loops are given identifying names which distinguish their position within the polypeptide, and on which domain they occur. CDRs in the VL domain are identified as L1, L2, and L3, with L1 occurring at the most distal end and L3 occurring closest to the CL domain. The CDRs may also be given the names CDR-1, CDR-2, and CDR-3. The L3 (CDR-3) is generally the region of highest variability among all antibody molecules produced by a given organism. The CDRs are regions of the polypeptide chain arranged linearly in the primary structure, and separated from each other by Framework Regions. The amino terminal (N-terminal) end of the VL chain is named FR1. The region identified as FR2 occurs between L1 and L2 hypervariable loops. FR3 occurs between L2 and L3 hypervariable loops, and the FR4 region is closest to the CL domain. This structure and nomenclature is repeated for the VH chain, which includes three CDRs identified as H1, H2 and H3. The majority of amino acid residues in the variable domains, or Fv fragments (VH and VL), are part of the framework regions (approximately 85%). The three dimensional, or tertiary, structure of an antibody molecule is such that the framework regions are more internal to the molecule and provide the majority of the structure, with the CDRs on the extrenal surface of the molecule.


Several methods have been developed and can be used by one skilled in the art to identify the exact amino acids that constitute each of these regions. This can be done using any of a number of multiple sequence alignment methods and algorithms, which identify the conserved amino acid residues that make up the framework regions, therefore identifying the CDRs that may vary in length but are located between framework regions. Three commonly used methods have been developed for identification of the CDRs of antibodies: Kabat (as described in T. T. Wu and E. A. Kabat, “AN ANALYSIS OF THE SEQUENCES OF THE VARIABLE REGIONS OF BENCE JONES PROTEINS AND MYELOMA LIGHT CHAINS AND THEIR IMPLICATIONS FOR ANTIBODY COMPLEMENTARITY,” J Exp Med, vol. 132, no. 2, pp. 211-250, August 1970); Chothia (as described in C. Chothia et al., “Conformations of immunoglobulin hypervariable regions,” Nature, vol. 342, no. 6252, pp. 877-883, December 1989); and IMGT (as described in M.-P. Lefranc et al., “IMGT unique numbering for immunoglobulin and T cell receptor variable domains and Ig superfamily V-like domains,” Developmental & Comparative Immunology, vol. 27, no. 1, pp. 55-77, January 2003). These methods each include unique numbering systems for the identification of the amino acid residues that constitute the variable regions. In most antibody molecules, the amino acid residues that actually contact the epitope of the antigen occur in the CDRs, although in some cases, residues within the framework regions contribute to antigen binding.


One skilled in the art can use any of several methods to determine the paratope of an antibody. These methods include: 1) Computational predictions of the tertiary structure of the antibody/epitope binding interactions based on the chemical nature of the amino acid sequence of the antibody variable region and composition of the epitope; 2) Hydrogen-deuterium exchange and mass spectroscopy; 3) Polypeptide fragmentation and peptide mapping approaches in which one generates multiple overlapping peptide fragments from the full length of the polypeptide and evaluates the binding affinity of these peptides for the epitope; 4) Antibody Phage Display Library analysis in which the antibody Fab fragment encoding genes of the mammal are expressed by bacteriophage in such a way as to be incorporated into the coat of the phage. This population of Fab expressing phage are then allowed to interact with the antigen which has been immobilized or may be expressed in by a different exogenous expression system. Non-binding Fab fragments are washed away, thereby leaving only the specific binding Fab fragments attached to the antigen. The binding Fab fragments can be readily isolated and the genes which encode them determined. This approach can also be used for smaller regions of the Fab fragment including Fv fragments or specific VH and VL domains as appropriate.


In certain aspects, affinity matured antibodies are enhanced with one or more modifications in one or more CDRs thereof that result in an improvement in the affinity of the antibody for a target antigen as compared to a parent antibody that does not possess those alteration(s). Certain affinity matured antibodies will have nanomolar or picomolar affinities for the target antigen. Affinity matured antibodies are produced by procedures known in the art, e.g., Marks et al., Bio/Technology 10:779 (1992) describes affinity maturation by VH and VL domain shuffling, random mutagenesis of CDR and/or framework residues employed in phage display is described by Rajpal et al., PNAS. 24: 8466-8471 (2005) and Thie et al., Methods Mol Biol. 525:309-22 (2009) in conjugation with computation methods as demonstrated in Tiller et al., Front. Immunol. 8:986 (2017).


Chimeric immunoglobulins are the products of fused genes derived from different species; “humanized” chimeras generally have the framework region (FR) from human immunoglobulins and one or more CDRs are from a non-human source.


In certain aspects, portions of the heavy and/or light chain are identical or homologous to corresponding sequences from another particular species or belonging to a particular antibody class or subclass, while the remainder of the chain(s) is identical or homologous to corresponding sequences in antibodies derived from another species or belonging to another antibody class or subclass, as well as fragments of such antibodies, so long as they exhibit the desired biological activity. U.S. Pat. No. 4,816,567; and Morrison et al., Proc. Natl. Acad. Sci. USA 81:6851 (1984). For methods relating to chimeric antibodies, see, e.g., U.S. Pat. No. 4,816,567; and Morrison et al., Proc. Natl. Acad. Sci. USA 81:6851-6855 (1985), each of which are specifically incorporated herein by reference in their entirety. CDR grafting is described, for example, in U.S. Pat. Nos. 6,180,370, 5,693,762, 5,693,761, 5,585,089, and 5,530,101, which are all hereby incorporated by reference for all purposes.


In some embodiments, minimizing the antibody polypeptide sequence from the non-human species optimizes chimeric antibody function and reduces immunogenicity. Specific amino acid residues from non-antigen recognizing regions of the non-human antibody are modified to be homologous to corresponding residues in a human antibody or isotype. One example is the “CDR-grafted” antibody, in which an antibody comprises one or more CDRs from a particular species or belonging to a specific antibody class or subclass, while the remainder of the antibody chain(s) is identical or homologous to a corresponding sequence in antibodies derived from another species or belonging to another antibody class or subclass. For use in humans, the V region composed of CDR1, CDR2, and partial CDR3 for both the light and heavy chain variance region from a non-human immunoglobulin, are grafted with a human antibody framework region, replacing the naturally occurring antigen receptors of the human antibody with the non-human CDRs. In some instances, corresponding non-human residues replace framework region residues of the human immunoglobulin. Furthermore, humanized antibodies may comprise residues that are not found in the recipient antibody or in the donor antibody to further refine performance. The humanized antibody may also comprise at least a portion of an immunoglobulin constant region (Fc), typically that of a human immunoglobulin. See, e.g., Jones et al., Nature 321:522 (1986); Riechmann et al., Nature 332:323 (1988); Presta, Curr. Op. Struct. Biol. 2:593 (1992); Vaswani and Hamilton, Ann. Allergy, Asthma and Immunol. 1:105 (1998); Harris, Biochem. Soc. Transactions 23; 1035 (1995); Hurle and Gross, Curr. Op. Biotech. 5:428 (1994); Verhoeyen et al., Science 239:1534-36 (1988).


Intrabodies are intracellularly localized immunoglobulins that bind to intracellular antigens as opposed to secreted antibodies, which bind antigens in the extracellular space.


Polyclonal antibody preparations typically include different antibodies against different determinants (epitopes). In order to produce polyclonal antibodies, a host, such as a rabbit or goat, is immunized with the antigen or antigen fragment, generally with an adjuvant and, if necessary, coupled to a carrier. Antibodies to the antigen are subsequently collected from the sera of the host. The polyclonal antibody can be affinity purified against the antigen rendering it monospecific.


Monoclonal antibodies or “mAb” refer to an antibody obtained from a population of homogeneous antibodies from an exclusive parental cell, e.g., the population is identical except for naturally occurring mutations that may be present in minor amounts. Each monoclonal antibody is directed against a single antigenic determinant.


A. Functional Antibody Fragments and Antigen-Binding Fragments


1. Antigen-Binding Fragments


Certain aspects relate to antibody fragments, such as antibody fragments that bind to a cell surface protein on a cancer cell. The term functional antibody fragment includes antigen-binding fragments of an antibody that retain the ability to specifically bind to an antigen. These fragments are constituted of various arrangements of the variable region heavy chain (VH) and/or light chain (VL); and in some embodiments, include constant region heavy chain 1 (CH1) and light chain (CL). In some embodiments, theylack the Fc region constituted of heavy chain 2 (CH2) and 3 (CH3) domains. Embodiments of antigen binding fragments and the modifications thereof may include: (i) the Fab fragment type constituted with the VL, VH, CL, and CH1 domains; (ii) the Fd fragment type constituted with the VH and CH1 domains; (iii) the Fv fragment type constituted with the VH and VL domains; (iv) the single domain fragment type, dAb, (Ward, 1989; McCafferty et al., 1990; Holt et al., 2003) constituted with a single VH or VL domain; (v) isolated complementarity determining region (CDR) regions. Such terms are described, for example, in Harlow and Lane, Antibodies: A Laboratory Manual, Cold Spring Harbor Laboratory, NY (1989); Molec. Biology and Biotechnology: A Comprehensive Desk Reference (Myers, R. A. (ed.), New York: VCH Publisher, Inc.); Huston et al., Cell Biophysics, 22:189-224 (1993); Pluckthun and Skerra, Meth. Enzymol., 178:497-515 (1989) and in Day, E. D., Advanced Immunochemistry, 2d ed., Wiley-Liss, Inc. New York, N.Y. (1990); Antibodies, 4:259-277 (2015). The citations in this paragraph are all incorporated by reference.


Antigen-binding fragments also include fragments of an antibody that retain exactly, at least, or at most 1, 2, or 3 complementarity determining regions (CDRs) from a light chain variable region. Fusions of CDR-containing sequences to an Fc region (or a CH2 or CH3 region thereof) are included within the scope of this definition including, for example, scFv fused, directly or indirectly, to an Fc region are included herein.


The term Fab fragment means a monovalent antigen-binding fragment of an antibody containing the VL, VH, CL and CH1 domains. The term Fab′ fragment means a monovalent antigen-binding fragment of a monoclonal antibody that is larger than a Fab fragment. For example, a Fab′ fragment includes the VL, VH, CL and CH1 domains and all or part of the hinge region. The term F(ab′)2 fragment means a bivalent antigen-binding fragment of a monoclonal antibody comprising two Fab′ fragments linked by a disulfide bridge at the hinge region. An F(ab′)2 fragment includes, for example, all or part of the two VH and VL domains, and can further include all or part of the two CL and CH1 domains.


The term Fd fragment means a fragment of the heavy chain of a monoclonal antibody, which includes all or part of the VH, including the CDRs. An Fd fragment can further include CH1 region sequences.


The term Fv fragment means a monovalent antigen-binding fragment of a monoclonal antibody, including all or part of the VL and VH, and absent of the CL and CH1 domains. The VL and VH include, for example, the CDRs. Single-chain antibodies (sFv or scFv) are Fv molecules in which the VL and VH regions have been connected by a flexible linker to form a single polypeptide chain, which forms an antigen-binding fragment. Single chain antibodies are discussed in detail in International Patent Application Publication No. WO 88/01649 and U.S. Pat. Nos. 4,946,778 and 5,260,203, the disclosures of which are herein incorporated by reference. The term (scFv)2 means bivalent or bispecific sFv polypeptide chains that include oligomerization domains at their C-termini, separated from the sFv by a hinge region (Pack et al. 1992). The oligomerization domain comprises self-associating a-helices, e.g., leucine zippers, which can be further stabilized by additional disulfide bonds. (scFv)2 fragments are also known as “miniantibodies” or “minibodies.”


A single domain antibody is an antigen-binding fragment containing only a VH or the VL domain. In some instances, two or more VH regions are covalently joined with a peptide linker to create a bivalent domain antibody. The two VH regions of a bivalent domain antibody may target the same or different antigens.


2. Fragment Crystallizable Region, Fc


An Fc region contains two heavy chain fragments comprising the CH2 and CH3 domains of an antibody. The two heavy chain fragments are held together by two or more disulfide bonds and by hydrophobic interactions of the CH3 domains. The term “Fc polypeptide” as used herein includes native and mutein forms of polypeptides derived from the Fc region of an antibody. Truncated forms of such polypeptides containing the hinge region that promotes dimerization are included.


B. Polypeptides with antibody CDRs & Scaffolding Domains that Display the CDs


Antigen-binding peptide scaffolds, such as complementarity-determining regions (CDRs), are used to generate protein-binding molecules in accordance with the embodiments. Generally, a person skilled in the art can determine the type of protein scaffold on which to graft at least one of the CDRs. It is known that scaffolds, optimally, must meet a number of criteria such as: good phylogenetic conservation; known three-dimensional structure; small size; few or no post-transcriptional modifications; and/or be easy to produce, express, and purify. Skerra, J Mol Recognit, 13:167-87 (2000).


The protein scaffolds can be sourced from, but not limited to: fibronectin type III FN3 domain (known as “monobodies”), fibronectin type III domain 10, lipocalin, anticalin, Z-domain of protein A of Staphylococcus aureus, thioredoxin A or proteins with a repeated motif such as the “ankyrin repeat”, the “armadillo repeat”, the “leucine-rich repeat” and the “tetratricopeptide repeat”. Such proteins are described in US Patent Publication Nos. 2010/0285564, 2006/0058510, 2006/0088908, 2005/0106660, and PCT Publication No. WO2006/056464, each of which are specifically incorporated herein by reference in their entirety. Scaffolds derived from toxins from scorpions, insects, plants, mollusks, etc., and the protein inhibiters of neuronal NO synthase (PIN) may also be used.


V. Sample Preparation

In certain aspects, methods involve obtaining a sample (also “biological sample”) from a subject. The methods of obtaining provided herein may include methods of biopsy such as fine needle aspiration, core needle biopsy, vacuum assisted biopsy, incisional biopsy, excisional biopsy, punch biopsy, shave biopsy, or skin biopsy. In certain embodiments the sample is obtained from a biopsy from lung tissue by any of the biopsy methods previously mentioned. In other embodiments the sample may be obtained from any of the tissues provided herein that include but are not limited to non-cancerous or cancerous tissue and non-cancerous or cancerous tissue from the serum, gall bladder, mucosal, skin, heart, lung, breast, pancreas, blood, liver, muscle, kidney, smooth muscle, bladder, colon, intestine, brain, prostate, esophagus, or thyroid tissue. Alternatively, the sample may be obtained from any other source including but not limited to blood, plasma, serum, sweat, hair follicle, buccal tissue, tears, menses, feces, or saliva. In certain aspects of the current methods, any medical professional such as a doctor, nurse or medical technician may obtain a biological sample for testing. Yet further, the biological sample can be obtained without the assistance of a medical professional.


A sample may include but is not limited to, tissue, cells, or biological material from cells or derived from cells of a subject. The biological sample may be a heterogeneous or homogeneous population of cells or tissues. A sample may also include a sample devoid of cells, for example a cell-free sample comprising cell-free nucleic acid, such as a serum sample. The biological sample may be obtained using any method known to the art that can provide a sample suitable for the analytical methods described herein. The sample may be obtained by non-invasive methods including but not limited to: scraping of the skin or cervix, swabbing of the cheek, saliva collection, urine collection, blood collection, plasma collection, feces collection, collection of menses, tears, or semen.


The sample may be obtained by methods known in the art. In certain embodiments the samples are obtained by biopsy. In other embodiments the sample is obtained by swabbing, endoscopy, scraping, phlebotomy, or any other methods known in the art. In some cases, the sample may be obtained, stored, or transported using components of a kit of the present methods. In some cases, multiple samples, such as multiple lung samples or multiple blood or plasma samples, may be obtained for diagnosis by the methods described herein. In other cases, multiple samples, such as one or more samples from one tissue type (for example lung) and one or more samples from another specimen (for example serum) may be obtained for diagnosis by the methods. In some cases, multiple samples such as one or more samples from one tissue type (e.g. lung) and one or more samples from another specimen (e.g. serum) may be obtained at the same or different times.


In some embodiments, a biological sample analyzed hereis is a liquid sample. In some embodiments, the sample is a blood sample. In some embodiments, the sample is a plasma sample. In some embodiments, the sample is a serum sample. A liquid sample may comprise tumor DNA. Tumor DNA from a liquid sample may be cell-free DNA (cfDNA) and/or DNA from circulating tumor cells. As described herein, “circulating tumor DNA,” or “ctDNA” describes tumor DNA obtained from blood or a blood component (e.g., plasma, serum) from a subject. Tumor DNA, including circulating tumor DNA (ctDNA), may be isolated from a sample and analyzed as disclosed herein (e.g., by sequencing such as bisulfite sequencing).


In some embodiments the biological sample may be obtained by a physician, nurse, or other medical professional such as a medical technician, endocrinologist, cytologist, phlebotomist, radiologist, or a pulmonologist. The medical professional may indicate the appropriate test or assay to perform on the sample. In certain aspects a molecular profiling business may consult on which assays or tests are most appropriately indicated. In further aspects of the current methods, the patient or subject may obtain a biological sample for testing without the assistance of a medical professional, such as obtaining a whole blood sample, a urine sample, a fecal sample, a buccal sample, or a saliva sample.


In other cases, the sample is obtained by an invasive procedure including but not limited to: biopsy, needle aspiration, endoscopy, or phlebotomy. The method of needle aspiration may further include fine needle aspiration, core needle biopsy, vacuum assisted biopsy, or large core biopsy. In some embodiments, multiple samples may be obtained by the methods herein to ensure a sufficient amount of biological material.


In some embodiments of the present methods, the molecular profiling business may obtain the biological sample from a subject directly, from a medical professional, from a third party, or from a kit provided by a molecular profiling business or a third party. In some cases, the biological sample may be obtained by the molecular profiling business after the subject, a medical professional, or a third party acquires and sends the biological sample to the molecular profiling business. In some cases, the molecular profiling business may provide suitable containers, and excipients for storage and transport of the biological sample to the molecular profiling business.


In some embodiments of the methods described herein, a medical professional need not be involved in the initial diagnosis or sample acquisition. An individual may alternatively obtain a sample through the use of an over the counter (OTC) kit. An OTC kit may contain a means for obtaining said sample as described herein, a means for storing said sample for inspection, and instructions for proper use of the kit. In some cases, molecular profiling services are included in the price for purchase of the kit. In other cases, the molecular profiling services are billed separately. A sample suitable for use by the molecular profiling business may be any material containing tissues, cells, nucleic acids, genes, gene fragments, expression products, gene expression products, or gene expression product fragments of an individual to be tested. Methods for determining sample suitability and/or adequacy are provided.


In some embodiments, the subject may be referred to a specialist such as an oncologist, surgeon, or endocrinologist. The specialist may likewise obtain a biological sample for testing or refer the individual to a testing center or laboratory for submission of the biological sample. In some cases the medical professional may refer the subject to a testing center or laboratory for submission of the biological sample. In other cases, the subject may provide the sample. In some cases, a molecular profiling business may obtain the sample.


VI. Assay Methods

A. Detection of Methylated DNA


Aspects of the methods include assaying nucleic acids (e.g., tumor DNA) to determine expression levels and/or methylation levels of nucleic acids. In some embodiments, disclosed are methods comprising determining a methylation status of one or more methylation sites from methylated DNA. The disclosed methods may comprise determining a subject (i.e., DNA from a subject such as tumor DNA) to have differential methylation at one or more methylation sites. As used herein, “differential methylation” of a methylation site describes a significant difference in methylation status of the methylation site in a sample (e.g., a sample comprising tumor DNA from a subject having cancer) as compared to a control or reference (e.g., DNA from a healthy subject). For example, in some embodiments, a methylation site from a sample comprising tumor DNA has significantly increased methylation levels compared to the same methylation site from control (e.g., healthy, non-tumor) DNA. In some embodiments, a methylation site from a sample comprising tumor DNA has significantly decreased methylation levels compared to the same methylation site from control (e.g., healthy, non-tumor) DNA. Assays for the detection of methylated DNA are known in the art. Methylated DNA includes, for example, methylated circulating tumor DNA. Certain, non-limiting examples of such methods are described herein.


1. HPLC-UV


The technique of HPLC-UV (high performance liquid chromatography-ultraviolet), developed by Kuo and colleagues in 1980 (described further in Kuo K. C. et al., Nucleic Acids Res. 1980; 8:4763-4776, which is herein incorporated by reference) can be used to quantify the amount of deoxycytidine (dC) and methylated cytosines (5 mC) present in a hydrolysed DNA sample. The method includes hydrolyzing the DNA into its constituent nucleoside bases, the 5 mC and dC bases are separated chromatographically and, then, the fractions are measured. Then, the 5 mC/dC ratio can be calculated for each sample, and this can be compared between the experimental and control samples.


2. LC-MS/MS


Liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS) is an high-sensitivity approach to HPLC-UV, which requires much smaller quantities of the hydrolysed DNA sample. In the case of mammalian DNA, of which ˜2%-5% of all cytosine residues are methylated, LC-MS/MS has been validated for detecting levels of methylation levels ranging from 0.05%-10%, and it can confidently detect differences between samples as small as ˜0.25% of the total cytosine residues, which corresponds to ˜5% differences in global DNA methylation. The procedure routinely requires 50-100 ng of DNA sample, although much smaller amounts (as low as 5 ng) have been successfully profiled. Another major benefit of this method is that it is not adversely affected by poor-quality DNA (e.g., DNA derived from FFPE samples).


3. ELISA-Based Methods


There are several commercially available kits, all enzyme-linked immunosorbent assay (ELISA) based, that enable the quick assessment of DNA methylation status. These assays include Global DNA Methylation ELISA, available from Cell Biolabs; Imprint Methylated DNA Quantification kit (sandwich ELISA), available from Sigma-Aldrich; EpiSeeker methylated DNA Quantification Kit, available from abcam; Global DNA Methylation Assay—LINE-1, available from Active Motif; 5-mC DNA ELISA Kit, available from Zymo Research; MethylFlash Methylated DNAS-mC Quantification Kit and MethylFlash Methylated DNAS-mC Quantification Kit, available from Epigentek.


Briefly, the DNA sample is captured on an ELISA plate, and the methylated cytosines are detected through sequential incubations steps with: (1) a primary antibody raised against 5 Mc; (2) a labelled secondary antibody; and then (3) colorimetric/fluorometric detection reagents.


The Global DNA Methylation Assay—LINE-1 specifically determines the methylation levels of LINE-1 (long interspersed nuclear elements-1) retrotransposons, of which ˜17% of the human genome is composed. These are well established as a surrogate for global DNA methylation. Briefly, fragmented DNA is hybridized to biotinylated LINE-1 probes, which are then subsequently immobilized to a streptavidin-coated plate. Following washing and blocking steps, methylated cytosines are quantified using an anti-5 mC antibody, HRP-conjugated secondary antibody and chemiluminescent detection reagents. Samples are quantified against a standard curve generated from standards with known LINE-1 methylation levels. The manufacturers claim the assay can detect DNA methylation levels as low as 0.5%. Thus, by analysing a fraction of the genome, it is possible to achieve better accuracy in quantification.


4. LINE-1 Pyrosequencing


Levels of LINE-1 methylation can alternatively be assessed by another method that involves the bisulfite conversion of DNA, followed by the PCR amplification of LINE-1 conservative sequences. The methylation status of the amplified fragments is then quantified by pyrosequencing, which is able to resolve differences between DNA samples as small as ˜5%. Even though the technique assesses LINE-1 elements and therefore relatively few CpG sites, this has been shown to reflect global DNA methylation changes very well. The method is particularly well suited for high throughput analysis of cancer samples, where hypomethylation is very often associated with poor prognosis. This method is particularly suitable for human DNA, but there are also versions adapted to rat and mouse genomes.


5. AFLP and RFLP


Detection of fragments that are differentially methylated could be achieved by traditional PCR-based amplification fragment length polymorphism (AFLP), restriction fragment length polymorphism (RFLP) or protocols that employ a combination of both.


6. LUMA


The LUMA (luminometric methylation assay) technique utilizes a combination of two DNA restriction digest reactions performed in parallel and subsequent pyrosequencing reactions to fill-in the protruding ends of the digested DNA strands. One digestion reaction is performed with the CpG methylation-sensitive enzyme HpaII; while the parallel reaction uses the methylation-insensitive enzyme Mspl, which will cut at all CCGG sites. The enzyme EcoRI is included in both reactions as an internal control. Both Mspl and HpaII generate 5′-CG overhangs after DNA cleavage, whereas EcoRI produces 5′-AATT overhangs, which are then filled in with the subsequent pyrosequencing-based extension assay. Essentially, the measured light signal calculated as the HpaII/Mspl ratio is proportional to the amount of unmethylated DNA present in the sample. As the sequence of nucleotides that are added in pyrosequencing reaction is known, the specificity of the method is very high and the variability is low, which is essential for the detection of small changes in global methylation. LUMA requires only a relatively small amount of DNA (250-500 ng), demonstrates little variability and has the benefit of an internal control to account for variability in the amount of DNA input.


7. Bisulfite Sequencing


The bisulfite treatment of DNA mediates the deamination of cytosine into uracil, and these converted residues will be read as thymine, as determined by PCR-amplification and subsequent Sanger sequencing analysis. However, 5 mC residues are resistant to this conversion and, so, will remain read as cytosine. Thus, comparing the Sanger sequencing read from an untreated DNA sample to the same sample following bisulfite treatment enables the detection of the methylated cytosines. With the advent of next-generation sequencing (NGS) technology, this approach can be extended to DNA methylation analysis across an entire genome. To ensure complete conversion of non-methylated cytosines, controls may be incorporated for bisulfite reactions.


Whole genome bisulfite sequencing (WGBS) is similar to whole genome sequencing, except for the additional step of bisulfite conversion. Sequencing of the 5 mC-enriched fraction of the genome is not only a less expensive approach, but it also allows one to increase the sequencing coverage and, therefore, precision in revealing differentially-methylated regions. Sequencing could be done using any existing NGS platform; Illumina and Life Technologies both offer kits for such analysis.


Bisulfite sequencing methods include reduced representation bisulfite sequencing (RRBS), where only a fraction of the genome is sequenced. In RRBS, enrichment of CpG-rich regions is achieved by isolation of short fragments after Mspl digestion that recognizes CCGG sites (and it cut both methylated and unmethylated sites). It ensures isolation of ˜85% of CpG islands in the human genome. Then, the same bisulfite conversion and library preparation is performed as for WGBS. The RRBS procedure normally requires ˜100 ng-1 μg of DNA.


8. Methods that Exclude Bisulfite Conversion


In some aspects, direct detection of modified bases without bisulfite conversion may be used to detect methylation. For example, Pacific Biosciences company has developed a way to detect methylated bases directly by monitoring the kinetics of polymerase during single molecule sequencing and offers a commercial product for such sequencing (further described in Flusberg B. A., et al., Nat. Methods. 2010; 7:461-465, which is herein incorporated by reference). Other methods include nanopore-based single-molecule real-time sequencing technology (SMRT), which is able to detect modified bases directly (described in Laszlo A. H. et al., Proc. Natl. Acad. Sci. USA. 2013 and Schreiber J., et al., Proc. Natl. Acad. Sci. USA. 2013, which are herein incorporated by reference).


9. Array or Bead Hybridization


Methylated DNA fractions of the genome, usually obtained by immunoprecipitation, could be used for hybridization with microarrays. Currently available examples of such arrays include: the Human CpG Island Microarray Kit (Agilent), the GeneChip Human Promoter 1.0R Array and the GeneChip Human Tiling 2.0R Array Set (Affymetrix).


The search for differentially-methylated regions using bisulfite-converted DNA could be done with the use of different techniques. Some of them are easier to perform and analyse than others, because only a fraction of the genome is used. The most pronounced functional effect of DNA methylation occurs within gene promoter regions, enhancer regulatory elements and 3′ untranslated regions (3′UTRs). Assays that focus on these specific regions, such as the Infinium HumanMethylation450 Bead Chip array by Illumina, can be used. The arrays can be used to detect methylation status of genes, including miRNA promoters, 5′ UTR, 3′ UTR, coding regions (˜17 CpG per gene) and island shores (regions ˜2 kb upstream of the CpG islands).


Briefly, bisulfite-treated genomic DNA is mixed with assay oligos, one of which is complimentary to uracil (converted from original unmethylated cytosine), and another is complimentary to the cytosine of the methylated (and therefore protected from conversion) site. Following hybridization, primers are extended and ligated to locus-specific oligos to create a template for universal PCR. Finally, labelled PCR primers are used to create detectable products that are immobilized to bar-coded beads, and the signal is measured. The ratio between two types of beads for each locus (individual CpG) is an indicator of its methylation level.


It is possible to purchase kits that utilize the extension of methylation-specific primers for validation studies. In the VeraCode Methylation assay from Illumina, 96 or 384 user-specified CpG loci are analysed with the GoldenGate Assay for Methylation. Differently from the BeadChip assay, the VeraCode assay requires the BeadXpress Reader for scanning.


10. Methyl-Sensitive Cut Counting: Endonuclease Digestion Followed by Sequencing


As an alternative to sequencing a substantial amount of methylated (or unmethylated) DNA, one could generate snippets from these regions and map them back to the genome after sequencing. The technique of serial analysis of gene expression (SAGE) has been adapted for this purpose and is known as methylation-specific digital karyotyping, as well as a similar technique, called methyl-sensitive cut counting (MSCC).


In summary, in all of these methods, methylation-sensitive endonuclease(s), e.g., HpaII is used for initial digestion of genomic DNA in unmethylated sites followed by adaptor ligation that contains the site for another digestion enzyme that is cut outside of its recognized site, e.g., EcoP15I or Mmel. These ways, small fragments are generated that are located in close proximity to the original HpaII site. Then, NGS and mapping to the genome are performed. The number of reads for each HpaII site correlates with its methylation level.


A number of restriction enzymes have been discovered that use methylated DNA as a substrate (methylation-dependent endonucleases). Most of them were discovered and are sold by SibEnzyme: Bisl, BlsI, Glal. GluI, Krol, Mtel, Pcsl, Pkrl. The unique ability of these enzymes to cut only methylated sites has been utilized in the method that achieved selective amplification of methylated DNA. Three methylation-dependent endonucleases that are available from New England Biolabs (FspEI, MspJI and LpnPI) are type IIS enzymes that cut outside of the recognition site and, therefore, are able to generate snippets of 32 bp around the fully-methylated recognition site that contains CpG. These short fragments could be sequences and aligned to the reference genome. The number of reads obtained for each specific 32-bp fragment could be an indicator of its methylation level. Similarly, short fragments could be generated from methylated CpG islands with Escherichia coli's methyl-specific endonuclease McrBC, which cuts DNA between two half-sites of (G/A) mC that are lying within 50 bp-3000 bp from each other. This is a very useful tool for isolation of methylated CpG islands that again can be combined with NGS. Being bisulfite-free, these three approaches have a great potential for quick whole genome methylome profiling.


B. Sequencing


In some embodiments, the methods of the disclosure include a sequencing method. Example sequencing methods include those described below.


1. Massively Parallel Signature Sequencing (MPSS).


The first of the next-generation sequencing technologies, massively parallel signature sequencing (or MPSS), was developed in the 1990s at Lynx Therapeutics. MPSS was a bead-based method that used a complex approach of adapter ligation followed by adapter decoding, reading the sequence in increments of four nucleotides. This method made it susceptible to sequence-specific bias or loss of specific sequences. Because the technology was so complex, MPSS was only performed ‘in-house’ by Lynx Therapeutics and no DNA sequencing machines were sold to independent laboratories. Lynx Therapeutics merged with Solexa (later acquired by Illumina) in 2004, leading to the development of sequencing-by-synthesis, a simpler approach acquired from Manteia Predictive Medicine. The essential properties of the MPSS output were typical of later “next-generation” data types, including hundreds of thousands of short DNA sequences. In the case of MPSS, these were typically used for sequencing cDNA for measurements of gene expression levels. Indeed, the powerful Illumina HiSeq2000, HiSeq2500 and MiSeq systems are based on MPSS.


2. Polony Sequencing.


The Polony sequencing method, developed in the laboratory of George M. Church at Harvard, was among the first next-generation sequencing systems and was used to sequence a full genome in 2005. It combined an in vitro paired-tag library with emulsion PCR, an automated microscope, and ligation-based sequencing chemistry to sequence an E. coli genome at an accuracy of >99.9999% and a cost approximately 1/9 that of Sanger sequencing.


3. 454 Pyrosequencing.


A parallelized version of pyrosequencing was developed by 454 Life Sciences, which has since been acquired by Roche Diagnostics. The method amplifies DNA inside water droplets in an oil solution (emulsion PCR), with each droplet containing a single DNA template attached to a single primer-coated bead that then forms a clonal colony. The sequencing machine contains many picoliter-volume wells each containing a single bead and sequencing enzymes. Pyrosequencing uses luciferase to generate light for detection of the individual nucleotides added to the nascent DNA, and the combined data are used to generate sequence read-outs. This technology provides intermediate read length and price per base compared to Sanger sequencing on one end and Solexa and SOLiD on the other.


4. Illumina (Solexa) Sequencing.


Solexa, now part of Illumina, developed a sequencing method based on reversible dye-terminators technology, and engineered polymerases, that it developed internally. The terminated chemistry was developed internally at Solexa and the concept of the Solexa system was invented by Balasubramanian and Klennerman from Cambridge University's chemistry department. In 2004, Solexa acquired the company Manteia Predictive Medicine in order to gain a massivelly parallel sequencing technology based on “DNA Clusters”, which involves the clonal amplification of DNA on a surface. The cluster technology was co-acquired with Lynx Therapeutics of California. Solexa Ltd. later merged with Lynx to form Solexa Inc.


In this method, DNA molecules and primers are first attached on a slide and amplified with polymerase so that local clonal DNA colonies, later coined “DNA clusters”, are formed. To determine the sequence, four types of reversible terminator bases (RT-bases) are added and non-incorporated nucleotides are washed away. A camera takes images of the fluorescently labeled nucleotides, then the dye, along with the terminal 3′ blocker, is chemically removed from the DNA, allowing for the next cycle to begin. Unlike pyrosequencing, the DNA chains are extended one nucleotide at a time and image acquisition can be performed at a delayed moment, allowing for very large arrays of DNA colonies to be captured by sequential images taken from a single camera.


Decoupling the enzymatic reaction and the image capture allows for optimal throughput and theoretically unlimited sequencing capacity. With an optimal configuration, the ultimately reachable instrument throughput is thus dictated solely by the analog-to-digital conversion rate of the camera, multiplied by the number of cameras and divided by the number of pixels per DNA colony required for visualizing them optimally (approximately 10 pixels/colony). In 2012, with cameras operating at more than 10 MHz A/D conversion rates and available optics, fluidics and enzymatics, throughput can be multiples of 1 million nucleotides/second, corresponding roughly to one human genome equivalent at 1× coverage per hour per instrument, and one human genome re-sequenced (at approx. 30×) per day per instrument (equipped with a single camera).


5. Solid Sequencing.


Applied Biosystems' (now a Thermo Fisher Scientific brand) SOLiD technology employs sequencing by ligation. Here, a pool of all possible oligonucleotides of a fixed length are labeled according to the sequenced position. Oligonucleotides are annealed and ligated; the preferential ligation by DNA ligase for matching sequences results in a signal informative of the nucleotide at that position. Before sequencing, the DNA is amplified by emulsion PCR. The resulting beads, each containing single copies of the same DNA molecule, are deposited on a glass slide. The result is sequences of quantities and lengths comparable to Illumina sequencing. This sequencing by ligation method has been reported to have some issue sequencing palindromic sequences.


6. Ion Torrent Semiconductor Sequencing.


Ion Torrent Systems Inc. (now owned by Thermo Fisher Scientific) developed a system based on using standard sequencing chemistry, but with a novel, semiconductor based detection system. This method of sequencing is based on the detection of hydrogen ions that are released during the polymerization of DNA, as opposed to the optical methods used in other sequencing systems. A microwell containing a template DNA strand to be sequenced is flooded with a single type of nucleotide. If the introduced nucleotide is complementary to the leading template nucleotide it is incorporated into the growing complementary strand. This causes the release of a hydrogen ion that triggers a hypersensitive ion sensor, which indicates that a reaction has occurred. If homopolymer repeats are present in the template sequence multiple nucleotides will be incorporated in a single cycle. This leads to a corresponding number of released hydrogens and a proportionally higher electronic signal.


7. DNA Nanoball Sequencing.


DNA nanoball sequencing is a type of high throughput sequencing technology used to determine the entire genomic sequence of an organism. The company Complete Genomics uses this technology to sequence samples submitted by independent researchers. The method uses rolling circle replication to amplify small fragments of genomic DNA into DNA nanoballs. Unchained sequencing by ligation is then used to determine the nucleotide sequence. This method of DNA sequencing allows large numbers of DNA nanoballs to be sequenced per run and at low reagent costs compared to other next generation sequencing platforms. However, only short sequences of DNA are determined from each DNA nanoball which makes mapping the short reads to a reference genome difficult. This technology has been used for multiple genome sequencing projects.


8. Heliscope Single Molecule Sequencing.


Heliscope sequencing is a method of single-molecule sequencing developed by Helicos Biosciences. It uses DNA fragments with added poly-A tail adapters which are attached to the flow cell surface. The next steps involve extension-based sequencing with cyclic washes of the flow cell with fluorescently labeled nucleotides (one nucleotide type at a time, as with the Sanger method). The reads are performed by the Heliscope sequencer. The reads are short, up to 55 bases per run, but recent improvements allow for more accurate reads of stretches of one type of nucleotides. This sequencing method and equipment were used to sequence the genome of the M13 bacteriophage.


9. Single Molecule Real Time (SMRT) Sequencing.


SMRT sequencing is based on the sequencing by synthesis approach. The DNA is synthesized in zero-mode wave-guides (ZMWs)—small well-like containers with the capturing tools located at the bottom of the well. The sequencing is performed with use of unmodified polymerase (attached to the ZMW bottom) and fluorescently labelled nucleotides flowing freely in the solution. The wells are constructed in a way that only the fluorescence occurring by the bottom of the well is detected. The fluorescent label is detached from the nucleotide at its incorporation into the DNA strand, leaving an unmodified DNA strand. According to Pacific Biosciences, the SMRT technology developer, this methodology allows detection of nucleotide modifications (such as cytosine methylation). This happens through the observation of polymerase kinetics. This approach allows reads of 20,000 nucleotides or more, with average read lengths of 5 kilobases.


VII. Cancer Therapy

In some embodiments, the method further comprises administering a cancer therapy to the patient. The cancer therapy may be chosen based on expression level measurements, alone or in combination with a clinical risk score calculated for the patient. In some embodiments, the cancer therapy comprises a local cancer therapy. In some embodiments, the cancer therapy excludes a systemic cancer therapy. In some embodiments, the cancer therapy excludes a local therapy. In some embodiments, the cancer therapy comprises a local cancer therapy without the administration of a system cancer therapy. In some embodiments, the cancer therapy comprises an immunotherapy, which may be an immune checkpoint therapy. Any of these cancer therapies may also be excluded. Combinations of these therapies may also be administered. The term “cancer,” as used herein, may be used to describe a solid tumor, metastatic cancer, or non-metastatic cancer. In certain embodiments, the cancer may originate in the bladder, blood, bone, bone marrow, brain, breast, colon, esophagus, duodenum, small intestine, large intestine, colon, rectum, anus, gum, head, kidney, liver, lung, nasopharynx, neck, ovary, pancreas, prostate, skin, stomach, testis, tongue, or uterus. In some embodiments, the cancer is recurrent cancer. In some embodiments, the cancer is Stage I cancer. In some embodiments, the cancer is Stage II cancer. In some embodiments, the cancer is Stage III cancer. In some embodiments, the cancer is Stage IV cancer.


The cancer may specifically be of the following histological type, though it is not limited to these: neoplasm, malignant; carcinoma; carcinoma, undifferentiated; giant and spindle cell carcinoma; small cell carcinoma; papillary carcinoma; squamous cell carcinoma; lymphoepithelial carcinoma; basal cell carcinoma; pilomatrix carcinoma; transitional cell carcinoma; papillary transitional cell carcinoma; adenocarcinoma; gastrinoma, malignant; cholangiocarcinoma; hepatocellular carcinoma; combined hepatocellular carcinoma and cholangiocarcinoma; trabecular adenocarcinoma; adenoid cystic carcinoma; adenocarcinoma in adenomatous polyp; adenocarcinoma, familial polyposis coli; solid carcinoma; carcinoid tumor, malignant; branchiolo-alveolar adenocarcinoma; papillary adenocarcinoma; chromophobe carcinoma; acidophil carcinoma; oxyphilic adenocarcinoma; basophil carcinoma; clear cell adenocarcinoma; granular cell carcinoma; follicular adenocarcinoma; papillary and follicular adenocarcinoma; nonencapsulating sclerosing carcinoma; adrenal cortical carcinoma; endometroid carcinoma; skin appendage carcinoma; apocrine adenocarcinoma; sebaceous adenocarcinoma; ceruminous adenocarcinoma; mucoepidermoid carcinoma; cystadenocarcinoma; papillary cystadenocarcinoma; papillary serous cystadenocarcinoma; mucinous cystadenocarcinoma; mucinous adenocarcinoma; signet ring cell carcinoma; infiltrating duct carcinoma; medullary carcinoma; lobular carcinoma; inflammatory carcinoma; paget's disease, mammary; acinar cell carcinoma; adenosquamous carcinoma; adenocarcinoma w/squamous metaplasia; thymoma, malignant; ovarian stromal tumor, malignant; thecoma, malignant; granulosa cell tumor, malignant; androblastoma, malignant; sertoli cell carcinoma; leydig cell tumor, malignant; lipid cell tumor, malignant; paraganglioma, malignant; extra-mammary paraganglioma, malignant; pheochromocytoma; glomangiosarcoma; malignant melanoma; amelanotic melanoma; superficial spreading melanoma; malignant melanoma in giant pigmented nevus; epithelioid cell melanoma; blue nevus, malignant; sarcoma; fibrosarcoma; fibrous histiocytoma, malignant; myxosarcoma; liposarcoma; leiomyosarcoma; rhabdomyosarcoma; embryonal rhabdomyosarcoma; alveolar rhabdomyosarcoma; stromal sarcoma; mixed tumor, malignant; mullerian mixed tumor; nephroblastoma; hepatoblastoma; carcinosarcoma; mesenchymoma, malignant; brenner tumor, malignant; phyllodes tumor, malignant; synovial sarcoma; mesothelioma, malignant; dysgerminoma; embryonal carcinoma; teratoma, malignant; struma ovarii, malignant; choriocarcinoma; mesonephroma, malignant; hemangiosarcoma; hemangioendothelioma, malignant; kaposi's sarcoma; hemangiopericytoma, malignant; lymphangiosarcoma; osteosarcoma; juxtacortical osteosarcoma; chondrosarcoma; chondroblastoma, malignant; mesenchymal chondrosarcoma; giant cell tumor of bone; ewing's sarcoma; odontogenic tumor, malignant; ameloblastic odontosarcoma; ameloblastoma, malignant; ameloblastic fibrosarcoma; pinealoma, malignant; chordoma; glioma, malignant; ependymoma; astrocytoma; protoplasmic astrocytoma; fibrillary astrocytoma; astroblastoma; glioblastoma; oligodendroglioma; oligodendroblastoma; primitive neuroectodermal; cerebellar sarcoma; ganglioneuroblastoma; neuroblastoma; retinoblastoma; olfactory neurogenic tumor; meningioma, malignant; neurofibrosarcoma; neurilemmoma, malignant; granular cell tumor, malignant; malignant lymphoma; hodgkin's disease; hodgkin's; paragranuloma; malignant lymphoma, small lymphocytic; malignant lymphoma, large cell, diffuse; malignant lymphoma, follicular; mycosis fungoides; other specified non-hodgkin's lymphomas; malignant histiocytosis; multiple myeloma; mast cell sarcoma; immunoproliferative small intestinal disease; leukemia; lymphoid leukemia; plasma cell leukemia; erythroleukemia; lymphosarcoma cell leukemia; myeloid leukemia; basophilic leukemia; eosinophilic leukemia; monocytic leukemia; mast cell leukemia; megakaryoblastic leukemia; myeloid sarcoma; and hairy cell leukemia.


A. Chemotherapies


In some embodiments, methods of the disclosure comprise administering a chemotherapy. Suitable classes of chemotherapeutic agents include (a) Alkylating Agents, such as nitrogen mustards (e.g., mechlorethamine, cylophosphamide, ifosfamide, melphalan, chlorambucil), ethylenimines and methylmelamines (e.g., hexamethylmelamine, thiotepa), alkyl sulfonates (e.g., busulfan), nitrosoureas (e.g., carmustine, lomustine, chlorozoticin, streptozocin) and triazines (e.g., dicarbazine), (b) Antimetabolites, such as folic acid analogs (e.g., methotrexate), pyrimidine analogs (e.g., 5-fluorouracil, floxuridine, cytarabine, azauridine) and purine analogs and related materials (e.g., 6-mercaptopurine, 6-thioguanine, pentostatin), (c) Natural Products, such as vinca alkaloids (e.g., vinblastine, vincristine), epipodophylotoxins (e.g., etoposide, teniposide), antibiotics (e.g., dactinomycin, daunorubicin, doxorubicin, bleomycin, plicamycin and mitoxanthrone), enzymes (e.g., L-asparaginase), and biological response modifiers (e.g., Interferon-α), and (d) Miscellaneous Agents, such as platinum coordination complexes (e.g., cisplatin, carboplatin), substituted ureas (e.g., hydroxyurea), methylhydiazine derivatives (e.g., procarbazine), and adreocortical suppressants (e.g., taxol and mitotane). In some embodiments, cisplatin is a particularly suitable chemotherapeutic agent. Other suitable chemotherapeutic agents include antimicrotubule agents, e.g., Paclitaxel (“Taxol”) and doxorubicin hydrochloride (“doxorubicin”).


Additional suitable chemotherapeutic agents include pyrimidine analogs, such as cytarabine (cytosine arabinoside), 5-fluorouracil (fluouracil; 5-FU) and floxuridine (fluorode-oxyuridine; FudR). 5-FU may be administered to a subject in a dosage of anywhere between about 7.5 to about 1000 mg/m 2. Further, 5-FU dosing schedules may be for a variety of time periods, for example up to six weeks, or as determined by one of ordinary skill in the art to which this disclosure pertains.


The amount of the chemotherapeutic agent delivered to the patient may be variable. In one suitable embodiment, the chemotherapeutic agent may be administered in an amount effective to cause arrest or regression of the cancer in a host. In other embodiments, the chemotherapeutic agent may be administered in an amount that is anywhere between 2 to fold less than the chemotherapeutic effective dose of the chemotherapeutic agent. For example, the chemotherapeutic agent may be administered in an amount that is about 20 fold less, about 500 fold less or even about 5000 fold less than the chemotherapeutic effective dose of the chemotherapeutic agent. The chemotherapeutics of the disclosure can be tested in vivo for the desired therapeutic activity in combination with the construct, as well as for determination of effective dosages. For example, such compounds can be tested in suitable animal model systems prior to testing in humans, including, but not limited to, rats, mice, chicken, cows, monkeys, rabbits, etc. In vitro testing may also be used to determine suitable combinations and dosages, as described in the examples.


B. Surgery


In some embodiments, the disclosed methods comprise surgery. Approximately 60% of persons with cancer will undergo surgery of some type, which includes preventative, diagnostic or staging, curative, and palliative surgery. Curative surgery includes resection in which all or part of cancerous tissue is physically removed, excised, and/or destroyed and may be used in conjunction with other therapies, such as the treatment of the present embodiments, chemotherapy, radiotherapy, hormonal therapy, gene therapy, immunotherapy, and/or alternative therapies. Tumor resection refers to physical removal of at least part of a tumor. In addition to tumor resection, treatment by surgery includes laser surgery, cryosurgery, electrosurgery, and microscopically-controlled surgery (Mohs' surgery).


Upon excision of part or all of cancerous cells, tissue, or tumor, a cavity may be formed in the body. Treatment may be accomplished by perfusion, direct injection, or local application of the area with an anti-cancer therapy, such as a chemotherapeutic. Such treatment may be repeated, for example, every 1, 2, 3, 4, 5, 6, or 7 days, or every 1, 2, 3, 4, and 5 weeks or every 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months. These treatments may be of varying dosages as well.


C. Immunotherapy


In some embodiments, the disclosed methods comprise administration of a cancer immunotherapy. Cancer immunotherapy (sometimes called immuno-oncology, abbreviated IO) is the use of the immune system to treat cancer. Immunotherapies can be categorized as active, passive or hybrid (active and passive). These approaches exploit the fact that cancer cells often have molecules on their surface that can be detected by the immune system, known as tumour-associated antigens (TAAs); they are often proteins or other macromolecules (e.g. carbohydrates). Active immunotherapy directs the immune system to attack tumor cells by targeting TAAs. Passive immunotherapies enhance existing anti-tumor responses and include the use of monoclonal antibodies, lymphocytes and cytokines. Immumotherapies are known in the art, and some are described below. In some embodiments, a cancer immunotherapy is administered to a subject having been determined to have a cancer of the SCLC-I subtype. In some embodiments, a cancer immunotherapy is administered to a subject in combination with one or more additional cancer therapies.


1. Checkpoint Inhibitors and Combination Treatment


Embodiments of the disclosure may include administration of immune checkpoint inhibitors, which are further described below.


a. PD-1, PDL1, and PDL2 Inhibitors


PD-1 can act in the tumor microenvironment where T cells encounter an infection or tumor. Activated T cells upregulate PD-1 and continue to express it in the peripheral tissues. Cytokines such as IFN-gamma induce the expression of PDL1 on epithelial cells and tumor cells. PDL2 is expressed on macrophages and dendritic cells. The main role of PD-1 is to limit the activity of effector T cells in the periphery and prevent excessive damage to the tissues during an immune response. Inhibitors of the disclosure may block one or more functions of PD-1 and/or PDL1 activity.


Alternative names for “PD-1” include CD279 and SLEB2. Alternative names for “PDL1” include B7-H1, B7-4, CD274, and B7-H. Alternative names for “PDL2” include B7-DC, Btdc, and CD273. In some embodiments, PD-1, PDL1, and PDL2 are human PD-1, PDL1 and PDL2.


In some embodiments, the PD-1 inhibitor is a molecule that inhibits the binding of PD-1 to its ligand binding partners. In a specific aspect, the PD-1 ligand binding partners are PDL1 and/or PDL2. In another embodiment, a PDL1 inhibitor is a molecule that inhibits the binding of PDL1 to its binding partners. In a specific aspect, PDL1 binding partners are PD-1 and/or B7-1. In another embodiment, the PDL2 inhibitor is a molecule that inhibits the binding of PDL2 to its binding partners. In a specific aspect, a PDL2 binding partner is PD-1. The inhibitor may be an antibody, an antigen binding fragment thereof, an immunoadhesin, a fusion protein, or oligopeptide. Exemplary antibodies are described in U.S. Pat. Nos. 8,735,553, 8,354,509, and 8,008,449, all incorporated herein by reference. Other PD-1 inhibitors for use in the methods and compositions provided herein are known in the art such as described in U.S. Patent Application Nos. US2014/0294898, US2014/022021, and US2011/0008369, all incorporated herein by reference.


In some embodiments, the PD-1 inhibitor is an anti-PD-1 antibody (e.g., a human antibody, a humanized antibody, or a chimeric antibody). In some embodiments, the anti-PD-1 antibody is selected from the group consisting of nivolumab, pembrolizumab, and pidilizumab. In some embodiments, the PD-1 inhibitor is an immunoadhesin (e.g., an immunoadhesin comprising an extracellular or PD-1 binding portion of PDL1 or PDL2 fused to a constant region (e.g., an Fc region of an immunoglobulin sequence). In some embodiments, the PDL1 inhibitor comprises AMP-224. Nivolumab, also known as MDX-1106-04, MDX-1106, ONO-4538, BMS-936558, and OPDIVO®, is an anti-PD-1 antibody described in WO2006/121168. Pembrolizumab, also known as MK-3475, Merck 3475, lambrolizumab, KEYTRUDA®, and SCH-900475, is an anti-PD-1 antibody described in WO2009/114335. Pidilizumab, also known as CT-011, hBAT, or hBAT-1, is an anti-PD-1 antibody described in WO2009/101611. AMP-224, also known as B7-DCIg, is a PDL2-Fc fusion soluble receptor described in WO2010/027827 and WO2011/066342. Additional PD-1 inhibitors include MEDI0680, also known as AMP-514, and REGN2810.


In some embodiments, the immune checkpoint inhibitor is a PDL1 inhibitor such as Durvalumab, also known as MEDI4736, atezolizumab, also known as MPDL3280A, avelumab, also known as MSB00010118C, MDX-1105, BMS-936559, or combinations thereof. In certain aspects, the immune checkpoint inhibitor is a PDL2 inhibitor such as rHIgM 12B7.


In some embodiments, the inhibitor comprises the heavy and light chain CDRs or VRs of nivolumab, pembrolizumab, or pidilizumab. Accordingly, in one embodiment, the inhibitor comprises the CDR1, CDR2, and CDR3 domains of the VH region of nivolumab, pembrolizumab, or pidilizumab, and the CDR1, CDR2 and CDR3 domains of the VL region of nivolumab, pembrolizumab, or pidilizumab. In another embodiment, the antibody competes for binding with and/or binds to the same epitope on PD-1, PDL1, or PDL2 as the above-mentioned antibodies. In another embodiment, the antibody has at least about 70, 75, 80, 85, 90, 95, 97, or 99% (or any derivable range therein) variable region amino acid sequence identity with the above-mentioned antibodies.


b. CTLA-4, B7-1, and B7-2


Another immune checkpoint that can be targeted in the methods provided herein is the cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), also known as CD152. The complete cDNA sequence of human CTLA-4 has the Genbank accession number L15006. CTLA-4 is found on the surface of T cells and acts as an “off” switch when bound to B7-1 (CD80) or B7-2 (CD86) on the surface of antigen-presenting cells. CTLA4 is a member of the immunoglobulin superfamily that is expressed on the surface of Helper T cells and transmits an inhibitory signal to T cells. CTLA4 is similar to the T-cell co-stimulatory protein, CD28, and both molecules bind to B7-1 and B7-2 on antigen-presenting cells. CTLA-4 transmits an inhibitory signal to T cells, whereas CD28 transmits a stimulatory signal. Intracellular CTLA-4 is also found in regulatory T cells and may be important to their function. T cell activation through the T cell receptor and CD28 leads to increased expression of CTLA-4, an inhibitory receptor for B7 molecules. Inhibitors of the disclosure may block one or more functions of CTLA-4, B7-1, and/or B7-2 activity. In some embodiments, the inhibitor blocks the CTLA-4 and B7-1 interaction. In some embodiments, the inhibitor blocks the CTLA-4 and B7-2 interaction.


In some embodiments, the immune checkpoint inhibitor is an anti-CTLA-4 antibody (e.g., a human antibody, a humanized antibody, or a chimeric antibody), an antigen binding fragment thereof, an immunoadhesin, a fusion protein, or oligopeptide.


Anti-human-CTLA-4 antibodies (or VH and/or VL domains derived therefrom) suitable for use in the present methods can be generated using methods well known in the art. Alternatively, art recognized anti-CTLA-4 antibodies can be used. For example, the anti-CTLA-4 antibodies disclosed in: U.S. Pat. No. 8,119,129, WO 01/14424, WO 98/42752; WO 00/37504 (CP675,206, also known as tremelimumab; formerly ticilimumab), U.S. Pat. No. 6,207,156; Hurwitz et al., 1998; can be used in the methods disclosed herein. The teachings of each of the aforementioned publications are hereby incorporated by reference. Antibodies that compete with any of these art-recognized antibodies for binding to CTLA-4 also can be used. For example, a humanized CTLA-4 antibody is described in International Patent Application No. WO2001/014424, WO2000/037504, and U.S. Pat. No. 8,017,114; all incorporated herein by reference.


A further anti-CTLA-4 antibody useful as a checkpoint inhibitor in the methods and compositions of the disclosure is ipilimumab (also known as 10D1, MDX-010, MDX-101, and Yervoy®) or antigen binding fragments and variants thereof (see, e.g., WOO 1/14424).


In some embodiments, the inhibitor comprises the heavy and light chain CDRs or VRs of tremelimumab or ipilimumab. Accordingly, in one embodiment, the inhibitor comprises the CDR1, CDR2, and CDR3 domains of the VH region of tremelimumab or ipilimumab, and the CDR1, CDR2 and CDR3 domains of the VL region of tremelimumab or ipilimumab. In another embodiment, the antibody competes for binding with and/or binds to the same epitope on PD-1, B7-1, or B7-2 as the above-mentioned antibodies. In another embodiment, the antibody has at least about 70, 75, 80, 85, 90, 95, 97, or 99% (or any derivable range therein) variable region amino acid sequence identity with the above-mentioned antibodies.


c. LAG3


Another immune checkpoint that can be targeted in the methods provided herein is the lymphocyte-activation gene 3 (LAG3), also known as CD223 and lymphocyte activating 3. The complete mRNA sequence of human LAG3 has the Genbank accession number NM_002286. LAG3 is a member of the immunoglobulin superfamily that is found on the surface of activated T cells, natural killer cells, B cells, and plasmacytoid dendritic cells. LAG3's main ligand is MHC class II, and it negatively regulates cellular proliferation, activation, and homeostasis of T cells, in a similar fashion to CTLA-4 and PD-1, and has been reported to play a role in Treg suppressive function. LAG3 also helps maintain CD8+ T cells in a tolerogenic state and, working with PD-1, helps maintain CD8 exhaustion during chronic viral infection. LAG3 is also known to be involved in the maturation and activation of dendritic cells. Inhibitors of the disclosure may block one or more functions of LAG3 activity.


In some embodiments, the immune checkpoint inhibitor is an anti-LAG3 antibody (e.g., a human antibody, a humanized antibody, or a chimeric antibody), an antigen binding fragment thereof, an immunoadhesin, a fusion protein, or oligopeptide.


Anti-human-LAG3 antibodies (or VH and/or VL domains derived therefrom) suitable for use in the present methods can be generated using methods well known in the art. Alternatively, art recognized anti-LAG3 antibodies can be used. For example, the anti-LAG3 antibodies can include: GSK2837781, IMP321, FS-118, Sym022, TSR-033, MGD013, BI754111, AVA-017, or GSK2831781. The anti-LAG3 antibodies disclosed in: U.S. Pat. No. 9,505,839 (BMS-986016, also known as relatlimab); U.S. Pat. No. 10,711,060 (IMP-701, also known as LAG525); U.S. Pat. No. 9,244,059 (IMP731, also known as H5L7BW); U.S. Pat. No. 10,344,089 (25F7, also known as LAG3.1); WO 2016/028672 (MK-4280, also known as 28G-10); WO 2017/019894 (BAP050); Burova E., et al., J. ImmunoTherapy Cancer, 2016; 4(Supp. 1):P195 (REGN3767); Yu, X., et al., mAbs, 2019; 11:6 (LBL-007) can be used in the methods disclosed herein. These and other anti-LAG-3 antibodies useful in the claimed invention can be found in, for example: WO 2016/028672, WO 2017/106129, WO 2017062888, WO 2009/044273, WO 2018/069500, WO 2016/126858, WO 2014/179664, WO 2016/200782, WO 2015/200119, WO 2017/019846, WO 2017/198741, WO 2017/220555, WO 2017/220569, WO 2018/071500, WO 2017/015560; WO 2017/025498, WO 2017/087589, WO 2017/087901, WO 2018/083087, WO 2017/149143, WO 2017/219995, US 2017/0260271, WO 2017/086367, WO 2017/086419, WO 2018/034227, and WO 2014/140180. The teachings of each of the aforementioned publications are hereby incorporated by reference. Antibodies that compete with any of these art-recognized antibodies for binding to LAG3 also can be used.


In some embodiments, the inhibitor comprises the heavy and light chain CDRs or VRs of an anti-LAG3 antibody. Accordingly, in one embodiment, the inhibitor comprises the CDR1, CDR2, and CDR3 domains of the VH region of an anti-LAG3 antibody, and the CDR1, CDR2 and CDR3 domains of the VL region of an anti-LAG3 antibody. In another embodiment, the antibody has at least about 70, 75, 80, 85, 90, 95, 97, or 99% (or any derivable range therein) variable region amino acid sequence identity with the above-mentioned antibodies.


d. TIM-3


Another immune checkpoint that can be targeted in the methods provided herein is the T-cell immunoglobulin and mucin-domain containing-3 (TIM-3), also known as hepatitis A virus cellular receptor 2 (HAVCR2) and CD366. The complete mRNA sequence of human TIM-3 has the Genbank accession number NM_032782. TIM-3 is found on the surface IFNγ-producing CD4+Th1 and CD8+ Tc 1 cells. The extracellular region of TIM-3 consists of a membrane distal single variable immunoglobulin domain (IgV) and a glycosylated mucin domain of variable length located closer to the membrane. TIM-3 is an immune checkpoint and, together with other inhibitory receptors including PD-1 and LAG3, it mediates the T-cell exhaustion. TIM-3 has also been shown as a CD4+Th1-specific cell surface protein that regulates macrophage activation. Inhibitors of the disclosure may block one or more functions of TIM-3 activity.


In some embodiments, the immune checkpoint inhibitor is an anti-TIM-3 antibody (e.g., a human antibody, a humanized antibody, or a chimeric antibody), an antigen binding fragment thereof, an immunoadhesin, a fusion protein, or oligopeptide.


Anti-human-TIM-3 antibodies (or VH and/or VL domains derived therefrom) suitable for use in the present methods can be generated using methods well known in the art. Alternatively, art recognized anti-TIM-3 antibodies can be used. For example, anti-TIM-3 antibodies including: MBG453, TSR-022 (also known as Cobolimab), and LY3321367 can be used in the methods disclosed herein. These and other anti-TIM-3 antibodies useful in the claimed invention can be found in, for example: U.S. Pat. Nos. 9,605,070, 8,841,418, US2015/0218274, and US 2016/0200815. The teachings of each of the aforementioned publications are hereby incorporated by reference. Antibodies that compete with any of these art-recognized antibodies for binding to LAG3 also can be used.


In some embodiments, the inhibitor comprises the heavy and light chain CDRs or VRs of an anti-TIM-3 antibody. Accordingly, in one embodiment, the inhibitor comprises the CDR1, CDR2, and CDR3 domains of the VH region of an anti-TIM-3 antibody, and the CDR1, CDR2 and CDR3 domains of the VL region of an anti-TIM-3 antibody. In another embodiment, the antibody has at least about 70, 75, 80, 85, 90, 95, 97, or 99% (or any derivable range therein) variable region amino acid sequence identity with the above-mentioned antibodies.


2. Activation of Co-Stimulatory Molecules


In some aspects, the immunotherapy comprises an activator (also “agonist”) of a co-stimulatory molecule. In some aspects, the agonist comprises an agonist of B7-1 (CD80), B7-2 (CD86), CD28, ICOS, OX40 (TNFRSF4), 4-1BB (CD137; TNFRSF9), CD40L (CD40LG), GITR (TNFRSF18), and combinations thereof. Agonists include activating antibodies, polypeptides, compounds, and nucleic acids.


3. Dendritic Cell Therapy


Dendritic cell therapy provokes anti-tumor responses by causing dendritic cells to present tumor antigens to lymphocytes, which activates them, priming them to kill other cells that present the antigen. Dendritic cells are antigen presenting cells (APCs) in the mammalian immune system. In cancer treatment they aid cancer antigen targeting. One example of cellular cancer therapy based on dendritic cells is sipuleucel-T.


One method of inducing dendritic cells to present tumor antigens is by vaccination with autologous tumor lysates or short peptides (small parts of protein that correspond to the protein antigens on cancer cells). These peptides are often given in combination with adjuvants (highly immunogenic substances) to increase the immune and anti-tumor responses. Other adjuvants include proteins or other chemicals that attract and/or activate dendritic cells, such as granulocyte macrophage colony-stimulating factor (GM-CSF).


Dendritic cells can also be activated in vivo by making tumor cells express GM-CSF. This can be achieved by either genetically engineering tumor cells to produce GM-CSF or by infecting tumor cells with an oncolytic virus that expresses GM-CSF.


Another strategy is to remove dendritic cells from the blood of a patient and activate them outside the body. The dendritic cells are activated in the presence of tumor antigens, which may be a single tumor-specific peptide/protein or a tumor cell lysate (a solution of broken down tumor cells). These cells (with optional adjuvants) are infused and provoke an immune response.


Dendritic cell therapies include the use of antibodies that bind to receptors on the surface of dendritic cells. Antigens can be added to the antibody and can induce the dendritic cells to mature and provide immunity to the tumor. Dendritic cell receptors such as TLR3, TLR7, TLR8 or CD40 have been used as antibody targets.


4. CAR-T Cell Therapy


Chimeric antigen receptors (CARs, also known as chimeric immunoreceptors, chimeric T cell receptors or artificial T cell receptors) are engineered receptors that combine a new specificity with an immune cell to target cancer cells. Typically, these receptors graft the specificity of a monoclonal antibody onto a T cell, natural killer (NK) cell, or other immune cell. The receptors are called chimeric because they are fused of parts from different sources. CAR-T cell therapy refers to a treatment that uses such transformed cells for cancer therapy, where the transformed cells are T cells. Similar therapies include, for example, CAR-NK cell therapy, which uses transformed NK cells.


The basic principle of CAR-T cell design involves recombinant receptors that combine antigen-binding and T-cell activating functions. The general premise of CAR-T cells is to artificially generate T-cells targeted to markers found on cancer cells. Scientists can remove T-cells from a person, genetically alter them, and put them back into the patient for them to attack the cancer cells. Once the T cell has been engineered to become a CAR-T cell, it acts as a “living drug”. CAR-T cells create a link between an extracellular ligand recognition domain to an intracellular signalling molecule which in turn activates T cells. The extracellular ligand recognition domain is usually a single-chain variable fragment (scFv). An important aspect of the safety of CAR-T cell therapy is how to ensure that only cancerous tumor cells are targeted, and not normal cells. The specificity of CAR-T cells is determined by the choice of molecule that is targeted.


Exemplary CAR-T therapies include Tisagenlecleucel (Kymriah) and Axicabtagene ciloleucel (Yescarta). In some embodiments, the CAR-T therapy targets CD19.


5. Cytokine Therapy


Cytokines are proteins produced by many types of cells present within a tumor. They can modulate immune responses. The tumor often employs them to allow it to grow and reduce the immune response. These immune-modulating effects allow them to be used as drugs to provoke an immune response. Two commonly used cytokines are interferons and interleukins.


Interferons are produced by the immune system. They are usually involved in anti-viral response, but also have use for cancer. They fall in three groups: type I (IFNα and IFNβ), type II (IFNγ) and type III (IFNλ).


Interleukins have an array of immune system effects. IL-2 is an exemplary interleukin cytokine therapy.


6. Adoptive T-Cell Therapy


Adoptive T cell therapy is a form of passive immunization by the transfusion of T-cells (adoptive cell transfer). They are found in blood and tissue and usually activate when they find foreign pathogens. Specifically they activate when the T-cell's surface receptors encounter cells that display parts of foreign proteins on their surface antigens. These can be either infected cells, or antigen presenting cells (APCs). They are found in normal tissue and in tumor tissue, where they are known as tumor infiltrating lymphocytes (TILs). They are activated by the presence of APCs such as dendritic cells that present tumor antigens. Although these cells can attack the tumor, the environment within the tumor is highly immunosuppressive, preventing immune-mediated tumour death.


Multiple ways of producing and obtaining tumour targeted T-cells have been developed. T-cells specific to a tumor antigen can be removed from a tumor sample (TILs) or filtered from blood. Subsequent activation and culturing is performed ex vivo, with the results reinfused. Activation can take place through gene therapy, or by exposing the T cells to tumor antigens.


It is contemplated that a cancer treatment may exclude any of the cancer treatments described herein. Furthermore, embodiments of the disclosure include patients that have been previously treated for a therapy described herein, are currently being treated for a therapy described herein, or have not been treated for a therapy described herein. In some embodiments, the patient is one that has been determined to be resistant to a therapy described herein. In some embodiments, the patient is one that has been determined to be sensitive to a therapy described herein.


VIII. Administration of Therapeutic Compositions

The therapy provided herein may comprise administration of a combination of therapeutic agents, such as a first cancer therapy and a second cancer therapy. The therapies may be administered in any suitable manner known in the art. For example, the first and second cancer treatment may be administered sequentially (at different times) or concurrently (at the same time). In some embodiments, the first and second cancer treatments are administered in a separate composition. In some embodiments, the first and second cancer treatments are in the same composition.


Embodiments of the disclosure relate to compositions and methods comprising therapeutic compositions. The different therapies may be administered in one composition or in more than one composition, such as 2 compositions, 3 compositions, or 4 compositions. Various combinations of the agents may be employed.


The therapeutic agents of the disclosure may be administered by the same route of administration or by different routes of administration. In some embodiments, the cancer therapy is administered intravenously, intramuscularly, subcutaneously, topically, orally, transdermally, intraperitoneally, intraorbitally, by implantation, by inhalation, intrathecally, intraventricularly, or intranasally. In some embodiments, the antibiotic is administered intravenously, intramuscularly, subcutaneously, topically, orally, transdermally, intraperitoneally, intraorbitally, by implantation, by inhalation, intrathecally, intraventricularly, or intranasally. The appropriate dosage may be determined based on the type of disease to be treated, severity and course of the disease, the clinical condition of the individual, the individual's clinical history and response to the treatment, and the discretion of the attending physician.


The treatments may include various “unit doses.” Unit dose is defined as containing a predetermined-quantity of the therapeutic composition. The quantity to be administered, and the particular route and formulation, is within the skill of determination of those in the clinical arts. A unit dose need not be administered as a single injection but may comprise continuous infusion over a set period of time. In some embodiments, a unit dose comprises a single administrable dose.


The quantity to be administered, both according to number of treatments and unit dose, depends on the treatment effect desired. An effective dose is understood to refer to an amount necessary to achieve a particular effect. In the practice in certain embodiments, it is contemplated that doses in the range from 10 mg/kg to 200 mg/kg can affect the protective capability of these agents. Thus, it is contemplated that doses include doses of about 0.1, 0.5, 1, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 100, 105, 110, 115, 120, 125, 130, 135, 140, 145, 150, 155, 160, 165, 170, 175, 180, 185, 190, 195, and 200, 300, 400, 500, 1000 μg/kg, mg/kg, μg/day, or mg/day or any range derivable therein. Furthermore, such doses can be administered at multiple times during a day, and/or on multiple days, weeks, or months.


In certain embodiments, the effective dose of the pharmaceutical composition is one which can provide a blood level of about 1 μM to 150 μM. In another embodiment, the effective dose provides a blood level of about 4 μM to 100 μM; or about 1 μM to 100 μM; or about 1 μM to 50 μM; or about 1 μM to 40 μM; or about 1 μM to 30 μM; or about 1 μM to 20 μM; or about 1 μM to 10 μM; or about 10 μM to 150 μM; or about 10 μM to 100 μM; or about μM to 50 μM; or about 25 μM to 150 μM; or about 25 μM to 100 μM; or about 25 μM to μM; or about 50 μM to 150 μM; or about 50 μM to 100 μM (or any range derivable therein). In other embodiments, the dose can provide the following blood level of the agent that results from a therapeutic agent being administered to a subject: about, at least about, or at most about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, or 100 μM or any range derivable therein. In certain embodiments, the therapeutic agent that is administered to a subject is metabolized in the body to a metabolized therapeutic agent, in which case the blood levels may refer to the amount of that agent. Alternatively, to the extent the therapeutic agent is not metabolized by a subject, the blood levels discussed herein may refer to the unmetabolized therapeutic agent.


Precise amounts of the therapeutic composition also depend on the judgment of the practitioner and are peculiar to each individual. Factors affecting dose include physical and clinical state of the patient, the route of administration, the intended goal of treatment (alleviation of symptoms versus cure) and the potency, stability and toxicity of the particular therapeutic substance or other therapies a subject may be undergoing.


It will be understood by those skilled in the art and made aware that dosage units of μg/kg or mg/kg of body weight can be converted and expressed in comparable concentration units of μg/ml or mM (blood levels), such as 4 μM to 100 μM. It is also understood that uptake is species and organ/tissue dependent. The applicable conversion factors and physiological assumptions to be made concerning uptake and concentration measurement are well-known and would permit those of skill in the art to convert one concentration measurement to another and make reasonable comparisons and conclusions regarding the doses, efficacies and results described herein.


IX. Pharmaceutical Compositions

Administration of the compositions according to the current disclosure will typically be via any common route. This includes, but is not limited to parenteral, orthotopic, intradermal, subcutaneous, orally, transdermally, intramuscular, intraperitoneal, intraperitoneally, intraorbitally, by implantation, by inhalation, intraventricularly, intranasally or intravenous injection. In some embodiments, compositions of the present disclosure (e.g., compositions comprising targeting agents) are administered to a subject intravenously.


The manner of application may be varied widely. Any of the conventional methods for administration of pharmaceutical compositions are applicable. The dosage of the pharmaceutical composition will depend on the route of administration and will vary according to the size and health of the subject.


In many instances, it will be desirable to have multiple administrations of at most or at least 3, 4, 5, 6, 7, 8, 9, 10 or more. The administrations may range from 2-day to 12-week intervals, more usually from one to two week intervals.


The phrases “pharmaceutically acceptable” or “pharmacologically acceptable” refer to molecular entities and compositions that do not produce an adverse, allergic, or other untoward reaction when administered to an animal, or human. As used herein, “pharmaceutically acceptable carrier” includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like. The use of such media and agents for pharmaceutical active substances is well known in the art. Except insofar as any conventional media or agent is incompatible with the active ingredients, its use in immunogenic and therapeutic compositions is contemplated. The pharmaceutical compositions of the current disclosure are pharmaceutically acceptable compositions.


The compositions of the disclosure can be formulated for parenteral administration, e.g., formulated for injection via the intravenous, intramuscular, sub-cutaneous, or even intraperitoneal routes. Typically, such compositions can be prepared as injectables, either as liquid solutions or suspensions and the preparations can also be emulsified.


Pharmaceutical forms suitable for injectable use include sterile aqueous solutions or dispersions; formulations including sesame oil, peanut oil, or aqueous propylene glycol. It also should be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms, such as bacteria and fungi.


Sterile injectable solutions are prepared by incorporating the active ingredients (e.g., polypeptides of the disclosure) in the required amount in the appropriate solvent with various of the other ingredients enumerated above, as required, followed by filtered sterilization. Generally, dispersions are prepared by incorporating the various sterilized active ingredients into a sterile vehicle which contains the basic dispersion medium and the required other ingredients from those enumerated above.


An effective amount of a composition is determined based on the intended goal. The term “unit dose” or “dosage” refers to physically discrete units suitable for use in a subject, each unit containing a predetermined quantity of the composition calculated to produce the desired responses discussed herein in association with its administration, i.e., the appropriate route and regimen. The quantity to be administered, both according to number of treatments and unit dose, depends on the result and/or protection desired. Precise amounts of the composition also depend on the judgment of the practitioner and are peculiar to each individual. Factors affecting dose include physical and clinical state of the subject, route of administration, intended goal of treatment (alleviation of symptoms versus cure), and potency, stability, and toxicity of the particular composition. Upon formulation, solutions will be administered in a manner compatible with the dosage formulation and in such amount as is therapeutically or prophylactically effective. The formulations are easily administered in a variety of dosage forms, such as the type of injectable solutions described above.


The compositions and related methods of the present disclosure, particularly administration of a composition of the disclosure may also be used in combination with the administration of additional therapies such as the additional therapeutics described herein or in combination with other traditional therapeutics known in the art.


The therapeutic compositions and treatments disclosed herein may precede, be co-current with and/or follow another treatment or agent by intervals ranging from minutes to weeks. In embodiments where agents are applied separately to a cell, tissue or organism, one would generally ensure that a significant period of time did not expire between the time of each delivery, such that the therapeutic agents would still be able to exert an advantageously combined effect on the cell, tissue or organism. For example, in such instances, it is contemplated that one may contact the cell, tissue or organism with two, three, four or more agents or treatments substantially simultaneously (i.e., within less than about a minute). In other aspects, one or more therapeutic agents or treatments may be administered or provided within 1 minute, 5 minutes, 10 minutes, 20 minutes, 30 minutes, 45 minutes, 60 minutes, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 13 hours, 14 hours, 15 hours, 16 hours, 17 hours, 18 hours, 19 hours, 20 hours, 21 hours, 22 hours, 22 hours, 23 hours, 24 hours, 25 hours, 26 hours, 27 hours, 28 hours, 29 hours, 30 hours, 31 hours, 32 hours, 33 hours, 34 hours, 35 hours, 36 hours, 37 hours, 38 hours, 39 hours, 40 hours, 41 hours, 42 hours, 43 hours, 44 hours, 45 hours, 46 hours, 47 hours, 48 hours, 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 15 days, 16 days, 17 days, 18 days, 19 days, 20 days, 21 days, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, or 8 weeks or more, and any range derivable therein, prior to and/or after administering another therapeutic agent or treatment.


The treatments may include various “unit doses.” Unit dose is defined as containing a predetermined-quantity of the therapeutic composition. The quantity to be administered, and the particular route and formulation, is within the skill of determination of those in the clinical arts. A unit dose need not be administered as a single injection but may comprise continuous infusion over a set period of time. In some embodiments, a unit dose comprises a single administrable dose.


The quantity to be administered, both according to number of treatments and unit dose, depends on the treatment effect desired. An effective dose is understood to refer to an amount necessary to achieve a particular effect. In the practice in certain embodiments, it is contemplated that doses in the range from 10 mg/kg to 200 mg/kg can affect the protective capability of these agents. Thus, it is contemplated that doses include doses of about 0.1, 0.5, 1, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 100, 105, 110, 115, 120, 125, 130, 135, 140, 145, 150, 155, 160, 165, 170, 175, 180, 185, 190, 195, and 200, 300, 400, 500, 1000 μg/kg, mg/kg, μg/day, or mg/day or any range derivable therein. Furthermore, such doses can be administered at multiple times during a day, and/or on multiple days, weeks, or months.


In some embodiments, the therapeutically effective or sufficient amount of the immune checkpoint inhibitor, such as an antibody and/or microbial modulator, that is administered to a human will be in the range of about 0.01 to about 50 mg/kg of patient body weight whether by one or more administrations. In some embodiments, the therapy used is about 0.01 to about 45 mg/kg, about 0.01 to about 40 mg/kg, about 0.01 to about 35 mg/kg, about 0.01 to about 30 mg/kg, about 0.01 to about 25 mg/kg, about 0.01 to about 20 mg/kg, about 0.01 to about 15 mg/kg, about 0.01 to about 10 mg/kg, about 0.01 to about 5 mg/kg, or about 0.01 to about 1 mg/kg administered daily, for example. In one embodiment, a therapy described herein is administered to a subject at a dose of about 100 mg, about 200 mg, about 300 mg, about 400 mg, about 500 mg, about 600 mg, about 700 mg, about 800 mg, about 900 mg, about 1000 mg, about 1100 mg, about 1200 mg, about 1300 mg or about 1400 mg on day 1 of 21-day cycles. The dose may be administered as a single dose or as multiple doses (e.g., 2 or 3 doses), such as infusions. The progress of this therapy is easily monitored by conventional techniques.


In certain embodiments, the effective dose of the pharmaceutical composition is one which can provide a blood level of about 1 μM to 150 μM. In another embodiment, the effective dose provides a blood level of about 4 μM to 100 μM; or about 1 μM to 100 μM; or about 1 μM to 50 μM; or about 1 μM to 40 μM; or about 1 μM to 30 μM; or about 1 μM to 20 μM; or about 1 μM to 10 μM; or about 10 μM to 150 μM; or about 10 μM to 100 μM; or about 10 μM to 50 μM; or about 25 μM to 150 μM; or about 25 μM to 100 μM; or about 25 μM to 50 μM; or about 50 μM to 150 μM; or about 50 μM to 100 μM (or any range derivable therein). In other embodiments, the dose can provide the following blood level of the agent that results from a therapeutic agent being administered to a subject: about, at least about, or at most about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, or 100 μM or any range derivable therein. In certain embodiments, the therapeutic agent that is administered to a subject is metabolized in the body to a metabolized therapeutic agent, in which case the blood levels may refer to the amount of that agent. Alternatively, to the extent the therapeutic agent is not metabolized by a subject, the blood levels discussed herein may refer to the unmetabolized therapeutic agent.


Precise amounts of the therapeutic composition also depend on the judgment of the practitioner and are peculiar to each individual. Factors affecting dose include physical and clinical state of the patient, the route of administration, the intended goal of treatment (alleviation of symptoms versus cure) and the potency, stability and toxicity of the particular therapeutic substance or other therapies a subject may be undergoing.


It will be understood by those skilled in the art and made aware that dosage units of μg/kg or mg/kg of body weight can be converted and expressed in comparable concentration units of μg/ml or mM (blood levels), such as 4 μM to 100 μM. It is also understood that uptake is species and organ/tissue dependent. The applicable conversion factors and physiological assumptions to be made concerning uptake and concentration measurement are well-known and would permit those of skill in the art to convert one concentration measurement to another and make reasonable comparisons and conclusions regarding the doses, efficacies and results described herein.


X. Kits

Certain aspects of the present invention also concern kits containing compositions of the invention or compositions to implement methods of the invention. In some embodiments, kits can be used to evaluate one or more biomarkers. In certain embodiments, a kit contains, contains at least or contains at most 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 100, 500, 1,000 or more probes, primers or primer sets, synthetic molecules or inhibitors, or any value or range and combination derivable therein. In some embodiments, there are kits for evaluating biomarker activity in a cell.


Kits may comprise components, which may be individually packaged or placed in a container, such as a tube, bottle, vial, syringe, or other suitable container means.


Individual components may also be provided in a kit in concentrated amounts; in some embodiments, a component is provided individually in the same concentration as it would be in a solution with other components. Concentrations of components may be provided as 1×, 2×, 5×, 10×, or 20× or more.


Kits for using probes, synthetic nucleic acids, nonsynthetic nucleic acids, and/or inhibitors of the disclosure for prognostic or diagnostic applications are included as part of the disclosure. Specifically contemplated are any such molecules corresponding to any biomarker identified herein, which includes nucleic acid primers/primer sets and probes that are identical to or complementary to all or part of a biomarker, which may include noncoding sequences of the biomarker, as well as coding sequences of the biomarker.


In certain aspects, negative and/or positive control nucleic acids, probes, and inhibitors are included in some kit embodiments.


Any embodiment of the disclosure involving specific biomarker by name is contemplated also to cover embodiments involving biomarkers whose sequences are at least 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99% identical to the mature sequence of the specified nucleic acid.


Embodiments of the disclosure include kits for analysis of a pathological sample by assessing biomarker profile for a sample comprising, in suitable container means, two or more biomarker probes, wherein the biomarker probes detect one or more of the biomarkers identified herein. The kit can further comprise reagents for labeling nucleic acids in the sample. The kit may also include labeling reagents, including at least one of amine-modified nucleotide, poly(A) polymerase, and poly(A) polymerase buffer. Labeling reagents can include an amine-reactive dye.


It is contemplated that any method or composition described herein can be implemented with respect to any other method or composition described herein and that different embodiments may be combined. The claims originally filed are contemplated to cover claims that are multiply dependent on any filed claim or combination of filed claims.


EXAMPLES

The following examples are included to demonstrate certain embodiments of the invention. It should be appreciated by those of skill in the art that the techniques disclosed in the examples which follow represent techniques discovered by the inventor to function well in the practice of the invention, and thus can be considered to constitute certain modes for its practice. However, those of skill in the art should, in light of the present disclosure, appreciate that many changes can be made in the specific embodiments which are disclosed and still obtain a like or similar result without departing from the spirit and scope of the invention.


Example 1—Surfaceome Analysis of SCLC Subtypes
Methods

Data sets: Three datasets were examined to identify surfaceome targets: published RNA-Seq data from 81 treatment-naïve patient tumors (George data set)18, published microarray data from 23 cancerous and 42 normal patient samples (Sato data set)17, and RNA-Seq data from an in-house collection of 63 SCLC cell lines (Cell Line data set)16,23,24.


Statistical analysis: Each tumor or cell line sample was sorted into its respective subtype using a 1300-gene signature19, then compared expression of the surfaceome25 transcripts between the subtypes in each of the three data sets utilizing ANOVA p-values, characterizing hits as a p-value less than 0.05 based on a FDR of 0.01 for the Sato and cell line sets and a FDR of 0.0001 for the George data set (FIG. 2). The FDR was adjusted for the George data set because, as the largest data set, it gave many more significant genes using the established FDR of 0.01. To ensure rigor in the hits, the FDR was lowered accordingly. In parallel, the inventors examined the percent difference of transcript expression between each subtype within each data set. Each transcript was binned into the subset for which it exhibits the highest expression, and the percent difference in expression across subtypes was calculated. Any gene for which the expression in its highest subtype was 10% or more than any other subtype was considered a hit. Hits from both analysis methods across all three data sets were consolidated into a list of target candidates, shown in Tables 1-12. Targets associated with the SCLC-A subtype are shown in Tables 1-3. Targets associated with the SCLC-N subtype are shown in Tables 4-6. Targets associated with the SCLC-P subtype are shown in Tables 7-9. Targets associated with the SCLC-I subtype are shown in Tables 10-12. To be considered a hit (i.e. associated with a particular subtype), a candidate transcript had to either have a) an ANOVA p value less than or equal to 0.05 or b) have an increase in expression by at least 10% in the subtype for which the transcript exhibits the highest expression. Importantly, the inventors classified proteins as surface-expressed based on a report detailing the in silico human surfaceome25.


Results

The hits analysis revealed a list of 2373 surface-expressed transcripts that are differentially expressed across the four different subtypes of SCLC (Tables A-I). A subset of candidates are listed below and are shown in FIGS. 2A-2D.


SCLC-A: DLL3 was previously shown to be predominantly expressed in SCLC-A, and this analysis correlated these findings. The inventors additionally found CEA Cell Adhesion Molecule 5 (CEACAM5) and Sodium Channel Epithelial 1 Subunit Alpha (SCNN1A) to be strongly expressed in SCLC-A.


SCLC-N: Somatostatin receptor type 2 (SSTR2), Semaphorin 6D (SEMAD6) and Sarcoglycan Delta (SGCD) are strongly expressed in SCLC-N.


SCLC-P: MHC Class I Polypeptide-Related Sequence A (MICA), Transmembrane Protein 87A (TMEM87A) and ADP-Ribosyltransferase 3 (ART3) are strongly expressed in SCLC-P.


SCLC-I: SLAM Family Member 8 (SLAMF8), Mannose Receptor C Type 2 (MRC2), and Piezo Type Mechanosensitive Ion Channel Component 1 (PIEZO1) are highly expressed in SCLC-I.









TABLE 1







Surface proteins associated with the SCLC-A subtype from the George et al. dataset











Surface Protein
ANOVA P value
A vs N
A vs P
A vs I














ROBO1
2.84105E−15
0.513318
65.52%
41.66%


SCN3A
3.94687E−13
0.477538
89.30%
51.39%


PTPRN2
7.98399E−13
0.223642
72.06%
37.88%


DLL3
 9.9566E−13
0.22315
81.31%
36.96%


SCN2A
 1.3185E−12
0.72742
96.86%
71.38%


SEZ6L2
3.03851E−09
0.167686
62.51%
38.45%


EPOR
6.58233E−09
0.109658
44.58%
30.25%


SGCE
 1.4434E−08
0.107614
43.60%
24.78%


ALCAM
2.27058E−08
0.474648
36.19%
40.92%


JAM3
2.50974E−08
0.140215
45.45%
22.18%


PTPRH
5.79499E−08
0.518246
69.24%
76.74%


SLC6A17
9.06298E−08
0.217736
78.00%
46.12%


BDKRB1
 1.4514E−07
0.382055
77.14%
47.77%


LRP11
1.54942E−07
0.120421
24.43%
11.95%


KCNMB2
 1.6141E−07
0.161155
81.80%
50.54%


CEACAM5
1.92784E−07
0.602428
88.52%
51.91%


DNER
1.94019E−07
0.108691
79.60%
39.20%


GPR6
2.04931E−07
0.111667
88.53%
54.81%


GJB1
4.11699E−07
0.622747
59.82%
65.16%


MFSD12
7.75528E−07
0.226654
25.44%
11.62%


SLC7A2
 1.3774E−06
0.685447
38.09%
54.71%


NPC1L1
1.78602E−06
0.591312
87.93%
65.71%


GRIN2C
1.93207E−06
0.48594
78.53%
36.29%


PTPRN
2.91319E−06
0.150986
85.16%
50.66%


CALY
3.26088E−06
0.676083
92.31%
79.19%


SLC36A4
4.15749E−06
0.121561
32.42%
12.06%


SLC2A12
4.69219E−06
0.392637
51.60%
31.32%


TMEM154
8.21862E−06
0.584381
44.31%
26.01%


CLDN12
9.05944E−06
0.248436
19.94%
26.53%


FAM174A
 1.2936E−05
0.197447
25.50%
18.90%


TMEM184A
1.40777E−05
0.293346
58.31%
19.06%


NLGN1
1.84516E−05
0.30062
71.46%
56.87%


TNFRSF11A
1.97931E−05
0.353285
53.16%
36.22%


CDH1
3.73036E−05
0.224274
11.44%
20.78%


CPD
4.07671E−05
0.217368
26.62%
25.05%


ILDR1
5.77417E−05
0.430687
39.11%
43.25%


CCR10
6.25666E−05
0.428066
55.65%
38.61%


CLDN7
8.61026E−05
0.289436
10.60%
22.28%


SLC7A4
0.000102933
0.162167
65.25%
40.36%


SPINT2
0.000113296
0.108017
16.78%
15.31%


GPR111
0.000119261
0.802409
95.08%
74.09%


SLC39A14
0.00013616
0.183869
31.59%
20.17%


KIAA1644
0.000150509
0.334594
78.28%
45.61%


BCAM
0.000151493
0.26964
24.32%
25.53%


TAAR1
0.00016684
0.831891
96.97%
89.12%


HTR3A
0.000175471
0.524177
81.02%
69.83%


NMUR2
0.000195944
0.805154
83.86%
71.98%


ABCA3
0.00020242
0.156733
35.63%
17.30%


SCNN1A
0.000240791
0.243577
37.52%
27.11%


RXFP3
0.000262175
0.138332
94.50%
82.36%


ENTPD3
0.000273885
0.226454
61.17%
38.28%


CD320
0.000302997
0.186224
14.27%
16.31%


SV2B
0.000420383
0.402711
56.07%
55.39%


GPR152
0.000426642
0.531875
67.95%
56.92%


SLCO3A1
0.0005138
0.239712
18.42%
19.49%


DPP10
0.000542401
0.401299
75.13%
45.96%


APP
0.00059644
0.102058
14.20%
14.64%


SLC18A1
0.000598735
0.360389
87.06%
83.53%


SDK2
0.000668337
0.216239
42.42%
46.03%


PKD1L3
0.000677872
0.705778
87.82%
52.10%


ANO9
0.0006877
0.29025
18.17%
29.43%


NKAIN2
0.000691291
0.272325
58.62%
52.84%


IL17RE
0.000720317
0.30643
38.50%
40.86%


GRIN1
0.000721706
0.701276
92.56%
70.58%


GLRA3
0.000810376
0.744026
90.13%
79.86%


TSPAN1
0.00081067
0.308206
44.58%
41.76%


SLC5A2
0.000882596
0.270054
70.63%
63.71%


IL20RA
0.000979405
0.666634
20.55%
42.30%


SPACA4
0.000989342
0.693894
54.32%
64.00%


SHISA8
0.00100122
0.14828
74.43%
43.82%


EPHA7
0.001092927
0.281773
49.57%
34.01%


TMEM116
0.001113645
0.135198
27.06%
15.94%


DLL1
0.00112921
0.283026
33.02%
19.35%


ZP1
0.001561421
0.257511
86.96%
69.24%


LRFN3
0.001566479
0.101462
25.75%
14.84%


CDH8
0.001633859
0.671096
48.60%
53.86%


LRIG1
0.001657351
0.114158
20.55%
10.86%


EPHB1
0.002010498
0.2352
53.22%
37.33%


TSPAN8
0.002121172
0.470899
31.34%
42.28%


GFRA3
0.002175194
0.605733
56.86%
54.19%


SLC26A6
0.002260401
0.225542
33.52%
21.22%


CLDN18
0.002408984
0.735808
31.77%
32.65%


FZD5
0.002557049
0.169006
29.95%
29.23%


UGT8
0.00262277
0.270944
14.21%
30.72%


NIPAL1
0.002640345
0.367205
14.44%
59.31%


PTH2R
0.002718192
0.572014
85.11%
22.22%


CCKBR
0.002950713
0.348152
80.04%
44.82%


SLC4A10
0.003102873
0.836458
61.29%
83.55%


HEPACAM2
0.003364408
0.288534
11.89%
37.82%


OR51E1
0.003670912
0.529062
64.78%
56.07%


BAMBI
0.003937506
0.124444
32.72%
23.27%


TMEM25
0.005076015
0.113137
16.13%
22.82%


GPR27
0.00595835
0.107616
48.84%
25.40%


CD47
0.005971164
0.155759
16.43%
16.99%


LYPD6B
0.006667331
0.515922
16.45%
32.77%


TPBG
0.006918377
0.317762
15.23%
22.57%


SLC22A23
0.007282072
0.254882
14.87%
32.56%


KIRREL2
0.007553205
0.197278
90.11%
62.60%


SLC2A13
0.008133276
0.367651
17.22%
17.06%


ACVRIC
0.008198981
0.549338
76.39%
62.72%


DLL4
0.008400227
0.172189
22.50%
14.75%


UNC93A
0.008486685
0.548395
87.31%
67.17%


CDH7
0.008507328
0.525223
86.31%
28.86%


SLITRK5
0.009181416
0.409606
81.31%
58.10%


NEGR1
0.009654704
0.368091
59.26%
46.39%


SLITRK6
0.010256541
0.249755
53.01%
52.15%


SLC37A1
0.010299059
0.154556
20.04%
12.30%


PCDHA1
0.010469816
0.200406
77.07%
73.88%


LRFN2
0.011657549
0.313324
14.95%
67.99%


GPR115
0.012887629
0.724504
64.64%
63.34%


BCAN
0.013082657
0.705165
58.46%
71.33%


GP2
0.014390617
0.870841
63.97%
87.05%


KISS1R
0.014691855
0.631176
59.36%
46.96%


NCAM2
0.01495719
0.574525
13.22%
13.53%


JAG2
0.015320507
0.123251
28.91%
17.83%


PRPH2
0.015938273
0.218703
59.46%
56.88%


OR8G1
0.016332738
0.812903
100.00%
100.00%


PTGER1
0.016428746
0.464843
48.69%
44.24%


OR51G2
0.017016783
0.610332
90.24%
92.32%


NRN1
0.017114781
0.296517
41.60%
17.56%


LPHN3
0.017398384
0.105528
48.07%
36.49%


NPHS1
0.018038642
0.391864
92.90%
66.15%


KIAA1324
0.019204802
0.144505
42.06%
18.99%


PCDHB14
0.01989985
0.23259
30.09%
24.50%


SLC45A2
0.020204874
0.146653
56.00%
65.47%


SCARB1
0.02091067
0.215994
18.81%
14.26%


SLC5A1
0.023194202
0.352354
65.18%
41.98%


AMIGO2
0.023669182
0.250072
15.46%
36.48%


GLRB
0.023978169
0.250079
41.21%
36.23%


ENPP1
0.025333073
0.202569
55.34%
31.01%


GABRA2
0.02581235
0.898768
83.82%
95.94%


CADM2
0.026724848
0.262917
88.15%
68.40%


SLITRK3
0.02779597
0.419223
65.59%
54.37%


OR51E2
0.027850862
0.601597
84.61%
76.27%


MET
0.029443618
0.163592
28.79%
33.81%


PKD2L1
0.033329961
0.597712
74.03%
52.20%


OR51S1
0.03443262
0.695061
100.00%
100.00%


CEACAM3
0.034736354
0.627567
43.70%
13.53%


SLC7A9
0.034866161
0.132988
61.12%
42.60%


ABCA12
0.036267598
0.659658
18.44%
70.41%


CDHR3
0.036445654
0.179738
65.97%
54.34%


OR51F1
0.037238532
0.560063
100.00%
100.00%


OR51L1
0.037274686
0.912869
100.00%
67.13%


SLC1A5
0.038122893
0.131175
13.31%
14.63%


SLC4A5
0.039046047
0.171187
10.99%
19.33%


DAG1
0.039359211
0.156186
11.94%
13.56%


OR8D1
0.044146729
0.906771
100.00%
100.00%


CD24
0.04478253
0.126977
15.70%
10.14%


GJB4
0.045238901
0.368761
79.41%
48.66%


SLITRK1
0.045845498
0.649526
61.33%
40.37%


SCN9A
0.046290464
0.319877
24.27%
51.12%


PTGDR2
0.046940022
0.556022
48.74%
59.95%


SSTR5
0.049548712
0.428603
97.85%
80.92%


LYPD5
0.050390723
0.168328
11.83%
39.82%


FZD3
0.050840924
0.121895
16.82%
28.70%


LINGO2
0.051488414
0.497153
61.92%
85.78%


SLC39A4
0.05155746
0.230646
22.47%
21.11%


SLC8A1
0.055683173
0.2683
19.48%
17.76%


CEACAM20
0.05645749
0.94661
97.66%
98.38%


MANSC1
0.060362259
0.126194
12.53%
16.79%


IL5RA
0.061991206
0.292696
47.81%
35.85%


OR8A1
0.064199917
0.947314
90.89%
79.37%


OR56A5
0.066441287
0.757234
34.32%
95.44%


SLC8A3
0.070473098
0.295359
87.15%
71.17%


OR52B4
0.070833748
1
17.16%
100.00%


SLCO1A2
0.071664988
0.484353
48.62%
69.20%


NCR2
0.081128593
0.599899
45.53%
78.69%


GPC3
0.082397966
0.226161
33.74%
31.63%


OR51A7
0.085724844
0.757758
85.91%
100.00%


GPR56
0.085744928
0.203505
20.94%
19.17%


CHL1
0.085856017
0.499857
35.93%
22.98%


OR1J2
0.086388495
0.813048
16.42%
49.95%


SGCZ
0.086457707
0.721765
55.72%
73.90%


PCDHA13
0.087239323
0.492689
88.37%
54.59%


ZACN
0.088033335
0.305461
79.39%
41.84%


MUC12
0.091755769
0.4751
84.60%
67.64%


PCDHB8
0.091950401
0.336234
33.55%
48.22%


UTS2R
0.09236842
0.236408
77.45%
20.44%


HTR1E
0.098631893
0.510789
86.27%
96.13%


SYNPR
0.099424732
0.424215
49.20%
70.90%


ACPT
0.101996953
0.172541
81.16%
61.02%


MFSD2B
0.104647085
0.199805
51.22%
44.30%


TMC7
0.109715468
0.191021
16.52%
26.12%


MS4A15
0.110898446
0.746087
52.09%
24.32%


OR51F2
0.114529932
0.698836
100.00%
65.11%


GRIA2
0.115696545
0.502523
37.59%
56.31%


GALR1
0.120909898
0.420528
76.19%
56.16%


SLC32A1
0.121131002
0.738544
97.93%
78.76%


FFAR2
0.129810246
0.119595
55.02%
36.60%


SLC13A3
0.131090881
0.436619
19.72%
49.03%


RNF150
0.133545778
0.237511
37.88%
34.97%


CHRM5
0.134954761
0.643328
19.81%
47.44%


OR52R1
0.135308114
0.743844
91.81%
81.51%


NETO1
0.136383182
0.435375
85.26%
33.43%


SLC5A12
0.138407917
0.451971
48.11%
62.46%


GRIK1
0.13890028
0.774247
40.96%
61.64%


ADAM29
0.139801139
0.641763
24.58%
63.82%


SLCO5A1
0.141583549
0.316595
27.90%
23.05%


ADAM21
0.147660529
0.148199
51.40%
50.57%


GPR37
0.148497131
0.335368
45.21%
34.83%


PCDHB16
0.14964025
0.253341
17.74%
39.49%


OR56B4
0.155286966
0.416374
36.04%
69.88%


CNTNAP3B
0.156215375
0.198115
68.70%
38.14%


SLC38A11
0.165681894
0.598921
78.94%
45.42%


HTR4
0.166055241
0.414149
68.27%
81.77%


MST1R
0.171722942
0.134391
16.71%
31.26%


PMEL
0.172241872
0.233045
31.54%
42.33%


SLC15A5
0.177222694
0.435818
80.62%
100.00%


MEP1B
0.179479737
0.209065
57.17%
63.18%


ART1
0.184855852
0.512029
77.07%
78.94%


LGR5
0.190299628
0.214657
56.92%
32.17%


GABRR1
0.191134594
0.935444
97.84%
100.00%


OR51T1
0.192575362
0.534236
73.02%
71.37%


PIGR
0.195634422
0.381963
23.44%
14.43%


PCDHA7
0.198105226
0.152205
59.22%
59.88%


SLC2A7
0.200172164
0.389601
63.39%
55.87%


OR2T2
0.202845671
0.540744
100.00%
100.00%


PLXNA2
0.205565774
0.148909
17.56%
20.13%


CHRNA4
0.21323047
0.422938
97.08%
53.37%


MRGPRX2
0.215983064
0.855124
55.81%
62.84%


CHRM3
0.217633548
0.23049
25.72%
53.53%


GPR148
0.219300333
0.525458
74.64%
91.55%


SLC44A5
0.236569238
0.293996
31.83%
32.39%


PLD5
0.237947047
0.463887
62.94%
30.98%


TGFBR3
0.238729359
0.223404
33.42%
12.27%


OR1J4
0.238749781
0.47034
63.96%
50.28%


OR1Q1
0.241675133
0.404288
19.54%
64.39%


BEST2
0.244576766
0.592918
78.39%
83.86%


OR1F1
0.247679011
0.716483
93.01%
82.59%


OR14I1
0.254154812
0.654576
87.93%
81.23%


TACR3
0.256873797
0.138153
48.76%
74.79%


SLC20A2
0.260899684
0.47988
36.02%
20.25%


TBXA2R
0.261240502
0.22995
35.56%
16.61%


GPR101
0.262437498
0.576105
83.17%
61.26%


OR2G2
0.263274302
0.711543
100.00%
64.36%


OR10P1
0.264740003
0.285346
100.00%
68.65%


ZP3
0.265528678
0.115483
19.26%
21.51%


HTR3C
0.271703182
0.868092
36.92%
32.33%


SLC5A7
0.273328515
0.419321
95.31%
90.15%


RXFP1
0.274291063
0.640113
31.88%
29.69%


CDHR4
0.275830566
0.445499
52.06%
61.96%


GABRA3
0.276147578
0.510692
37.78%
43.02%


PCDHB10
0.279015447
0.202287
25.58%
20.18%


BEST4
0.279529035
0.252307
29.91%
27.63%


OR2F2
0.285177702
0.832881
100.00%
81.99%


OR51Q1
0.287759935
0.801022
54.15%
100.00%


LHFPL5
0.293518396
0.21691
30.72%
34.51%


GPR37L1
0.298958368
0.38006
20.98%
30.12%


PCDHB6
0.303185061
0.139004
23.24%
54.67%


SLC12A1
0.304749154
0.821557
60.97%
89.86%


CFC1
0.311391988
0.990789
100.00%
89.23%


GPR119
0.311805215
0.457402
100.00%
77.97%


IL1RAPL1
0.3136187
0.471525
62.18%
75.23%


BRS3
0.317560714
0.275005
91.46%
64.32%


OR2L3
0.325542542
0.791928
62.09%
100.00%


NMBR
0.32639682
0.138086
51.40%
36.03%


SLC34A3
0.343822185
0.369108
87.55%
43.72%


ZNRF4
0.351218852
0.505083
95.65%
74.00%


CHRNA2
0.352021588
0.852557
89.06%
88.78%


GALR3
0.353632174
0.586378
27.76%
57.48%


GIPR
0.354815735
0.213851
50.07%
22.04%


GABRA4
0.358534778
0.768526
86.57%
74.43%


PTPRZ1
0.364759277
0.633729
21.92%
41.20%


P2RX6
0.372284329
0.184313
29.40%
46.40%


OR51G1
0.374237004
0.514699
100.00%
84.28%


CNTN5
0.383557411
0.676637
56.38%
64.09%


OR1C1
0.388589636
1
56.15%
62.78%


GABRB1
0.390463253
0.618987
58.03%
49.04%


OR51B2
0.394225873
1
54.28%
17.48%


TACR2
0.394580056
0.21082
51.40%
10.06%


SLC6A18
0.394713425
0.263789
100.00%
61.92%


OR8G2
0.396345118
0.545095
100.00%
100.00%


OR1L1
0.397354663
0.83068
70.82%
73.51%


OR10AG1
0.401198599
0.52291
84.67%
100.00%


OR2S2
0.41170195
0.587798
58.68%
73.04%


CCR9
0.417804595
0.393008
57.09%
66.87%


GJB5
0.421998357
0.180577
50.83%
20.16%


CACNG3
0.425279062
0.230333
97.52%
86.12%


OR2L13
0.426916519
0.7394
10.94%
78.54%


NUP210L
0.430722039
0.157832
61.64%
67.34%


SLC26A3
0.432045118
0.738256
75.74%
46.73%


GPRC6A
0.446303254
0.982045
87.55%
95.09%


OR7D4
0.455205742
0.603949
100.00%
83.33%


MUC17
0.46122426
0.32458
96.89%
53.84%


OR1L3
0.468035802
0.58562
46.99%
68.65%


LRRC4C
0.47309339
0.790211
53.14%
75.68%


RXFP2
0.47356422
1
49.20%
100.00%


NPBWR1
0.478981981
0.384959
19.76%
55.23%


OR7C2
0.482071482
0.928642
73.97%
100.00%


GCGR
0.484284551
0.392066
89.68%
83.91%


OR8B12
0.495204567
0.199983
100.00%
100.00%


PCDH10
0.49819273
0.238572
47.43%
66.75%


OR2A25
0.50715683
0.360482
73.54%
100.00%


GLRA2
0.512056674
0.661314
66.68%
95.27%


TAAR5
0.521170378
0.14502
100.00%
51.66%


OTOP2
0.527633573
0.756464
98.53%
57.66%


TMPRSS15
0.529964199
0.613393
67.52%
54.53%


OR13F1
0.530608489
0.742802
82.56%
68.24%


OR5A1
0.534414833
0.458599
100.00%
36.84%


ASGR2
0.534688
0.3959
43.47%
14.70%


GHSR
0.536780388
0.887473
91.92%
88.46%


KCNK18
0.548471162
0.761076
100.00%
38.39%


OR8K1
0.567010311
0.291298
100.00%
71.70%


LRRTM4
0.571301144
0.331909
21.06%
70.71%


CDH10
0.591179559
0.533814
32.21%
31.48%


OR2T10
0.592870688
1
14.66%
85.27%


NTNG1
0.592879926
0.240935
60.32%
22.78%


LRTM1
0.597870931
0.157215
80.49%
81.47%


TACR1
0.59816171
0.26735
36.79%
32.95%


OR11A1
0.598998302
0.295719
89.97%
58.08%


SLC17A1
0.599370324
0.502156
100.00%
60.50%


PCDHGB6
0.599663955
0.21695
30.34%
46.95%


OR10G3
0.611490713
0.74702
100.00%
20.64%


OR4D9
0.613727779
0.398394
48.70%
100.00%


SLC22A6
0.615993812
0.327099
90.60%
22.74%


TYR
0.622900631
0.788116
65.92%
85.10%


EGFR
0.627012522
0.173057
29.98%
21.94%


PKD1L2
0.627138204
0.170139
54.02%
29.57%


SLC22A14
0.627836328
0.837303
64.23%
72.07%


DRD3
0.628693142
0.319338
59.32%
12.29%


GPC5
0.636579657
0.400156
42.14%
34.80%


OR6A2
0.639116497
0.808372
93.39%
100.00%


OR4D6
0.644465007
0.89489
45.90%
100.00%


CACNA1I
0.647825326
0.482865
61.76%
35.82%


OR4X2
0.659557232
0.795779
100.00%
100.00%


SLC44A4
0.669722054
0.181155
13.03%
15.58%


PTCHD3
0.675579697
0.889982
57.94%
60.90%


AQP10
0.680129188
0.439666
15.42%
38.32%


OR7G3
0.683683855
0.2655
100.00%
51.56%


CRB1
0.691759031
0.171984
48.30%
47.33%


ADAM30
0.69755855
0.540237
65.31%
77.62%


OPN5
0.704011413
0.828511
96.92%
50.32%


OR9Q1
0.709790119
0.620133
73.87%
71.28%


LRRTM3
0.722653288
0.105728
79.85%
42.52%


SLC2A2
0.750041962
0.557398
20.44%
72.05%


TMEM114
0.761434161
0.206386
90.87%
50.03%


KCNJ3
0.773441601
0.242145
47.19%
34.73%


OR1K1
0.778808459
0.278018
46.73%
50.89%


MUC21
0.784645007
0.347383
35.29%
54.94%


GP5
0.787311346
0.230306
31.92%
30.11%


GYPA
0.79142846
0.682098
34.95%
34.81%


SLC16A12
0.800712751
0.102803
42.54%
33.24%


PTPRR
0.819079688
0.192063
12.44%
22.47%


NTSR2
0.821965712
0.483076
51.32%
62.11%


OR5B12
0.834986035
0.758609
64.29%
50.95%


GPR112
0.874242494
0.363501
29.65%
48.44%


TAAR8
0.905692412
0.361322
27.52%
49.90%


SLC9A7
0.931945612
0.410788
31.75%
14.70%


ADRA1D
0.933185867
0.230098
23.28%
23.30%


OR2A14
0.935214939
0.251381
45.19%
34.10%


OR52K2
0.993735068
0.260296
29.90%
19.22%


OR10J5
0.996448953
0.201452
16.77%
13.86%


CNTNAP2
9.47371E−12
0.045283
70.31%
26.44%


SYP
1.25311E−11
0.013618
48.43%
21.91%


SEZ6
6.94855E−11
0.050499
66.22%
35.83%


IL10RB
1.53692E−07
0.197341
11.50%
0.33%


VLDLR
1.90564E−07
0.388037
1.81%
47.00%


CHRNB2
1.50541E−06
0.050225
52.96%
21.24%


QSOX2
3.19787E−06
0.071822
27.20%
7.78%


NPTN
4.11171E−06
0.214732
8.05%
10.15%


SV2A
4.87056E−06
0.022505
27.04%
18.72%


SIGIRR
1.66864E−05
0.267117
4.46%
20.89%


ITFG1
2.99819E−05
0.145539
2.23%
5.25%


CADM1
3.06039E−05
0.064151
38.80%
10.40%


SLC29A4
5.87081E−05
0.001259
55.04%
20.99%


LRRC24
6.84993E−05
0.01443
47.89%
25.21%


TSPAN31
7.94379E−05
0.176463
5.43%
5.55%


PVR
0.000131708
0.296659
1.80%
33.59%


PODXL2
0.000171054
0.051888
19.39%
13.20%


FAM171B
0.000348213
0.090878
48.37%
27.73%


ENPP4
0.000556761
0.214433
7.41%
17.90%


PIGT
0.000621992
0.13698
1.94%
13.38%


SGCB
0.000624351
0.009972
23.21%
9.15%


RET
0.000700213
0.060464
65.72%
53.26%


LGR4
0.000718549
0.057668
26.04%
22.82%


ADCY5
0.000768431
0.031072
58.69%
31.66%


CLDN3
0.000786408
0.043539
25.59%
20.60%


SLC17A5
0.000819867
0.17861
16.12%
6.95%


LRP12
0.00085377
0.01955
22.90%
16.08%


GGT7
0.000985048
0.034975
5.67%
16.80%


TMEM182
0.001067196
0.289553
2.98%
25.17%


LMBR1
0.001082348
0.066479
16.03%
8.41%


PAM
0.001181299
0.018784
29.92%
26.30%


IFNAR1
0.001600572
0.10435
8.97%
1.88%


SERINC3
0.00186261
0.101053
1.84%
5.67%


SERINC1
0.001934137
0.061776
8.85%
5.34%


MFSD6
0.002322247
0.012274
15.95%
11.68%


SSR1
0.00248723
0.109119
2.80%
2.75%


P2RX4
0.002513039
0.146105
14.51%
0.66%


TMEM8B
0.002606002
0.050811
19.10%
28.71%


CRB3
0.002738949
0.290113
6.60%
29.70%


TMEM161A
0.003043568
0.10575
5.63%
14.62%


LIFR
0.003323269
0.021622
47.05%
9.40%


SLC37A3
0.00334168
0.068352
13.79%
12.12%


PVRL2
0.003954317
0.19781
0.97%
10.46%


ATP13A3
0.004788394
0.103693
7.02%
10.99%


CXADR
0.006731902
0.067652
19.39%
25.99%


SLC26A5
0.00719155
0.020972
66.27%
27.82%


OPRD1
0.008009037
0.025836
63.53%
47.62%


GPR160
0.009903187
0.299374
18.19%
6.12%


HIAT1
0.010748544
0.074637
5.61%
3.31%


ADAM28
0.011485543
0.426139
24.99%
3.02%


SPPL2B
0.011489005
0.028025
19.47%
12.83%


PTTG1IP
0.012178726
0.050763
6.79%
3.73%


NUP210
0.013228414
0.1221
11.14%
9.53%


EPCAM
0.013861589
0.066145
7.79%
12.85%


TMEM8A
0.014941666
0.140918
9.54%
7.66%


LRRC37B
0.015292209
0.070554
11.60%
15.48%


DIRC2
0.015750615
0.049001
21.44%
3.46%


TMEM219
0.015837944
0.099902
3.06%
1.95%


STT3B
0.01697836
0.076165
0.77%
0.49%


IGSF8
0.017926295
0.156815
6.89%
10.06%


TMEM123
0.018384773
0.10213
3.42%
7.79%


DAGLA
0.018990173
0.062827
32.83%
23.95%


FZD9
0.019025909
0.121833
64.78%
8.59%


SLC7A5
0.019735889
0.20518
11.27%
9.68%


SLC39A9
0.021042591
0.013011
13.62%
9.70%


FREM2
0.021128353
0.40561
8.44%
53.92%


ACVR1
0.02233146
0.164949
1.40%
4.97%


SLC9A6
0.023756876
0.07958
17.01%
15.55%


BSG
0.024425203
0.088992
7.17%
4.48%


SEMA4F
0.026736167
0.08673
23.60%
15.68%


TMEM108
0.028703465
0.110059
6.47%
29.28%


SLC2A11
0.028949765
0.084674
34.19%
23.56%


SLC41A3
0.031855762
0.046125
14.27%
16.88%


PPAP2C
0.03277155
0.195446
7.35%
27.08%


SLC2A8
0.036955992
0.122282
14.68%
5.91%


TMEM179B
0.03701416
0.084872
0.88%
0.36%


CLDN4
0.037642954
0.001793
14.24%
10.28%


TM9SF1
0.038196952
0.083833
10.12%
5.67%


NETO2
0.039255946
0.160351
8.82%
18.80%


RNF167
0.039610855
0.06436
1.73%
0.71%


TSPAN15
0.040748581
0.064938
14.20%
11.65%


GABRG3
0.043676947
0.094642
88.03%
5.54%


SLC3A2
0.046660579
0.105099
0.078519
0.056853
















TABLE 2







Surface proteins associated with the SCLC-A subtype from the cell line dataset











Surface Protein
ANOVA P value
A vs N
A vs P
A vs I














CLDN3
2.42551E−13
0.719746
59.47%
81.14%


NKAIN2
3.38063E−13
0.462799
20.37%
36.96%


SCNN1A
6.71207E−11
0.619875
36.18%
66.62%


PTPRN2
3.57913E−09
0.260752
45.18%
40.09%


DNER
5.17956E−09
0.563469
34.00%
32.34%


FAM174B
7.17107E−09
0.215947
29.42%
61.31%


GPR56
9.74635E−09
0.177952
27.01%
42.15%


DLL4
1.44489E−08
0.342869
48.18%
62.62%


KCNMB2
2.35185E−08
0.276975
14.63%
29.58%


CLDN4
2.51125E−08
0.373644
52.95%
65.47%


KIAA1324
8.52893E−08
0.202579
32.53%
47.27%


OR51F1
 2.5326E−07
0.741796
54.03%
52.07%


OR51T1
3.15478E−07
0.95222
73.14%
86.02%


F11R
 8.6059E−07
0.393838
10.45%
26.21%


GPR6
9.43586E−07
0.62593
69.64%
89.85%


TMEM116
9.49245E−07
0.116633
10.12%
11.75%


TMEM154
1.03977E−06
0.488411
56.73%
42.52%


OR51G1
1.18153E−06
0.894596
74.63%
79.00%


BAMBI
1.30824E−06
0.425267
16.33%
29.25%


OR51F2
1.76533E−06
0.684157
60.86%
65.69%


SDK2
2.79986E−06
0.215895
38.16%
36.37%


MTNR1B
2.85489E−06
0.718696
70.73%
61.65%


CXCR4
3.01882E−06
0.105171
31.48%
43.83%


SLC36A4
3.59191E−06
0.148415
18.74%
16.36%


OR52R1
5.08417E−06
0.62271
56.16%
62.29%


OR51H1P
6.71689E−06
0.835138
72.51%
70.11%


OR51S1
1.23112E−05
0.856013
54.78%
83.03%


CLDN7
1.36784E−05
0.445548
14.30%
75.36%


GRM8
1.56799E−05
0.255458
28.23%
57.22%


CEACAM5
1.67657E−05
0.456221
65.01%
41.14%


GPR39
 2.0823E−05
0.708464
54.81%
73.64%


OR51L1
2.76272E−05
0.944632
86.72%
71.37%


OR51A4
2.78456E−05
0.850676
60.23%
75.82%


OR51A2
3.46569E−05
0.883599
70.15%
77.76%


FRAS1
3.57098E−05
0.152946
16.43%
25.65%


OR51A7
5.13974E−05
0.926519
75.45%
88.77%


CEACAM6
 5.9763E−05
0.697588
75.50%
61.56%


LYPD1
6.97097E−05
0.576418
70.68%
71.19%


JAM3
7.10708E−05
0.100866
14.53%
14.09%


ATP4B
0.000124845
0.566772
53.35%
28.01%


KL
0.000150403
0.316534
44.43%
62.89%


TMEM255B
0.000210166
0.447391
48.21%
37.19%


OR52J3
0.00028157
0.858534
99.46%
79.47%


MUC1
0.000281706
0.418791
32.71%
11.27%


PTH2R
0.000394211
0.528961
70.03%
53.52%


CEACAM7
0.000401652
0.824287
99.43%
81.31%


DSCAML1
0.000428411
0.13678
19.10%
55.37%


NMUR2
0.000465995
0.531378
50.69%
62.11%


PROM1
0.000514814
0.321741
11.00%
25.20%


ABCB5
0.000650776
0.493423
65.55%
39.92%


TMEM132D
0.000699523
0.634272
21.33%
80.07%


TIGIT
0.000711936
0.318193
16.58%
37.50%


OR52A4
0.000743244
0.80462
82.39%
85.20%


NLGN1
0.000762407
0.12472
28.25%
33.92%


OR51G2
0.000815476
0.931449
80.30%
74.63%


PLXNA2
0.000883663
0.166267
27.84%
22.94%


PLB1
0.000886089
0.173229
60.91%
34.00%


TMEM211
0.000903827
0.451466
51.58%
56.14%


ADCY2
0.000924544
0.267393
48.20%
54.76%


FNDC9
0.001027742
0.163174
13.25%
37.72%


SLC6A17
0.001171438
0.113421
70.34%
20.86%


CSMD1
0.001541352
0.440894
18.89%
42.04%


TSPAN8
0.001664174
0.483321
58.42%
11.17%


MPZ
0.001960371
0.47327
32.86%
57.35%


SLC45A2
0.002061415
0.374183
42.86%
50.51%


CHL1
0.002097906
0.371243
24.96%
33.93%


IL5RA
0.002227456
0.335831
70.63%
52.82%


TMEM184A
0.002336914
0.178724
16.50%
18.00%


SLC2A12
0.002557362
0.208757
18.09%
20.29%


PCDHB1
0.002591703
0.675631
44.57%
50.61%


LIFR
0.003185162
0.13777
15.37%
20.51%


SPPL2B
0.003313453
0.16231
13.59%
15.28%


SLC5A9
0.003729648
0.328247
21.84%
21.12%


STEAP4
0.004297974
0.285109
25.12%
28.78%


TMEM178B
0.004738132
0.118263
23.28%
22.80%


SLC18A1
0.005078518
0.538404
59.10%
82.23%


SCN2A
0.005183802
0.203847
43.44%
18.98%


GPR158
0.00559701
0.182099
33.50%
11.00%


TSPAN11
0.005935321
0.105031
10.63%
32.52%


OR51E2
0.006425491
0.464681
60.55%
42.55%


GRIN3A
0.006427088
0.166567
29.03%
27.53%


KLRC3
0.006460354
0.827042
10.83%
36.94%


HEPHL1
0.0066345
0.398492
17.78%
38.57%


OR52A5
0.006876442
0.861014
40.41%
72.27%


CADM2
0.006912669
0.156053
36.21%
16.89%


BTLA
0.007819411
0.218228
64.45%
35.83%


GALR1
0.007873528
0.545259
87.08%
72.16%


THBD
0.008144678
0.836794
78.35%
83.67%


SLC6A5
0.008733233
0.218806
66.07%
50.55%


OR52E2
0.008875518
0.697298
65.95%
88.60%


TM4SF1
0.009828902
0.582092
99.69%
11.90%


PANX2
0.011500501
0.450012
22.26%
34.62%


RET
0.013323451
0.473224
29.09%
34.46%


SCN3A
0.015665583
0.133641
14.93%
26.18%


SLITRK4
0.017598956
0.266781
56.08%
40.87%


TNFSF15
0.017811031
0.565279
35.26%
20.46%


OR2AE1
0.019078549
0.565892
31.70%
14.00%


MS4A1
0.019332289
0.520081
79.02%
45.30%


OR52A1
0.019887299
0.842151
98.90%
100.00%


CD200
0.02032333
0.382683
28.45%
45.42%


FFAR4
0.020384015
0.493797
83.70%
50.67%


TSPAN1
0.020737739
0.479562
52.59%
21.83%


EPHB1
0.025803765
0.16633
23.58%
30.74%


PCDH1
0.025925525
0.367423
26.26%
15.43%


CNTN4
0.030821929
0.222679
22.61%
29.36%


GPR143
0.031196622
0.170402
16.21%
19.95%


OR2AG2
0.031381897
0.559685
59.72%
100.00%


AVPRIA
0.031769305
0.315882
67.64%
72.54%


GPR144
0.031815936
0.520263
79.86%
75.54%


GPR114
0.033564891
0.266623
99.60%
43.90%


TLR10
0.033774749
0.63845
57.09%
50.25%


GJB1
0.034227595
0.7153
99.37%
66.03%


TLR1
0.037289655
0.603098
57.60%
13.88%


MAMDC4
0.038907212
0.314596
61.24%
14.98%


SLC24A3
0.039275276
0.129541
77.30%
27.28%


ICAM2
0.046963398
0.82728
98.97%
26.99%


CDH17
0.049357256
0.149412
33.39%
10.67%


LRTM1
0.049881692
0.254531
56.65%
26.87%


OR51E1
0.057873303
0.39426
36.42%
53.85%


HTR5A
0.060966983
0.781424
98.81%
73.90%


NETO1
0.061280475
0.124161
63.66%
37.61%


HTR1D
0.062424675
0.276345
44.16%
33.15%


OR10AD1
0.063295452
0.547734
11.47%
31.82%


SCNN1G
0.064272807
0.428267
74.48%
31.38%


TLR6
0.065104936
0.373262
54.56%
23.45%


P2RY12
0.068122543
0.112945
16.74%
18.63%


SLC34A2
0.07384138
0.525343
52.77%
32.40%


GLRA3
0.076258206
0.362804
13.84%
56.15%


SLC7A9
0.076612149
0.233394
40.58%
27.54%


CCKAR
0.077838652
0.451114
45.93%
45.25%


CHRNA10
0.079366153
0.490539
50.10%
11.94%


KIAA1644
0.081777828
0.213633
28.13%
57.82%


OR1L6
0.082566594
0.61398
59.91%
60.94%


LCT
0.083929719
0.214314
11.57%
26.17%


LRRN4
0.084831855
0.335084
20.92%
25.28%


GRPR
0.093599699
0.329395
23.64%
37.35%


FCRL6
0.094053988
0.512733
78.37%
18.41%


PCDH17
0.094280193
0.138028
20.28%
29.82%


OR2C1
0.105489764
0.691383
98.84%
22.78%


GPR139
0.109840931
0.563193
99.15%
100.00%


AQP9
0.114420742
0.268749
77.44%
60.90%


CSMD2
0.117920936
0.127842
37.00%
24.12%


GABRP
0.119858515
0.285521
79.33%
37.78%


GP2
0.12109813
0.697751
63.22%
60.18%


SLC2A9
0.127552251
0.461735
12.09%
34.53%


CCR8
0.129503819
0.608588
50.07%
63.52%


GPR115
0.139420627
0.199964
63.64%
74.58%


PRSS8
0.143302283
0.20152
22.70%
56.78%


PCDHA7
0.149025155
0.21111
21.37%
22.73%


TEX101
0.151357321
0.740308
48.34%
75.46%


MUC4
0.151998995
0.17201
14.73%
30.74%


NTM
0.152298627
0.173338
35.80%
52.44%


CHRM4
0.154316689
0.310639
32.01%
39.36%


NAALADL1
0.155664822
0.273845
53.82%
25.66%


KIRREL3
0.160339999
0.102269
47.57%
18.30%


BTNL10
0.161012809
0.321967
23.15%
44.76%


GLRA4
0.161339509
0.104277
33.06%
44.28%


GJB3
0.163399011
0.383729
77.33%
23.67%


ADAM28
0.163421263
0.180578
21.58%
30.85%


OR51D1
0.167235034
0.977668
98.09%
100.00%


TAAR1
0.169676454
0.830415
70.38%
64.32%


LRRC4C
0.172968676
0.303982
78.07%
20.22%


CASR
0.180071376
0.72817
10.51%
78.51%


TMPRSS13
0.180606284
0.106
18.38%
73.91%


MPL
0.181982745
0.132992
16.82%
18.75%


RXFP3
0.195262717
0.974637
97.83%
100.00%


PLP1
0.196855329
0.202745
19.78%
12.92%


UMOD
0.203472941
0.984645
98.68%
16.14%


NPC1L1
0.208111162
0.177569
50.34%
59.47%


SLC16A12
0.211359962
0.384344
26.26%
46.91%


ADAM29
0.219564057
0.674931
11.48%
15.95%


TPO
0.230214212
0.410634
73.11%
34.47%


CLDN8
0.230826406
0.975655
97.91%
100.00%


SLAMF9
0.239443665
0.803716
45.21%
60.42%


OR56A4
0.24526769
0.712488
16.24%
53.43%


GRIA1
0.247999743
0.118381
41.28%
47.55%


GPR61
0.269250031
0.147287
98.77%
27.41%


TACSTD2
0.270576747
0.843263
29.07%
100.00%


GPR111
0.270949315
0.27181
45.49%
53.23%


RXFP4
0.275641874
0.756933
43.73%
59.35%


SSTR5
0.285760023
0.621207
47.10%
100.00%


ZP1
0.286417239
0.275397
52.04%
45.41%


LHFPL1
0.290557161
0.130155
64.05%
67.56%


TREM1
0.291276251
0.529909
60.56%
29.12%


P2RY6
0.293812431
0.761492
98.18%
100.00%


SLITRK3
0.298052908
0.114055
24.70%
40.92%


OR2AG1
0.298981285
0.317617
19.95%
57.95%


CX3CR1
0.308359296
0.379878
99.10%
35.66%


MUC15
0.322581996
0.102786
38.91%
32.52%


CDH9
0.336510422
0.111464
82.27%
23.50%


DCSTAMP
0.346386452
0.428186
98.10%
100.00%


PCDH11X
0.350927663
0.228486
35.53%
15.12%


TRAT1
0.356444465
0.292886
98.95%
72.35%


OR13C4
0.363448784
0.250674
98.37%
100.00%


GPR97
0.364496471
0.241852
98.68%
56.91%


GPR50
0.366015279
0.253139
80.25%
18.80%


DRD1
0.373528691
0.198974
57.45%
48.01%


CHRM5
0.390903944
0.323917
26.60%
22.80%


PVRL4
0.395927064
0.471404
98.64%
18.51%


SCN1A
0.40052708
0.133629
25.29%
15.61%


SLC22A7
0.417435959
0.421769
29.45%
26.09%


TREML2
0.429760152
0.654546
97.80%
51.60%


CDH26
0.442764199
0.170486
13.77%
18.62%


CLDN9
0.448499624
0.121858
98.73%
51.50%


OR6A2
0.464019468
0.375298
10.04%
30.22%


OR52N4
0.46837279
0.543369
21.42%
16.84%


SORCS3
0.470945076
0.334882
29.37%
37.19%


SELL
0.482522576
0.270109
20.95%
18.33%


OR51B2
0.49050313
0.238092
39.15%
75.52%


VIPR1
0.493166622
0.174589
25.55%
13.23%


SLC44A4
0.493325335
0.124078
23.96%
52.04%


PKD1L2
0.499836618
0.260788
73.53%
17.54%


DRD5
0.501647631
0.443843
67.66%
31.39%


OR2G6
0.521852047
0.624042
98.44%
29.89%


OR52E4
0.528009097
0.414756
53.62%
30.49%


CCR7
0.528589134
0.284491
70.83%
17.59%


OR52E8
0.543144092
0.457579
99.12%
11.80%


OR52N2
0.54364032
0.469246
36.87%
29.28%


MS4A6A
0.56272475
0.468199
98.61%
43.98%


GPR37L1
0.569660997
0.454327
32.00%
29.86%


OR5AK2
0.571029371
0.52337
98.81%
25.01%


OR52L1
0.581079191
0.651071
18.47%
66.06%


OR6C70
0.589966926
0.385499
98.03%
55.10%


CEACAM21
0.591307598
0.512154
97.78%
51.31%


GRM1
0.603547953
0.199233
26.29%
15.28%


PTPRO
0.605148475
0.117836
10.83%
12.97%


OR56A3
0.605413463
0.233456
33.07%
70.48%


FCGR1B
0.611416363
0.157712
98.35%
26.50%


OR52N1
0.616368764
0.316361
27.49%
37.74%


OR51B4
0.625043893
0.212658
36.16%
63.84%


SIT1
0.670741496
0.454638
97.67%
47.24%


RNF128
0.698191117
0.168108
26.79%
25.13%


OR1E1
0.765370966
0.403748
96.91%
100.00%


OR2Z1
0.772339568
0.551807
97.14%
100.00%


MSLN
0.832716302
0.335762
31.86%
55.59%


TRGC2
0.877961037
0.308061
47.81%
24.39%


OR51Q1
0.89044125
0.216263
13.16%
40.13%


CD2
0.901949109
0.257533
96.63%
10.98%


OR3A3
0.918956986
0.355678
93.70%
100.00%


OR51I1
0.928903846
0.118784
12.11%
48.30%


OR51I2
0.933934547
0.234344
29.46%
23.59%


NPY1R
0.954579812
0.203248
20.47%
10.79%


NRXN1
2.81822E−13
0.000138
41.20%
32.71%


SLC37A1
1.73598E−10
0.282594
3.80%
54.72%


ILDR1
3.81693E−10
0.591516
9.63%
71.40%


CADM1
2.05992E−08
0.097347
18.55%
37.36%


CNTNAP2
1.93462E−07
0.080886
27.79%
36.81%


KIAA0319
1.99897E−06
0.268488
40.00%
9.84%


PLXNB1
2.56777E−06
0.193511
2.88%
6.29%


MANSC1
4.95483E−06
0.077139
11.71%
17.51%


CPM
5.92894E−06
0.35473
9.41%
34.60%


VSIG10
6.98693E−06
0.156953
5.37%
2.76%


PCNXL2
8.89734E−06
0.03691
6.30%
18.41%


TNFSF13B
1.08318E−05
0.572241
6.52%
38.67%


NCAM1
1.26863E−05
0.032152
0.36%
32.60%


TNFRSF11A
 1.7428E−05
0.195698
6.01%
47.87%


LAMP3
3.27086E−05
0.349462
7.97%
24.67%


SLCO3A1
4.23488E−05
0.133386
1.16%
20.47%


CD164
5.88986E−05
0.110949
4.87%
1.26%


LRRC19
6.40915E−05
0.132696
7.69%
12.78%


DLL3
6.99064E−05
0.021607
26.61%
38.03%


CELSR3
7.84076E−05
0.043083
21.81%
3.79%


SPINT2
 8.432E−05
0.463714
0.12%
27.87%


GPR98
0.000111511
0.080098
12.09%
30.63%


DSCAM
0.000142465
0.084568
37.30%
66.39%


MFSD6
0.000155596
0.078808
3.37%
11.82%


NRCAM
0.000241684
0.01606
4.02%
21.51%


CDHR2
0.000417751
0.048345
19.16%
19.90%


CD274
0.000435901
0.361162
2.78%
31.17%


SLC26A5
0.000457813
0.229818
6.87%
18.86%


SCN8A
0.00046048
0.030231
13.89%
6.97%


SLC19A2
0.000471901
0.017147
2.97%
14.87%


TMEM30A
0.00047847
0.049206
2.10%
1.18%


LTBR
0.000601952
0.558914
3.06%
45.93%


CNTNAP5
0.000944472
0.047497
55.74%
72.69%


GPR137B
0.001001296
0.160058
3.96%
15.19%


SLCO4C1
0.001355291
0.027975
25.08%
27.10%


CD226
0.00148
0.327766
7.32%
7.98%


SLC15A1
0.001495143
0.488211
0.18%
73.74%


IL17RE
0.001650383
0.549996
5.20%
9.29%


FAM174A
0.001831702
0.125693
11.96%
3.65%


OR13D1
0.002084051
0.482306
4.38%
37.76%


MEP1B
0.002138482
0.079696
25.53%
30.89%


SELP
0.002486472
0.329723
4.22%
52.38%


GPR171
0.00257369
0.130563
8.54%
33.36%


SV2B
0.002605544
0.14781
1.58%
58.45%


CDH2
0.002945579
0.005672
8.15%
17.29%


NIPAL2
0.003184126
0.292185
20.99%
5.70%


PCDHAC1
0.004493167
0.096666
10.94%
17.64%


SLC24A5
0.004530771
0.00781
2.82%
12.80%


EPHA7
0.00591625
0.105303
1.14%
23.73%


LRP11
0.006693531
0.057794
6.75%
3.65%


CADM4
0.007260938
0.165916
0.04%
12.91%


HTR4
0.007408214
0.785335
9.56%
61.17%


GPR107
0.007843444
0.045573
6.16%
2.48%


PAM
0.008245061
0.103585
8.72%
8.04%


SLC4A8
0.008671296
0.014193
20.01%
12.26%


NIPAL3
0.008955911
0.085266
1.17%
13.35%


GPR19
0.009621378
0.018444
25.07%
18.52%


ATP13A3
0.010339182
0.033086
2.61%
6.69%


CLCA4
0.011761077
0.365154
8.42%
36.31%


LMBRD2
0.013003468
0.052016
3.03%
4.46%


P2RY14
0.015391254
0.08558
9.26%
21.00%


DPP10
0.016109634
0.066815
15.21%
44.03%


SLC16A7
0.01830618
0.058351
7.28%
36.64%


SDK1
0.018394001
0.097402
5.86%
26.61%


KLRC2
0.0199057
0.665188
2.29%
6.94%


CHRNB2
0.019970912
0.009941
11.02%
15.33%


PGAP1
0.020448682
0.020757
6.72%
9.19%


SIDT1
0.020510928
0.07108
5.70%
24.67%


LDLRAD4
0.020833278
0.239747
8.54%
16.19%


CD5
0.021375005
0.025398
37.68%
56.44%


ABCA12
0.021687914
0.108906
12.30%
8.86%


KCNMB3
0.022103167
0.116531
6.05%
7.32%


HCAR1
0.023805255
0.02454
6.50%
5.35%


GPR137C
0.024235948
0.111747
8.34%
12.96%


OR13C3
0.024985001
0.331062
6.73%
79.87%


SLC39A6
0.029919702
0.020042
6.16%
3.60%


GPR87
0.030600045
0.129285
9.52%
15.34%


P2RY13
0.032230889
0.126106
9.27%
17.95%


TMEM9B
0.039014426
0.058556
2.24%
1.22%


NEGR1
0.0390838
0.021542
8.20%
30.64%


SLAMF8
0.039703797
0.570583
28.66%
9.38%


SEMA4D
0.041428257
0.023521
4.84%
13.37%


ZDHHC11
0.042993938
0.093724
17.59%
28.47%


SLC44A1
0.047262548
0.045964
0.62%
4.88%


ERMP1
0.048015557
0.058031
1.04%
4.27%


TMCO3
0.049898976
0.060559
1.78%
6.22%
















TABLE 3







Surface proteins associated with the SCLC-A subtype from the Sato dataset











Surface Protein
ANOVA p value
A vs N
A vs P
A vs I














SLC36A4
 3.6209E−17
0.15502
22.308%
22.861%


KCNMB2
2.12475E−11
0.147835
54.918%
52.805%


DLL3
4.95184E−11
0.174969
54.054%
43.414%


SCN3A
 8.2927E−10
0.3364
63.826%
73.498%


CNTNAP2
9.35797E−10
0.149454
60.412%
45.824%


EPHA7
4.09629E−06
0.103841
60.054%
27.894%


NCAM1
 1.0331E−05
0.193353
38.981%
43.300%


GPR6
3.04057E−05
0.206156
38.466%
47.680%


TMEM178B
6.39697E−05
0.102242
45.414%
38.991%


USH2A
0.000202096
0.339776
45.994%
47.909%


SLC10A4
0.000248882
0.274111
26.806%
30.060%


FZD9
0.000341704
0.24411
42.544%
32.753%


CSMD2
0.000359364
0.222779
26.009%
40.148%


GABRQ
0.000475856
0.384127
50.287%
51.070%


NKAIN2
0.000487651
0.370731
46.408%
75.324%


BAI3
0.000507217
0.264845
63.729%
50.032%


SLC13A3
0.000514257
0.497167
32.557%
37.717%


SLITRK6
0.000760758
0.410857
19.282%
29.530%


GABRB3
0.000836048
0.233776
55.244%
32.639%


GRIN3A
0.000988034
0.102544
39.707%
33.547%


TSPAN11
0.001296991
0.331247
40.427%
39.169%


SLC6A20
0.001507455
0.287331
58.519%
52.405%


IMPG2
0.002094285
0.656235
40.016%
48.251%


SLC38A11
0.002154783
0.384341
51.780%
39.107%


OR51B4
0.002313114
0.336505
44.933%
38.853%


KIAA0319
0.002483783
0.11467
36.340%
38.323%


SCNN1A
0.002953916
0.232782
22.755%
16.122%


HTR3A
0.003313948
0.179301
32.946%
25.480%


MEGF11
0.005261409
0.369124
31.185%
57.438%


SLCO5A1
0.005309677
0.154419
19.329%
22.456%


OR51E2
0.005385784
0.498221
43.895%
50.589%


SCN2A
0.005615783
0.579349
56.037%
69.463%


RXFP2
0.006741993
0.326676
48.979%
47.403%


PCDHB14
0.007987304
0.147473
20.708%
17.263%


MRGPRX2
0.008177888
0.570892
21.686%
56.823%


ZACN
0.008212913
0.523969
35.080%
36.087%


TMPRSS6
0.009348823
0.297175
33.980%
24.019%


SDK2
0.009660435
0.235089
26.388%
16.965%


EPHA8
0.011240564
0.370718
42.163%
38.458%


KIRREL3
0.011666252
0.469852
72.765%
67.381%


OPRD1
0.013540907
0.447248
42.558%
11.970%


OR51I1
0.014025586
0.376518
38.102%
35.813%


EPHB1
0.014465982
0.172161
33.125%
46.403%


TAS2R19
0.014590558
0.153296
39.139%
29.226%


TMEM132D
0.016265486
0.21735
28.160%
32.928%


GML
0.016952953
0.24852
16.805%
31.682%


CCR10
0.017943645
0.30845
14.425%
42.166%


CLDN9
0.019362449
0.165337
27.569%
20.463%


CHRM4
0.020057719
0.320558
41.741%
22.390%


GHRHR
0.025395908
0.473286
36.531%
36.426%


OR2C1
0.025539295
0.226252
15.137%
23.532%


LRRC52
0.025718703
0.347979
23.744%
29.467%


CLDN19
0.027568501
0.183315
34.096%
29.990%


NPC1L1
0.027664883
0.650431
45.735%
45.030%


LIFR
0.028042227
0.14005
34.930%
20.756%


KCNG4
0.035325371
0.323904
38.633%
30.792%


CADM2
0.03592761
0.170513
60.254%
66.949%


OR6A2
0.048402304
0.241793
47.158%
29.900%


PCDHB4
0.04915665
0.140332
12.870%
30.033%


DSCAM
0.049749306
0.442161
42.429%
38.937%


GPR3
0.053308509
0.370976
42.227%
11.756%


ZNRF4
0.054720302
0.254887
42.294%
17.092%


PCDHGC3
0.055137741
0.273287
36.717%
34.037%


SLC18A1
0.056847155
0.117628
29.841%
48.985%


PTH2R
0.057035473
0.200735
18.643%
21.415%


TMEM255B
0.058967754
0.122116
26.501%
21.509%


SSTR1
0.061635122
0.108684
39.195%
39.539%


ANO9
0.063449988
0.115157
22.862%
22.304%


OR51E1
0.064203033
0.184966
33.475%
22.616%


TNFRSF11A
0.071568554
0.158845
24.040%
22.870%


SLITRK3
0.072970747
0.130772
42.610%
55.146%


CACNG4
0.075295546
0.229757
26.340%
31.059%


PCDH8
0.075536069
0.137834
28.815%
38.716%


LRRC37A2
0.077267382
0.383611
29.502%
42.495%


MTNR1B
0.079530838
0.476711
21.629%
41.123%


SLC7A9
0.085711186
0.12475
10.928%
25.188%


RRH
0.088449346
0.172084
22.950%
31.787%


MLNR
0.093877884
0.246308
11.933%
67.321%


SSTR4
0.096475655
0.44798
33.174%
60.206%


SHISA8
0.104907471
0.26363
27.706%
25.560%


GNRHR2
0.105712198
0.302476
25.311%
30.786%


CHRNA6
0.107053817
0.135801
23.847%
20.954%


HTR1F
0.110049933
0.243619
25.437%
22.688%


PCDHB16
0.114264115
0.154052
28.878%
23.171%


OR5K1
0.11843297
0.534206
36.538%
10.684%


OR2J2
0.124912351
0.303661
47.232%
47.637%


CEACAM3
0.125467587
0.14594
33.235%
25.602%


FASLG
0.141651826
0.432049
10.029%
16.818%


FSHR
0.154384245
0.324573
31.452%
35.872%


OR10J1
0.155816912
0.36456
20.329%
22.753%


SLC2A9
0.157908097
0.233686
30.791%
32.036%


MAMDC4
0.159285638
0.271523
32.617%
40.752%


GRIA1
0.164707109
0.456342
50.002%
33.319%


OR5P2
0.168607105
0.386843
24.427%
35.804%


CCKBR
0.16991124
0.22797
39.953%
30.549%


SLC17A8
0.176197732
0.393595
10.957%
41.542%


OR12D3
0.193758767
0.477544
38.168%
22.809%


OR1C1
0.197981615
0.226152
40.991%
37.681%


EPHA10
0.217205955
0.137644
14.704%
36.381%


TMEM26
0.231754999
0.33384
13.250%
25.896%


RPRML
0.232422987
0.310727
31.976%
48.797%


ERVK13-1
0.246852182
0.285272
34.595%
37.679%


FCAMR
0.257489198
0.473894
10.823%
50.472%


TAS2R9
0.258115839
0.128005
32.008%
28.559%


OR51B5
0.272525891
0.358403
13.408%
23.503%


SLC22A12
0.282201725
0.394495
21.378%
39.099%


PLXNA4
0.287514564
0.272268
30.092%
27.292%


CATSPERG
0.287622709
0.123575
29.005%
41.241%


CNTNAP3
0.291475048
0.13097
16.321%
40.176%


SLC28A1
0.306710197
0.536389
19.634%
46.421%


GPR111
0.315373938
0.120573
34.760%
44.541%


OR7E24
0.330202419
0.147504
10.179%
17.082%


MRGPRX3
0.337045286
0.326367
14.929%
44.917%


LYPD4
0.342132517
0.231182
29.842%
34.120%


UPK2
0.376496111
0.259384
31.322%
13.881%


PMEL
0.378874334
0.162151
17.241%
34.662%


OR8B2
0.383388425
0.407016
38.383%
36.739%


NTSR1
0.400107773
0.243023
28.527%
15.852%


P2RX6
0.403276605
0.216562
18.287%
39.600%


GP2
0.421840526
0.331034
19.146%
33.302%


KIR2DL2
0.484815762
0.246266
16.226%
37.669%


SLC22A16
0.496766455
0.354668
31.261%
31.710%


DCT
0.498290319
0.106322
37.415%
35.608%


GPR150
0.502744828
0.258241
11.544%
20.003%


GPR52
0.506798691
0.215444
17.122%
26.294%


ADRA2B
0.508365779
0.115223
13.314%
20.612%


GRIN2C
0.508812967
0.515733
26.706%
46.268%


SYNPR
0.531601558
0.153175
45.827%
20.640%


NPBWR2
0.531726436
0.174621
26.632%
13.088%


LHFPL5
0.551998942
0.347731
26.548%
31.810%


SLC17A1
0.552893145
0.245995
20.117%
38.775%


OR10D3
0.579559865
0.306504
22.682%
27.642%


KIR3DL3
0.633760997
0.363982
12.189%
21.245%


SLC12A5
0.634871755
0.131703
34.205%
27.162%


AQP8
0.66424754
0.318738
21.762%
43.638%


GALR1
0.707401413
0.139824
22.635%
30.150%


CACNG2
0.72884106
0.244945
30.076%
24.906%


OR1J2
0.745542617
0.1659
21.786%
20.816%


LRRC19
0.757790628
0.114687
20.488%
35.039%


GALR2
0.786281062
0.20244
25.392%
10.962%


KIR2DS3
0.839037134
0.212415
15.550%
24.822%


TMEM194A
1.99109E−17
0.008766
3.285%
12.698%


FLVCR1
9.54416E−15
0.010361
6.615%
6.187%


GPR180
1.67834E−12
0.095857
5.913%
1.526%


GPR137C
5.94514E−12
0.010676
22.977%
33.222%


PGAP1
9.93308E−09
0.027223
19.227%
22.341%


OPRK1
2.46524E−08
0.029869
42.001%
35.326%


FRAS1
1.61818E−07
0.016696
22.242%
30.497%


RET
4.51872E−07
0.045272
65.408%
44.954%


CDH2
4.37339E−06
0.055668
33.107%
47.125%


DPP10
9.64044E−06
0.028249
57.339%
47.124%


IL17RB
4.05664E−05
0.029719
0.358%
22.944%


NCR3LG1
4.55152E−05
0.201455
20.909%
66.651%


GPC2
5.95108E−05
0.044895
0.566%
9.423%


CXADR
6.75458E−05
0.01686
7.438%
8.463%


DNER
7.50498E−05
0.00785
67.506%
50.615%


CEACAM5
0.000117654
0.435062
59.590%
3.722%


PTCHD2
0.000155344
0.040558
21.106%
31.835%


JAG2
0.000169434
0.060764
25.767%
25.102%


GPR19
0.000186837
0.137129
8.450%
16.650%


OR10A5
0.000263957
0.373593
3.957%
16.729%


ABCA5
0.000303787
0.021574
13.007%
16.271%


UNC5A
0.000444148
0.077637
74.208%
73.358%


L1CAM
0.000470882
0.014761
44.031%
44.644%


SLC35A5
0.000489255
0.041868
1.928%
7.461%


ACVR2A
0.000518356
0.054361
17.915%
18.037%


JAM3
0.000628884
0.140538
25.566%
21.465%


NRCAM
0.000647028
0.003451
18.231%
20.282%


KITLG
0.000827928
0.065612
20.623%
12.737%


ZP4
0.000873488
0.083478
23.152%
29.585%


C1orf159
0.000929423
0.067247
11.866%
16.926%


CLDN3
0.001973181
0.013
1.869%
21.120%


FAT3
0.002040177
0.094829
43.475%
52.371%


VSIG10
0.002186823
0.11297
7.153%
25.989%


PTPRN
0.002502007
0.021962
34.813%
40.511%


ACPT
0.003274664
0.033291
13.466%
16.473%


UGT8
0.003431098
0.001063
6.485%
23.446%


SCN8A
0.003916188
0.071417
39.470%
35.926%


LRP6
0.005394716
0.047986
1.142%
6.706%


PTPRN2
0.005602401
0.005449
52.180%
31.704%


EPOR
0.005607685
0.08905
31.528%
50.431%


SCN10A
0.005978571
0.163899
8.624%
9.264%


LYNX1
0.006849684
0.118617
32.773%
5.580%


TMEM63C
0.006996996
0.017557
47.104%
25.882%


CD24
0.00729205
0.075986
1.734%
0.299%


LRP11
0.008244906
0.073493
8.653%
8.958%


ILDR1
0.008245603
0.21415
6.931%
9.684%


LPAR2
0.008734435
0.02919
12.803%
10.538%


LRRN3
0.008850131
0.029899
32.449%
27.768%


IGSF3
0.009066078
0.001982
11.764%
1.074%


FZD2
0.010682578
0.229173
27.342%
2.980%


LDLRAD3
0.011317141
0.141225
3.271%
16.778%


SLC38A1
0.011998963
0.004467
6.662%
10.621%


ABCC5
0.012124386
0.009045
12.557%
5.227%


PCDHB2
0.012378101
0.042525
2.905%
5.919%


TENM3
0.013055662
0.063878
34.445%
47.559%


AVPR1B
0.01539388
0.0787
25.662%
21.399%


SCN9A
0.015639788
0.328849
46.227%
0.169%


HRH3
0.016266498
0.084254
63.985%
48.046%


TGFBR1
0.017602758
0.026832
2.109%
0.454%


TECTB
0.017653043
0.262742
7.922%
22.696%


PCDH17
0.017795987
0.221154
15.208%
9.992%


SLC38A2
0.020800535
0.002456
1.595%
0.816%


NKAIN1
0.024737509
0.078601
45.852%
27.510%


OR2B6
0.025670547
0.055965
26.933%
11.751%


ZDHHC11
0.026038949
0.079895
12.171%
26.230%


TMEM104
0.029689108
0.092341
6.091%
7.052%


ANKH
0.029725716
0.185744
25.519%
27.744%


MC1R
0.02985773
0.094628
21.850%
10.537%


SLC46A1
0.030028088
0.492967
35.040%
38.739%


TPBGL
0.031590253
0.079668
26.967%
19.166%


DISP2
0.036826576
0.088057
56.065%
43.614%


BDKRB1
0.037433263
0.057829
33.314%
6.038%


TMEM158
0.037449315
0.01588
38.869%
22.698%


EDAR
0.039067345
0.058796
17.509%
17.615%


LRP8
0.039867424
0.000954
2.261%
2.149%


PCDHA9
0.042449507
0.05559
20.069%
28.474%


SLC4A8
0.043513887
0.083987
16.097%
8.934%


OR5112
0.046049029
0.33085
8.386%
19.753%


CRB1
0.048117789
0.011209
54.617%
75.610%
















TABLE 4







Surface proteins associated with the SCLC-N subtype from the George et al. dataset











Surface Protein
ANOVA p value
N vs P
N vs I
N vs A














CELSR3
 6.1925E−12
0.573759
27.31%
10.29%


ATP2B3
5.06576E−11
0.916577
70.82%
73.79%


LRFN5
1.72877E−10
0.905313
51.65%
57.69%


PRIMA1
8.69651E−10
0.698271
53.42%
70.49%


UNC5A
2.83215E−09
0.732281
41.62%
31.43%


SEMA6A
4.14523E−09
0.575409
44.51%
61.17%


CHRNA3
5.28743E−09
0.836309
42.61%
58.35%


SSTR2
6.71534E−09
0.683883
44.88%
65.50%


EFNB1
1.51695E−08
0.138497
10.89%
36.24%


ADAM22
2.59859E−08
0.595686
46.14%
26.59%


CHRM4
2.64172E−08
0.774461
35.51%
16.15%


GRM2
4.28391E−08
0.723294
54.88%
40.05%


SORCS2
1.02917E−07
0.66894
54.02%
59.16%


SLC7A14
1.32126E−07
0.811933
48.58%
22.88%


PTCHD2
1.32495E−07
0.662233
29.70%
36.92%


SLC17A6
1.60444E−07
0.831928
55.20%
89.15%


INSR
1.65814E−07
0.387762
34.54%
20.85%


SLC22A17
3.83495E−07
0.492411
28.13%
27.84%


SCN8A
4.49606E−07
0.500287
40.53%
24.47%


AJAP1
4.69171E−07
0.88978
57.28%
63.75%


PCDH8
5.12598E−07
0.823214
51.39%
53.43%


FNDC5
6.51458E−07
0.644115
17.52%
62.74%


MDGA1
2.12746E−06
0.620897
19.08%
53.44%


NRXN1
2.45923E−06
0.713869
38.37%
12.54%


LHFPL4
2.79358E−06
0.815741
54.64%
18.12%


NRXN3
3.07513E−06
0.737151
54.88%
35.34%


ALK
3.36763E−06
0.701165
43.01%
93.07%


BAI3
3.66247E−06
0.624551
61.51%
10.54%


GRIK3
3.82855E−06
0.777522
30.37%
19.97%


GRM8
4.24999E−06
0.781647
41.08%
27.83%


CNTNAP5
4.38812E−06
0.962856
53.24%
27.84%


CLDN11
5.95214E−06
0.602525
47.81%
38.43%


MEGF11
6.10315E−06
0.196511
66.73%
54.63%


CHRNB4
8.05596E−06
0.720094
44.93%
72.54%


SLC4A8
8.58488E−06
0.556254
34.02%
25.39%


SDK1
9.45195E−06
0.481539
16.48%
19.30%


FLRT1
9.98115E−06
0.667204
54.99%
53.55%


DISP2
1.05317E−05
0.608779
31.72%
14.02%


PGAP1
1.08883E−05
0.340334
24.89%
15.62%


GABRB3
1.09213E−05
0.795586
39.54%
19.03%


GPR137C
1.24293E−05
0.329891
37.01%
23.75%


NFASC
1.56363E−05
0.569673
39.02%
11.93%


ITGA2B
2.35216E−05
0.540112
61.10%
53.56%


TMEM132E
3.28842E−05
0.866342
64.00%
71.53%


PTPRS
3.31876E−05
0.480181
29.78%
24.19%


SLC6A3
3.84958E−05
0.876632
41.33%
38.10%


ADCY2
4.07443E−05
0.690115
39.83%
20.23%


ATP2B2
4.20568E−05
0.600252
57.74%
85.06%


CDH15
5.61025E−05
0.837607
56.88%
78.12%


GPR144
7.18573E−05
0.977342
74.92%
50.88%


ATP1A3
 7.5315E−05
0.646923
25.04%
15.72%


CDH23
 8.0446E−05
0.586608
68.71%
65.78%


INSRR
0.000153184
0.755215
71.90%
54.16%


CACNA1G
0.000202034
0.972712
68.33%
58.74%


BVES
0.0002091
0.162455
50.31%
56.05%


CADM3
0.000241401
0.432176
23.09%
70.31%


NTNG2
0.000249909
0.602432
28.97%
60.52%


PKDREJ
0.000266154
0.596165
51.05%
48.95%


EDA
0.000271187
0.579058
20.61%
82.46%


SLC7A3
0.000306704
0.654907
81.88%
74.69%


THSD7B
0.000312704
0.709072
37.16%
71.42%


CLSTN2
0.00035872
0.607084
29.01%
11.28%


GPR173
0.000394965
0.331256
22.46%
15.11%


LINGO4
0.000418643
0.852769
46.75%
60.74%


CACNG5
0.000424004
0.821964
57.53%
51.77%


OXER1
0.000429125
0.177194
25.55%
52.17%


EFNB3
0.000439341
0.650232
28.31%
24.45%


CDH24
0.000469432
0.260252
19.13%
19.41%


GPC1
0.000510653
0.286168
17.02%
14.91%


SEMA6D
0.000646567
0.618302
29.84%
28.25%


GRIN2A
0.000650613
0.61281
83.43%
86.03%


DRD2
0.000696344
0.427341
38.67%
14.41%


PROKR1
0.000699718
0.77653
58.40%
64.44%


PCDH19
0.000719942
0.254658
32.07%
72.44%


DSCAML1
0.000745893
0.452443
48.67%
30.73%


TMEM132C
0.00077889
0.26231
73.32%
83.45%


NLGN4X
0.000819876
0.458666
36.19%
53.09%


FRAS1
0.00084398
0.579842
42.06%
18.13%


PTPRU
0.000920643
0.567345
38.90%
10.40%


TSPAN5
0.000938159
0.259173
23.48%
34.34%


CDH4
0.000984619
0.587127
66.87%
55.81%


HCRTR1
0.000989857
0.671068
45.68%
75.85%


L1CAM
0.001036463
0.571241
29.52%
13.94%


OPRK1
0.001049209
0.776458
33.10%
51.70%


CDH20
0.001085102
0.830887
63.49%
69.78%


ADCYAP1R1
0.001095909
0.696811
39.19%
83.25%


LRRC37A
0.00112235
0.33307
23.59%
23.82%


KCNJ12
0.001148316
0.668503
56.52%
63.77%


GABRB2
0.001229154
0.59384
62.92%
83.16%


LPPR4
0.001234492
0.476717
32.76%
64.18%


CSPG5
0.001245776
0.595644
44.15%
30.60%


SLITRK2
0.001354932
0.807261
85.42%
95.56%


PCDHAC1
0.001439138
0.672744
41.03%
30.24%


GABRD
0.001458697
0.643466
41.17%
53.89%


PLXNA1
0.001533472
0.293294
16.17%
13.83%


DCHS1
0.001573525
0.181226
21.19%
24.88%


GPR179
0.001585972
0.729298
42.97%
52.29%


LRRC37A2
0.001591585
0.236561
22.36%
18.21%


CLDN24
0.001598158
0.890572
81.36%
73.96%


GRIK5
0.001613968
0.509031
20.18%
15.81%


BOC
0.001619979
0.28387
13.57%
37.33%


TSHR
0.001767578
0.588054
18.57%
82.58%


SGCD
0.001972312
0.505073
21.76%
62.76%


GPR98
0.002112942
0.769006
43.65%
21.31%


IGSF1
0.002133039
0.855788
58.27%
76.85%


ADRA2A
0.0025547
0.492519
42.01%
53.18%


PCDHGC4
0.002558076
0.760026
36.69%
24.75%


SLC10A4
0.002734957
0.589003
23.01%
12.44%


CNTFR
0.003007624
0.610219
56.94%
49.56%


GPR12
0.003164611
0.511798
74.50%
44.89%


SV2C
0.003228604
0.685839
56.96%
85.39%


PKD1
0.00377731
0.285687
24.31%
11.31%


GFRA2
0.003789973
0.632558
48.50%
62.45%


LRTM2
0.003804776
0.878045
47.05%
33.95%


GRM7
0.003870244
0.863609
61.35%
68.19%


PLXNA3
0.003954812
0.178186
21.09%
13.59%


DRD5
0.003987268
0.921329
72.11%
52.18%


FAT2
0.004082827
0.514623
39.27%
78.58%


PTCH1
0.004296687
0.466503
31.54%
17.59%


GPR162
0.004390574
0.394175
30.07%
32.00%


ADAM11
0.004402101
0.560331
32.64%
44.46%


DCC
0.004625318
0.717
49.85%
49.46%


ANO1
0.004855082
0.242015
12.52%
24.04%


CSMD2
0.004989606
0.720491
24.87%
16.54%


LGR6
0.005071809
0.467987
28.87%
62.90%


GABRQ
0.00536001
0.662686
56.27%
46.48%


GRID1
0.005829422
0.671908
45.20%
15.36%


SLC9A3
0.005943468
0.851469
39.41%
40.49%


RHO
0.006311015
0.605136
61.85%
54.93%


KREMEN1
0.006666046
0.335346
20.81%
28.75%


LYPD1
0.007059685
0.563758
23.82%
15.52%


ISLR2
0.007463654
0.785404
26.51%
31.74%


GRIN2D
0.007544549
0.504649
16.73%
46.36%


GFRA1
0.007650674
0.492506
44.83%
77.03%


LYNX1
0.007677437
0.633419
42.72%
30.35%


FZD10
0.008095895
0.525546
42.02%
54.09%


SLC24A3
0.008104277
0.410185
20.07%
29.26%


TMEM235
0.008171478
0.949558
40.09%
90.08%


ANO5
0.008677809
0.463405
58.16%
20.06%


OR2B2
0.008711431
0.78781
91.23%
80.23%


TSPAN7
0.008954136
0.264206
16.67%
15.43%


ASTN1
0.009088081
0.532796
40.82%
52.19%


TECTA
0.010110951
0.473739
37.27%
25.38%


CDHR1
0.010144136
0.733111
34.51%
40.51%


TMEM132B
0.010155423
0.495876
51.12%
68.27%


GLRA4
0.010404238
0.831564
64.29%
67.53%


ADRA2C
0.010641811
0.549583
52.72%
28.47%


UMODL1
0.01074962
0.705974
40.71%
68.13%


CEACAM7
0.011097401
0.947309
29.25%
29.07%


LRRTM2
0.011193361
0.686155
47.72%
50.61%


MRGPRE
0.011685277
0.693856
57.07%
10.50%


GRM4
0.01182794
0.659113
44.03%
15.64%


HTR1D
0.011978359
0.599101
61.72%
49.53%


AMHR2
0.012854106
0.680105
79.32%
77.95%


GABRG1
0.012961128
0.994729
97.24%
45.07%


IGSF9B
0.014781834
0.494546
42.48%
34.31%


IGDCC3
0.015128595
0.315368
38.83%
67.00%


SLC1A2
0.015955141
0.576281
59.31%
55.98%


RTN4R
0.016010016
0.121643
18.00%
28.74%


ASTN2
0.01669561
0.356192
41.62%
19.69%


ATRNL1
0.017493974
0.476618
57.72%
45.51%


SEMA6C
0.018030325
0.136158
21.77%
23.65%


SLC12A5
0.018092542
0.850817
57.68%
35.91%


GPR88
0.018097555
0.602736
37.97%
76.42%


EPHB2
0.018229314
0.238481
15.33%
28.82%


NRXN2
0.018463989
0.556142
32.16%
57.47%


SLC22A15
0.01869566
0.124534
26.80%
38.70%


NPR2
0.019561805
0.252443
21.21%
25.70%


TNFRSF19
0.020259707
0.375924
32.02%
31.68%


GLP1R
0.020563182
0.147739
70.03%
43.53%


GSG1
0.021129435
0.564146
56.49%
65.89%


SLC6A20
0.021140595
0.714618
47.68%
45.44%


BAI1
0.021520112
0.637911
21.14%
26.33%


HTR5A
0.022219521
0.920426
49.48%
76.13%


GPR176
0.022340355
0.266634
11.42%
29.24%


OPRL1
0.023260551
0.445688
22.02%
32.89%


CLDN20
0.024180702
0.493392
40.92%
58.17%


ACVR2B
0.025118042
0.154813
22.96%
16.13%


PCDHA11
0.025467667
0.698385
49.37%
37.21%


GPR142
0.025714425
0.669571
78.98%
37.59%


NKAIN3
0.026098592
0.614376
66.92%
86.32%


SCNN1G
0.026356187
0.543443
24.24%
11.22%


GRIN3A
0.027575955
0.614257
36.93%
26.26%


ATP4B
0.027634792
0.821483
31.44%
14.83%


PTPRK
0.028783658
0.153733
27.07%
16.89%


GPRC5B
0.029487306
0.106481
19.99%
10.62%


SCN1B
0.030230421
0.362256
16.62%
35.61%


TMEM132D
0.031012987
0.430694
50.01%
35.85%


PTCHD1
0.033026771
0.722026
49.78%
65.37%


GJD2
0.033878057
0.921458
61.02%
74.77%


PCDHA12
0.03449809
0.599527
20.26%
33.03%


OR2B6
0.03470576
0.446892
22.92%
55.09%


SLITRK4
0.03490951
0.377342
63.27%
58.86%


CHRNA5
0.036073469
0.118688
26.36%
17.26%


SLC5A5
0.037002817
0.669536
30.41%
63.30%


RGMA
0.037156731
0.298614
19.15%
41.66%


SLC18A2
0.037365146
0.239139
36.68%
12.65%


ADRA1B
0.037604704
0.339989
49.70%
59.94%


GABRA5
0.037612786
0.888907
48.42%
37.32%


PCDHB15
0.038247212
0.457324
46.02%
26.07%


GPR113
0.03910298
0.19598
33.87%
39.20%


S1PR5
0.040027269
0.503571
20.86%
24.99%


TNFRSF10D
0.040563215
0.112778
16.78%
40.69%


NAALADL1
0.041633372
0.32281
21.01%
16.92%


SCN4B
0.042046543
0.235185
33.82%
53.76%


BAI2
0.044092778
0.186591
32.26%
20.65%


PCDHB1
0.045495897
0.569972
47.98%
39.52%


PTPRT
0.046043953
0.220097
76.01%
39.36%


PCDHGC5
0.046051223
0.428101
58.50%
45.43%


LRRC37A3
0.047156678
0.308517
22.59%
15.33%


GSG1L
0.048008064
0.905281
41.76%
84.18%


SLC24A5
0.048509853
0.586259
47.38%
39.49%


HCRTR2
0.048826764
0.479918
57.57%
85.53%


HTR6
0.04978644
0.780251
42.16%
45.63%


SLC22A5
0.050327647
0.114529
13.12%
16.93%


SLC26A1
0.050911603
0.248366
28.84%
42.21%


GRIA1
0.051346761
0.876596
33.33%
10.16%


GABBR2
0.051787928
0.694487
10.38%
20.92%


LRRC19
0.052751568
0.651326
39.71%
19.77%


SHISA7
0.055958554
0.809785
75.22%
22.13%


GRIK2
0.057980021
0.595821
62.69%
21.62%


IGSF3
0.058652192
0.246259
20.17%
11.35%


CDHR2
0.06105779
0.690136
55.75%
28.98%


CA14
0.062443476
0.231984
56.13%
41.45%


CHRM2
0.064707827
0.149607
71.64%
72.70%


SLC14A2
0.065856992
0.49556
17.85%
48.46%


PRLHR
0.066523779
0.824816
77.68%
47.07%


UPK3A
0.067023796
0.665629
17.69%
23.50%


SEMA5B
0.067534396
0.508539
25.36%
44.52%


GPR63
0.07140615
0.596877
18.54%
23.90%


OR5B21
0.071451987
0.717285
70.81%
76.12%


OR2AG1
0.071653636
0.503131
77.81%
100.00%


GABRA1
0.074937804
0.342208
52.03%
98.93%


PCDHAC2
0.076426756
0.54551
33.89%
17.38%


QRFPR
0.078409284
0.842708
44.67%
78.95%


ADRA1A
0.079075418
0.530968
42.08%
72.94%


NTRK1
0.08095532
0.493323
32.02%
55.82%


OR2A4
0.086233397
1
61.00%
87.76%


PCDHA9
0.086649666
0.650196
75.97%
69.87%


PCDHA2
0.088809981
0.688657
39.93%
33.01%


ATP1B4
0.089019416
0.760612
47.09%
76.43%


PCDHA3
0.089955822
0.614149
42.37%
22.09%


TMPRSS6
0.090784591
0.609584
25.66%
11.54%


SCNN1D
0.090955327
0.433076
30.79%
40.04%


PCDHGA6
0.095085055
0.237052
48.07%
49.45%


GPR26
0.098104123
0.214137
60.48%
64.67%


SLC8A2
0.099351624
0.530086
50.23%
47.26%


CRHR1
0.10113572
0.943891
73.68%
25.96%


ITGA7
0.102129657
0.158528
23.70%
25.43%


SLC4A1
0.10323747
0.728947
25.33%
39.46%


CD164L2
0.103479618
0.460086
52.48%
41.58%


NPBWR2
0.103565566
0.826678
100.00%
49.33%


CACNG2
0.106254766
0.675472
46.75%
49.31%


PCDHA5
0.108397926
0.755615
54.92%
39.21%


GFRAL
0.108527048
0.825913
30.89%
78.44%


UPK1B
0.109771779
0.654696
59.96%
54.73%


GPR50
0.111874922
0.776348
92.25%
49.71%


LTB4R2
0.112299423
0.288312
13.15%
13.91%


NPFFR1
0.113729383
0.477906
38.50%
63.16%


DCBLD2
0.117216578
0.109382
12.93%
12.70%


OR2J3
0.12356801
1
55.96%
84.85%


EDA2R
0.12356868
0.324638
25.09%
55.05%


TMEFF1
0.124681705
0.201329
14.34%
19.06%


GJB6
0.128510814
0.276044
74.48%
92.02%


OR11H4
0.131825914
0.863813
90.29%
33.63%


IZUMO1
0.133641173
0.488788
51.99%
26.81%


OR2AG2
0.133735541
0.1305
78.49%
47.61%


ABCG4
0.133955414
0.646916
70.65%
77.52%


ROR2
0.137353073
0.402098
18.79%
10.64%


OR6B2
0.137356036
1
48.72%
56.32%


VN1R2
0.138478415
0.62155
39.71%
61.18%


FAT3
0.138738047
0.161872
23.59%
41.22%


CDH18
0.140554535
0.952295
73.14%
29.71%


OR4D2
0.140910482
1
100.00%
73.35%


SLC28A2
0.145661401
0.456536
12.63%
39.76%


OR8D4
0.146050474
1
100.00%
51.01%


GPRC5C
0.147380471
0.282132
18.71%
10.76%


SLC13A1
0.150531099
0.518005
25.06%
50.51%


SLC10A1
0.150710233
0.512691
35.13%
46.42%


GALR2
0.152318302
0.843032
54.90%
26.47%


CNR1
0.156618006
0.253929
25.88%
52.12%


GPR52
0.15668353
0.672409
47.46%
63.58%


ROBO2
0.159006583
0.479126
31.60%
32.30%


LRIT2
0.160418783
0.892687
66.37%
54.89%


NEO1
0.165814007
0.14697
13.21%
21.67%


HTR1A
0.168898456
0.856383
85.34%
50.51%


GPR139
0.170003836
0.677189
84.95%
17.37%


NTM
0.174732405
0.326119
23.63%
15.06%


OR2AT4
0.181563681
1
100.00%
43.87%


GPR83
0.183530926
0.427539
41.47%
35.86%


CRB2
0.185182959
0.841715
48.48%
55.31%


PROKR2
0.188278637
0.876786
73.61%
82.42%


OR5B2
0.18899064
0.305426
44.94%
87.64%


KCNK5
0.190722136
0.208355
15.28%
22.81%


GRAMD1B
0.196913999
0.250318
22.64%
21.29%


DCT
0.201840313
0.946325
85.82%
67.11%


ABCA4
0.206010528
0.390735
62.65%
74.46%


SLCO4C1
0.206429019
0.356972
26.87%
13.61%


TAS2R3
0.207462669
0.568402
49.74%
61.60%


IGSF11
0.214244988
0.477973
57.29%
34.47%


GRM6
0.215284295
0.28505
45.09%
49.85%


DPP6
0.216902254
0.572704
47.49%
50.87%


TMPRSS11B
0.23063236
0.858116
80.12%
78.23%


OR1M1
0.231785999
0.243261
100.00%
66.73%


SLC6A5
0.242516959
0.887958
18.10%
22.11%


CLDN19
0.243148596
0.322167
68.34%
95.83%


CA4
0.247950175
0.323519
24.17%
33.03%


OR6M1
0.253167148
0.795195
100.00%
62.25%


MTNR1B
0.255241956
0.736212
37.84%
14.13%


AMIGO1
0.257127443
0.120298
17.73%
16.18%


OR13C5
0.258888071
0.44996
59.55%
82.45%


PCDHGA10
0.26478046
0.514533
36.66%
42.78%


LHFPL1
0.264893521
0.532403
56.72%
22.21%


MYADML2
0.266453215
0.582998
36.92%
17.98%


GRIN2B
0.26961851
0.549027
52.34%
90.29%


CDHR5
0.270982511
0.401615
51.90%
34.09%


MOG
0.27177264
0.574946
35.47%
72.82%


HAVCR1
0.272617302
0.775078
69.71%
88.80%


SLC13A2
0.273916786
0.159327
77.07%
82.46%


SLC36A2
0.277083546
0.85674
38.55%
58.38%


OR1N2
0.278195396
0.826438
72.20%
36.75%


CNTN4
0.282985902
0.359715
25.08%
11.80%


SLC13A4
0.286149647
0.684887
39.63%
35.48%


ABCG2
0.287618112
0.114709
18.94%
36.29%


PCDHGB3
0.295723689
0.224143
49.39%
31.22%


ERBB4
0.308853178
0.382778
63.88%
22.20%


SCN4A
0.316000285
0.821599
74.29%
69.84%


GNRHR
0.316907837
0.370845
45.29%
36.49%


OR13C9
0.320154404
1
100.00%
51.92%


NTSR1
0.323538841
0.59583
71.88%
21.42%


RHCG
0.3241437
0.589922
55.93%
59.63%


TRHDE
0.32461021
0.209551
38.53%
51.77%


MC2R
0.32824809
0.547605
28.09%
57.17%


TAS2R39
0.329819205
1
100.00%
21.20%


GABBR1
0.332121366
0.156281
16.06%
18.13%


OR2B3
0.332675481
0.638935
100.00%
68.26%


PCDHGA7
0.339674098
0.296684
50.30%
40.61%


OR4D5
0.341888191
1
100.00%
47.13%


OR2D3
0.342106411
1
100.00%
46.89%


ABCB5
0.342783624
0.471764
35.66%
50.00%


CLRN1
0.347252491
0.952459
60.52%
98.20%


OR10A2
0.347589078
0.771626
100.00%
53.29%


PCDHGB2
0.361183917
0.477259
40.15%
18.37%


PCDHB12
0.364157737
0.281814
29.46%
13.75%


GRIA3
0.369555756
0.698176
18.87%
54.57%


MCHR1
0.370920252
0.382421
21.56%
30.68%


LRP4
0.378169328
0.325013
22.85%
11.48%


P2RX3
0.386829077
0.577645
53.99%
60.97%


TSPAN9
0.387084489
0.135846
10.34%
11.74%


KL
0.39392264
0.275568
29.86%
14.63%


SLC22A7
0.394749732
0.27349
51.46%
29.12%


UNC5B
0.399400787
0.158693
13.43%
12.45%


OR13D1
0.404831148
0.897819
41.36%
41.69%


GPR75
0.413547524
0.237937
20.28%
21.19%


SLCO1C1
0.416225466
0.133394
42.35%
59.99%


MUC22
0.440017184
0.601891
66.90%
55.21%


OR6V1
0.442695436
0.555368
81.88%
74.35%


MRGPRX4
0.44826783
0.484448
92.44%
57.78%


SLC4A4
0.448708428
0.409485
16.13%
18.64%


PCDHGA3
0.449935602
0.213279
40.07%
32.75%


OR1J1
0.455981474
0.324754
58.42%
23.70%


KCNG4
0.459670925
0.994065
98.79%
98.87%


OR13C2
0.464840185
0.222588
100.00%
45.32%


CASR
0.466024726
0.962777
46.88%
10.97%


PCDHGA8
0.469031739
0.387423
35.03%
41.07%


VN1R1
0.472551441
0.117911
29.86%
12.99%


OPN1SW
0.473487393
0.45325
83.91%
64.80%


OR9A2
0.476528085
0.359129
100.00%
62.99%


CSPG4
0.477082831
0.120924
16.17%
16.63%


DSG3
0.481302846
0.559901
57.02%
39.80%


GP6
0.483885944
0.472588
92.84%
26.29%


PCDHGB5
0.48553214
0.147241
52.04%
36.16%


OR1D5
0.486429736
1
100.00%
11.18%


AQP8
0.498490745
0.202887
46.22%
19.49%


CLCA4
0.499403367
0.883559
99.99%
89.75%


OR1L6
0.501994688
0.60964
100.00%
49.06%


SLC22A8
0.502894037
0.994337
98.97%
97.81%


GLRA1
0.50704449
0.976348
78.86%
88.16%


SUSD4
0.508846555
0.102802
28.87%
10.67%


TMPRSS11D
0.509886637
0.742177
82.71%
88.26%


SLC39A12
0.517221977
0.892125
79.08%
85.94%


CLCA2
0.522402852
0.273613
77.24%
66.05%


MFAP3L
0.52417151
0.105193
40.02%
16.15%


IMPG2
0.532722645
0.719932
83.25%
81.73%


OR5212
0.539612371
0.69605
100.00%
32.57%


LRIT1
0.541321911
0.929516
97.24%
97.89%


KCNV2
0.544091315
0.566779
55.27%
64.67%


OR1N1
0.547414613
0.798429
96.53%
88.63%


CLDN22
0.551313616
0.662127
98.20%
81.23%


SLC22A9
0.56629364
0.350639
71.92%
41.29%


OR14C36
0.570417938
0.356931
100.00%
61.64%


MRGPRX3
0.573764198
0.284008
15.99%
27.21%


HCAR1
0.5826713
0.19976
25.11%
26.17%


EPHA6
0.595670482
0.554812
80.43%
26.33%


OR2Z1
0.612170105
1
29.55%
39.09%


LCT
0.61778556
0.373601
44.96%
14.48%


PCDHA6
0.618019459
0.175603
60.70%
17.24%


PCDHGA4
0.618662906
0.12113
32.29%
13.15%


OR52W1
0.619688955
0.528846
49.71%
17.53%


OR13H1
0.628874747
0.346694
100.00%
22.41%


NMUR1
0.63483045
0.216403
33.89%
12.71%


OR5211
0.657234086
0.642073
37.79%
15.85%


TARM1
0.685020329
0.784951
12.28%
46.26%


TM4SF5
0.694652044
0.340664
53.14%
14.05%


GPR149
0.69635078
0.749785
10.71%
26.22%


GFRA4
0.703845483
0.778663
62.37%
17.40%


OR1B1
0.708505177
0.378375
34.98%
55.46%


CHRND
0.710960838
0.846842
76.70%
81.34%


OR2F1
0.713967693
0.686266
69.59%
17.75%


LY6G6C
0.714657465
0.185904
16.76%
28.41%


OR1L4
0.721171266
0.803927
31.58%
15.86%


MMEL1
0.724478565
0.320165
40.57%
19.03%


SSTR1
0.732605159
0.253167
22.25%
11.70%


RPRML
0.738811204
0.197745
27.90%
16.19%


OR4D10
0.760540662
0.807299
38.40%
20.73%


OR2T4
0.762070001
0.429879
100.00%
33.52%


CHRNA9
0.765428876
0.323677
25.70%
23.22%


SLC36A3
0.770560357
0.387518
37.75%
41.67%


SLC16A7
0.774871818
0.643722
32.04%
34.81%


GPR62
0.817990691
0.231936
26.97%
15.37%


OR4F21
0.823925642
0.458609
76.75%
19.24%


PCDHA10
0.825875628
0.185558
34.94%
40.43%


ZPLD1
0.852730583
0.606046
72.78%
37.88%


OR10A4
0.866305563
0.332936
13.24%
49.47%


OR4D1
0.896989595
0.646802
55.15%
30.11%


OR12D2
0.901044732
0.287823
39.59%
57.47%


ABCB11
0.918969979
0.450684
19.43%
13.04%


RAET1E
0.921247241
0.10264
26.48%
14.95%


OR51I2
0.964945223
0.433546
37.37%
22.50%


TMEM145
9.22598E−14
0.655183
34.42%
8.48%


TMEM63C
7.09855E−12
0.777888
41.17%
5.64%


APLP1
2.25526E−10
0.625369
26.50%
1.87%


NCAM1
8.41352E−07
0.356423
35.62%
2.38%


FAM171A2
1.78318E−06
0.382009
16.84%
2.68%


LPHN1
2.84774E−06
0.404436
29.66%
3.91%


CASD1
3.37792E−06
0.296332
19.59%
3.45%


NRCAM
1.33462E−05
0.40223
30.45%
7.53%


FAM174B
7.15263E−05
0.210908
19.06%
1.62%


TRIL
0.000107965
0.013682
16.90%
50.29%


DLK1
0.000174424
0.704542
20.38%
6.06%


KIAA0319
0.000239135
0.739105
33.78%
4.33%


CATSPERG
0.000885557
0.684191
49.75%
4.40%


GPR3
0.000960266
0.522747
24.50%
8.95%


DLK2
0.000978658
0.628065
28.52%
0.45%


KITLG
0.001094693
0.383245
21.14%
7.43%


RGMB
0.001584362
0.297021
12.49%
2.24%


SLC17A7
0.00189443
0.828683
6.62%
60.50%


CDH2
0.001994447
0.284006
10.71%
5.15%


KIRREL3
0.002490788
0.66314
25.72%
9.07%


BACE1
0.002659259
0.250099
17.96%
4.95%


KCNJ4
0.003522998
0.500352
0.61%
80.98%


GPR158
0.003849924
0.518036
48.45%
2.89%


LTB4R
0.003965967
0.350999
15.28%
8.30%


HRH3
0.004660425
0.711668
29.43%
2.01%


VSIG10
0.004738031
0.123191
17.79%
9.45%


ACVR2A
0.004792428
0.241655
13.98%
9.04%


ELFN1
0.005088737
0.346393
3.99%
49.61%


EPHA8
0.006531534
0.738639
63.04%
6.78%


PIEZO2
0.007216505
0.405748
8.04%
43.58%


GDPD5
0.00854805
0.042827
10.86%
25.91%


TSPAN18
0.008579339
0.045618
13.06%
37.82%


PANX2
0.009130224
0.502185
25.99%
6.56%


PTPRD
0.01030759
0.606429
50.63%
0.74%


SCN5A
0.011288902
0.013622
58.46%
46.05%


CLSTN1
0.01129717
0.160739
7.07%
8.18%


SLC12A6
0.01499558
0.182437
9.47%
23.37%


ADAM23
0.015480096
0.495738
10.39%
6.53%


DSCAM
0.017423827
0.646519
40.36%
3.58%


PLXNB1
0.017711547
0.094547
20.23%
5.73%


ANKH
0.0200025
0.208604
12.92%
2.19%


LRRN1
0.02076384
0.219567
9.45%
37.36%


MEGF8
0.02101423
0.19617
17.84%
9.03%


SLC38A1
0.022598169
0.090327
16.01%
1.49%


MAMDC4
0.027720219
0.356046
18.26%
3.76%


PSEN1
0.031499183
0.106095
4.01%
0.61%


TSPAN11
0.037174733
0.405398
29.57%
3.30%


SLC5A3
0.038078188
0.115521
16.48%
4.36%


ABCA5
0.04035996
0.313357
7.93%
1.59%


FZD1
0.041069243
0.19179
5.44%
2.70%


KIAA0247
0.046560714
0.146324
8.73%
6.21%
















TABLE 5







Surface proteins associated with the SCLC-N subtype from the cell line dataset











Surface Protein
ANOVA p value
N vs P
N vs I
N vs A














CMKLR1
2.10309E−10
0.994633
33.60%
89.35%


LRFN1
3.89482E−10
0.295799
39.58%
81.19%


SLC38A5
1.78419E−09
0.657236
63.58%
73.57%


ADAM11
1.37199E−08
0.290907
23.10%
69.87%


SYP
2.98276E−08
0.467823
30.20%
12.74%


SGCD
9.04582E−08
0.742385
72.77%
43.41%


SSTR2
 1.4378E−07
0.350274
53.14%
23.09%


SLC6A11
2.82888E−07
0.573283
42.82%
81.88%


ADCYAP1R1
8.02109E−07
0.444487
43.26%
66.45%


GSG1L
1.32378E−06
0.994036
45.92%
87.83%


SLC8A2
1.36584E−06
0.890928
33.16%
32.79%


ITGA4
1.48775E−06
0.454622
33.54%
45.75%


ATP1A3
 1.6528E−06
0.445611
36.38%
27.31%


ASIC1
1.69302E−06
0.187793
11.43%
38.78%


CA12
2.09371E−06
0.778806
33.32%
71.92%


SLC17A7
 2.5024E−06
0.498776
32.85%
56.07%


TYRO3
2.63407E−06
0.204461
11.24%
38.18%


LPAR3
4.24829E−06
0.361683
33.54%
73.21%


IGDCC3
5.00197E−06
0.307074
44.73%
55.91%


RTN4R
5.29657E−06
0.305786
57.86%
70.96%


CHRNA1
5.88627E−06
0.689204
73.15%
46.57%


ALPL
6.92758E−06
0.615717
24.45%
59.55%


SLC1A7
8.03356E−06
0.69823
45.19%
81.69%


TSPAN18
9.24494E−06
0.686971
36.83%
44.37%


SCN1B
1.08198E−05
0.820102
52.22%
61.39%


SLC6A1
2.74093E−05
0.78869
26.98%
69.88%


NRP2
2.76937E−05
0.237101
32.55%
35.10%


NTRK1
3.84528E−05
0.684687
75.66%
72.50%


TTYH2
4.06324E−05
0.592126
26.28%
32.44%


RTN4RL1
6.22085E−05
0.729972
10.86%
57.97%


SLC24A2
 6.4919E−05
0.875798
71.72%
34.95%


SLC7A14
7.20474E−05
0.443543
61.36%
12.11%


SLC18A3
7.63537E−05
0.147922
13.09%
74.04%


DRD2
0.000112404
0.396977
59.58%
19.18%


SHISA6
0.000134903
0.642699
31.33%
93.18%


ADCY7
0.000180527
0.232925
12.65%
21.78%


GRID2
0.000196834
0.538033
46.30%
46.92%


CNTN2
0.000209409
0.66165
37.26%
35.85%


KIRREL2
0.000295177
0.71616
43.48%
54.88%


ATP2B2
0.00029904
0.329493
35.48%
37.03%


GPR162
0.000423418
0.524142
13.19%
22.53%


IGSF11
0.000487053
0.301721
43.64%
33.49%


L1CAM
0.000727162
0.510092
41.21%
24.64%


LAYN
0.000741021
0.459238
35.88%
42.64%


KREMEN1
0.000814766
0.121875
24.25%
16.72%


THSD7B
0.000838425
0.384433
46.74%
38.96%


ROBO3
0.000870343
0.367212
10.48%
64.52%


GPR26
0.00088841
0.880061
100.00%
70.29%


GSG1
0.000900923
0.361862
15.67%
28.75%


GRIN2A
0.00090401
0.75203
53.87%
58.17%


EDA
0.000940211
0.390899
45.06%
50.17%


NGFR
0.000960785
0.803926
50.04%
78.38%


UNC5A
0.001036332
0.487779
45.32%
13.45%


GRIN2D
0.001044269
0.704023
56.99%
44.67%


LPPR5
0.001085015
0.354221
44.70%
50.23%


ATP1B2
0.00108724
0.344437
29.53%
49.63%


TMEM145
0.0011529
0.57685
15.99%
13.34%


GPR112
0.001296029
0.61633
43.01%
47.90%


IL2RG
0.001403184
0.99565
60.99%
55.93%


DPP4
0.001485449
0.505435
16.67%
38.05%


GABRB1
0.001515832
0.382421
71.83%
60.89%


LINGO1
0.001671438
0.175328
15.44%
34.85%


NTNG2
0.001704225
0.762589
53.84%
50.70%


SPNS2
0.001736529
0.255798
12.09%
29.05%


CA4
0.001737829
0.996609
46.64%
59.45%


DCC
0.001763163
0.611819
43.98%
29.89%


TRHDE
0.001799068
0.383545
52.28%
34.28%


CELSR2
0.002040013
0.121845
16.11%
14.90%


TSPAN7
0.002083182
0.238869
49.83%
24.13%


MC4R
0.00208658
0.870939
55.25%
37.07%


SEMA6B
0.002106013
0.757251
14.52%
34.40%


GABBR2
0.002129002
0.532527
41.64%
31.47%


P2RX1
0.00237415
0.993415
85.54%
67.36%


PTPRU
0.002397912
0.466814
28.44%
24.41%


LRTM2
0.002527202
0.717192
66.22%
59.82%


GABRA1
0.002636514
0.474428
69.15%
56.25%


NRXN2
0.002983103
0.376875
41.40%
42.94%


RPRML
0.003139945
0.306696
89.14%
53.12%


SLC22A8
0.003165052
0.770627
37.60%
78.30%


OR2H2
0.003310359
0.179019
26.05%
71.59%


SLC13A2
0.003800078
0.992882
59.02%
70.66%


SLC4A1
0.004556806
0.993162
15.74%
67.70%


CADM3
0.004840547
0.213281
66.08%
54.39%


CDHR1
0.00484115
0.459116
54.28%
19.66%


KCNJ3
0.004842937
0.447606
42.17%
42.06%


GABRA5
0.005154631
0.691099
49.46%
45.06%


KCNA3
0.0051888
0.378066
69.22%
24.06%


ABCC9
0.005193669
0.235473
12.88%
23.40%


SLC5A10
0.005218323
0.764052
48.17%
47.21%


CDH23
0.005255963
0.179502
18.66%
32.68%


GRM4
0.005587357
0.359874
45.93%
35.12%


DCT
0.006553942
0.643339
40.79%
29.24%


CHRND
0.006605221
0.617916
40.04%
65.48%


CDH7
0.006638763
0.618596
49.10%
25.69%


SUSD4
0.007377705
0.179487
40.25%
20.74%


SLC2A5
0.008238736
0.746701
22.84%
64.33%


SCN3B
0.008502617
0.243491
49.90%
19.07%


RTN4RL2
0.008820049
0.143139
34.66%
26.27%


HCAR3
0.008901462
0.68062
100.00%
60.12%


GRIN1
0.009078367
0.438567
75.12%
38.31%


NKAIN1
0.009642192
0.238997
28.49%
39.00%


SLC6A15
0.011264412
0.311918
21.00%
30.96%


CNTFR
0.011542929
0.51033
17.29%
38.92%


MDGA1
0.011585819
0.555585
14.59%
27.33%


EFNB1
0.011717381
0.237674
18.21%
31.38%


PCDH9
0.011810994
0.399979
24.32%
21.27%


ADORA3
0.012479083
0.23585
45.66%
75.94%


JAM2
0.014074375
0.182362
17.16%
25.17%


PTCHD2
0.016059586
0.578433
31.55%
17.98%


PTGFR
0.017080087
0.418004
27.46%
60.53%


HRH2
0.018605611
0.994053
19.38%
55.05%


APCDD1
0.018901357
0.486097
36.09%
42.53%


SUSD2
0.019612785
0.519213
34.52%
49.03%


CDH5
0.019710644
0.995518
68.16%
50.61%


SLCO4A1
0.02063237
0.258444
37.55%
39.35%


CHRNB4
0.022963416
0.253687
21.69%
48.54%


ADAM23
0.023793566
0.201117
25.79%
12.26%


GLP1R
0.023976932
0.384716
70.15%
47.25%


MEGF10
0.024891723
0.55549
16.40%
43.50%


GJD2
0.025351565
0.7403
85.67%
59.13%


NFAM1
0.025487119
0.994087
58.15%
41.45%


SLC46A2
0.025594673
0.323981
87.03%
27.75%


SLAMF1
0.027767997
0.992634
62.66%
74.52%


CHODL
0.029090402
0.297406
60.12%
21.76%


CACNA1C
0.030212047
0.203719
39.22%
14.86%


FNDC5
0.030917088
0.261243
27.07%
16.69%


SEMA5B
0.031412403
0.292277
23.64%
34.84%


TMEFF1
0.033544969
0.373938
86.67%
15.93%


ROR1
0.035371532
0.243011
22.08%
23.12%


NPHS1
0.036023319
0.995355
35.92%
27.66%


PRIMA1
0.036222923
0.326878
49.72%
33.84%


NPBWR2
0.037312881
0.172744
36.82%
47.18%


OR4F4
0.037514132
0.710837
44.21%
63.19%


ANTXRL
0.038021714
0.684813
19.46%
66.63%


THSD1
0.038144284
0.105326
26.56%
23.01%


GRM2
0.038277571
0.18788
49.84%
11.24%


ISLR2
0.039237948
0.790982
62.45%
10.29%


NTRK3
0.03961383
0.157584
38.91%
50.97%


SLITRK2
0.040807522
0.996703
58.42%
56.27%


ATP2B3
0.040933239
0.259398
37.97%
23.95%


SLC6A18
0.041500349
0.990155
100.00%
59.64%


CDH24
0.043112033
0.135478
15.85%
16.32%


KCNJ4
0.043328163
0.488501
71.06%
69.25%


HEPACAM
0.043981912
0.529568
31.42%
70.48%


OPRK1
0.044515264
0.482909
70.71%
32.76%


ADAM7
0.045375168
0.640254
38.89%
48.37%


P2RX3
0.046827172
0.710298
75.59%
58.24%


NTSR1
0.047718717
0.701568
39.60%
57.02%


EPHA8
0.04818322
0.425589
45.88%
35.55%


GPR128
0.050343275
0.857379
30.70%
57.17%


HTR3A
0.050668866
0.994507
77.79%
11.76%


GPR132
0.053112532
0.527031
100.00%
63.50%


SCN10A
0.053666478
0.745732
28.40%
59.70%


KREMEN2
0.053743604
0.423298
57.48%
56.54%


SLC17A6
0.054454318
0.500605
33.02%
38.37%


SLC22A17
0.05610198
0.343078
28.69%
34.59%


CLEC17A
0.060527134
0.261234
46.72%
62.53%


FOLR1
0.060997887
0.744579
100.00%
39.12%


TMEM225
0.061326362
0.416335
84.90%
64.68%


TMEM158
0.061563453
0.185954
15.25%
25.74%


SLC6A3
0.063368804
0.761258
56.75%
13.58%


CD163L1
0.063766131
0.190876
36.57%
43.36%


P2RY2
0.064606611
0.358441
42.33%
56.35%


OR10G6
0.066681201
0.337719
42.08%
74.02%


HRH4
0.066896804
0.211265
26.40%
26.54%


ESAM
0.067925809
0.116218
50.16%
36.09%


CD34
0.069053757
0.708813
17.97%
34.88%


GABRB2
0.071058093
0.287005
46.49%
27.13%


EQTN
0.071170782
0.366985
61.97%
39.63%


CCR4
0.072963763
0.681381
44.61%
61.98%


FCGR3B
0.075475097
0.398595
21.13%
63.24%


TMEM132E
0.078663019
0.890608
44.60%
42.21%


CACNA1G
0.079889527
0.656978
13.94%
25.13%


SLC5A5
0.080196733
0.990552
54.33%
59.06%


KCNJ12
0.082526325
0.601294
12.77%
48.72%


MIP
0.084603583
0.989031
100.00%
29.44%


HTR7
0.085060074
0.597565
52.08%
40.32%


GPR4
0.086853398
0.493402
25.78%
45.76%


GFRA1
0.091389977
0.31121
30.99%
45.59%


CHRNA4
0.092519633
0.463322
26.48%
55.71%


ITGA9
0.098490005
0.358721
26.47%
11.87%


GPR179
0.098980368
0.303806
25.92%
24.65%


CD19
0.099054329
0.780064
64.49%
46.73%


OR1F1
0.100497141
0.645749
33.17%
42.09%


OR4D5
0.100897942
0.301125
77.60%
69.39%


ADRA1B
0.102760655
0.987997
13.63%
69.32%


TSHR
0.103255459
0.223669
21.66%
23.71%


P2RX2
0.106303874
0.200903
79.16%
55.06%


CD3G
0.108333756
0.691807
100.00%
48.15%


CATSPERD
0.11451802
0.416627
30.67%
14.70%


LILRB3
0.118444169
0.99204
20.15%
31.06%


GPR62
0.119117633
0.171653
30.99%
38.51%


RAETIL
0.122171319
0.988156
100.00%
60.74%


SCN5A
0.125197844
0.12765
26.02%
27.05%


NALCN
0.126324161
0.288302
50.00%
17.14%


CACNG5
0.126702297
0.801518
23.59%
43.55%


TACR2
0.12872173
0.991203
79.94%
50.99%


P2RX6
0.132137039
0.42925
58.55%
41.37%


DISP2
0.136632357
0.368852
12.80%
17.22%


ASIC4
0.137388371
0.603354
56.16%
31.18%


CDH18
0.137540096
0.540003
20.13%
32.63%


CD80
0.139564702
0.225716
31.93%
10.98%


KIR2DL3
0.140628153
0.990679
49.43%
62.79%


IL10RA
0.142512933
0.143167
59.22%
19.44%


GABRA4
0.142536482
0.188001
47.22%
53.33%


SV2C
0.144743159
0.636311
57.08%
41.65%


GPR182
0.150943639
0.138552
55.49%
41.75%


SLAMF6
0.154931463
0.99269
13.54%
52.07%


ITGB2
0.156420219
0.988004
46.31%
55.62%


MUC12
0.166002909
0.186138
16.87%
24.63%


MSLNL
0.167171263
0.197801
100.00%
16.18%


CDH11
0.168646986
0.417411
27.47%
38.02%


PLXNA4
0.169702081
0.460245
20.46%
23.40%


IZUMO3
0.170663536
0.993242
35.87%
44.19%


CLDN11
0.175655291
0.433906
32.20%
13.43%


IL2RB
0.175689643
0.721105
42.21%
58.92%


RXFP2
0.178376998
0.217354
50.79%
45.03%


GRIA2
0.184534204
0.380533
16.88%
13.10%


ITGAM
0.186462375
0.992467
32.71%
34.46%


GABRA3
0.198028647
0.151829
34.41%
13.18%


TMEM106A
0.199951886
0.115534
16.91%
18.10%


UNC5D
0.202116639
0.648594
16.02%
27.90%


GPBAR1
0.202194834
0.989678
30.39%
35.56%


OPN1LW
0.203298156
0.634641
74.45%
59.93%


KCNV2
0.204382861
0.44157
21.37%
30.13%


SLC29A4
0.204428529
0.195657
12.10%
19.28%


CD28
0.207056522
0.99023
40.77%
42.46%


LAMP5
0.212140025
0.629302
16.73%
26.94%


CDH22
0.213523399
0.316892
42.90%
29.01%


CD244
0.214199101
0.670223
43.02%
62.53%


NRN1
0.21922131
0.413486
31.63%
35.04%


SLC1A2
0.224572726
0.141188
23.08%
21.40%


OR6T1
0.22917947
0.693875
100.00%
51.35%


ABCA8
0.230173119
0.448978
23.60%
22.18%


LRP3
0.232840961
0.635271
79.69%
37.56%


GABRA6
0.237650836
0.448059
100.00%
47.31%


SLC5A11
0.258308171
0.489338
22.42%
25.77%


CACNA1I
0.259023484
0.423733
31.86%
39.64%


HTR3D
0.272879718
0.629849
41.34%
50.01%


GRIK5
0.276461966
0.132461
32.16%
21.24%


OR8D4
0.28003768
0.984577
100.00%
61.68%


KCNK5
0.28098548
0.120781
46.90%
32.86%


CEACAM20
0.284553421
0.146899
100.00%
13.70%


PRLHR
0.29414723
0.509059
77.77%
55.19%


CACNG3
0.295588554
0.99419
73.19%
48.63%


EFNB3
0.315241589
0.165782
24.15%
14.50%


GGT3P
0.317782258
0.480757
51.23%
42.03%


IL9R
0.322374188
0.988545
48.86%
18.96%


SLC13A1
0.324645648
0.177374
56.62%
31.51%


IL21R
0.326899933
0.989428
29.42%
41.65%


IL12RB1
0.329517537
0.315774
39.97%
41.71%


FNDC4
0.330023313
0.326219
16.44%
50.37%


CD84
0.342037245
0.988013
15.16%
54.32%


FCGR2B
0.344726618
0.629271
33.76%
45.64%


UNC5B
0.3500249
0.283174
15.67%
13.14%


LHFPL4
0.359516303
0.581902
33.68%
27.93%


SLITRK1
0.360713323
0.459576
32.17%
15.41%


FAM171A2
0.364242476
0.707878
26.71%
13.84%


LRRC52
0.368908866
0.986423
64.18%
52.75%


SORCS2
0.381578535
0.266461
29.39%
11.33%


ATP1B4
0.406298514
0.987941
40.69%
23.38%


PLD5
0.427057522
0.357964
23.81%
12.14%


CD22
0.4272725
0.421516
28.85%
53.43%


LRFN2
0.428594101
0.44242
44.27%
23.40%


ENG
0.428716467
0.251264
49.68%
14.77%


BEST2
0.431081339
0.986523
56.01%
22.91%


CEACAM3
0.433555458
0.633021
73.49%
32.48%


SCARA5
0.434417137
0.250507
22.98%
49.38%


GPR84
0.456789252
0.621749
32.17%
11.01%


CACNG2
0.464836781
0.420652
38.08%
25.22%


CNTN1
0.465118408
0.19038
28.56%
15.45%


TMPRSS6
0.47137444
0.268083
39.11%
17.21%


LAG3
0.472254409
0.209448
22.43%
15.32%


SLC39A12
0.472461668
0.536181
32.26%
46.72%


SLCO2B1
0.482772795
0.593375
78.08%
31.80%


NKAIN3
0.488481981
0.388975
42.99%
39.64%


EDA2R
0.491285835
0.60597
17.88%
39.87%


CHRNB3
0.494834883
0.993082
30.98%
20.01%


LILRA2
0.497229088
0.979169
54.25%
56.50%


MC5R
0.502098427
0.990584
24.45%
35.99%


CD177
0.524615525
0.524602
100.00%
57.50%


PRPH2
0.530742822
0.601163
16.14%
37.43%


GHRHR
0.532953844
0.666291
22.38%
37.02%


GRID1
0.540289247
0.416137
20.36%
12.40%


TIE1
0.546505104
0.636402
13.85%
24.83%


RGR
0.55619227
0.705131
23.42%
51.08%


OR5AK3P
0.568639971
0.984924
100.00%
30.48%


PIGR
0.594033022
0.989134
44.92%
19.66%


CNTN3
0.597952987
0.291838
26.77%
17.96%


OR9K2
0.599544888
0.989015
50.83%
24.90%


FLRT2
0.6014282
0.116162
13.27%
11.54%


CD33
0.604088847
0.990909
53.91%
43.89%


GPR12
0.604440163
0.288298
42.12%
32.24%


OTOP2
0.630371681
0.43103
28.75%
41.61%


CSF3R
0.63851776
0.225314
31.46%
36.91%


DRD4
0.64210982
0.17982
36.22%
35.40%


SLC32A1
0.668412006
0.989054
33.30%
18.78%


EMR1
0.688837005
0.609496
16.90%
36.00%


OR51B6
0.690240883
0.285373
72.24%
15.43%


SLC11A1
0.692583273
0.539562
32.32%
44.84%


VNN3
0.693805196
0.980375
55.26%
18.10%


OR5H1
0.697717759
0.975923
21.42%
50.26%


SLAMF7
0.714983665
0.982987
44.47%
25.40%


NCAM2
0.720550155
0.143248
28.13%
13.53%


OPN5
0.733138726
0.476409
43.29%
11.61%


SHISA7
0.735659952
0.359804
27.03%
19.78%


OR11H2
0.740117488
0.322261
35.71%
29.55%


LY9
0.766677765
0.985067
14.03%
22.24%


PIEZO2
0.781736941
0.210634
24.06%
13.69%


QRFPR
0.790602115
0.661764
11.89%
23.84%


KIR2DS4
0.810759799
0.454782
23.88%
42.53%


FLT3LG
0.816222367
0.437917
19.03%
18.76%


C3AR1
0.830058634
0.205067
25.06%
25.11%


CD200R1L
0.844930358
0.108784
18.79%
17.73%


EMCN
0.873427457
0.158966
14.47%
19.92%


SIGLEC9
0.874007162
0.515003
29.71%
37.99%


AGTR2
0.884431885
0.599187
29.61%
12.42%


CD1E
0.88552805
0.977289
48.22%
18.34%


GPR133
0.89195899
0.303044
21.46%
13.99%


PEAR1
0.906066466
0.41424
23.50%
14.18%


ACVRL1
0.917990908
0.468943
21.40%
12.89%


OR7D2
0.935890303
0.393953
21.17%
17.74%


AOC3
0.936843859
0.116334
32.48%
12.88%


SEMA6D
4.46585E−12
0.317069
42.23%
4.32%


SLC5A6
1.07987E−09
0.107876
4.56%
17.95%


IGDCC4
 7.547E−07
0.101576
3.90%
47.41%


NFASC
1.19209E−06
0.357136
11.66%
0.57%


SLC47A1
1.21018E−06
0.576145
9.13%
47.16%


PCDH8
1.93596E−06
0.57831
64.52%
9.05%


SCARB1
2.06522E−06
0.170988
3.76%
24.15%


TSPAN13
2.29062E−06
0.044154
28.50%
2.55%


SEZ6
 4.4758E−06
0.397072
36.10%
3.74%


GABRR3
5.44958E−06
0.099033
91.64%
75.94%


FGFR2
6.71968E−06
0.070438
11.05%
41.79%


UNC5C
1.44512E−05
0.232361
1.69%
58.33%


PROCR
2.31358E−05
0.857643
5.20%
66.86%


PTPRN
2.42204E−05
0.640559
79.11%
9.87%


FZD7
3.49328E−05
0.230408
9.41%
38.30%


ITGA7
3.61828E−05
0.226449
3.72%
45.06%


SLC6A8
4.25538E−05
0.0428
9.56%
22.43%


IFNAR2
 4.4031E−05
0.048092
13.05%
8.93%


ANKH
5.17024E−05
0.114017
22.51%
4.72%


CHRNA7
7.47711E−05
0.09178
23.63%
38.77%


KIRREL
0.000102951
0.051516
3.48%
55.10%


SLC16A1
0.000109136
0.017519
2.32%
13.17%


LRP8
0.000122092
0.08106
7.32%
10.02%


GRIK3
0.00014315
0.473278
58.39%
6.05%


HAVCR1
0.000231816
0.437585
8.48%
48.67%


SLC24A4
0.00029119
0.588864
4.20%
61.94%


ABCC1
0.000367086
0.082036
2.51%
12.09%


ADAM22
0.000686889
0.043486
17.07%
0.36%


SLC26A4
0.000702325
0.07637
30.76%
33.93%


QSOX2
0.000738608
0.180563
9.75%
1.17%


CD4
0.000771855
0.021375
17.30%
47.77%


ACVR2A
0.000817634
0.070081
13.08%
1.09%


SLC46A1
0.000843757
0.157026
14.50%
7.70%


GPM6B
0.000858494
0.040771
16.26%
6.57%


TSPAN9
0.001071511
0.39753
0.12%
36.21%


SEZ6L2
0.001073125
0.324529
12.66%
3.52%


SYNPR
0.001438554
0.278522
83.05%
9.99%


ABCC4
0.001463226
0.028498
12.30%
23.91%


SLC29A2
0.001528701
0.359304
0.27%
22.31%


P2RY11
0.002550368
0.361858
2.61%
18.43%


GABRB3
0.002714039
0.421604
32.05%
9.71%


AMIGO1
0.002827694
0.123021
7.88%
21.64%


CXCR6
0.002924358
0.014913
14.00%
15.51%


FZD3
0.003412621
0.008765
21.25%
1.48%


RNF149
0.003809296
0.014678
4.00%
6.88%


ATP1B3
0.003954213
0.091451
3.59%
5.25%


NEO1
0.003978507
0.07129
10.47%
13.65%


MFSD2A
0.004074467
0.260661
33.29%
2.25%


SLC39A10
0.004413382
0.018327
4.18%
6.96%


IGSF9B
0.005258068
0.423308
23.72%
4.41%


ROBO2
0.005392348
0.486235
8.14%
22.18%


SLC2A2
0.005957685
0.088545
2.16%
30.39%


PODXL2
0.007807708
0.049172
21.38%
9.04%


CHRNA5
0.007954016
0.025146
19.48%
5.25%


TMEM132A
0.009928634
0.15216
1.63%
17.23%


ATP13A2
0.010573131
0.08218
0.45%
14.87%


RAMP2
0.01343539
0.615989
4.39%
27.87%


SLC2A4
0.014307518
0.72817
6.00%
44.04%


HM13
0.015066921
0.091903
1.80%
6.67%


CSPG5
0.01783607
0.056108
12.28%
18.88%


GPR113
0.02295274
0.036293
13.97%
16.62%


SLC12A5
0.024254771
0.337997
16.82%
4.50%


TMEM63C
0.024839859
0.316701
23.23%
4.36%


SLC44A3
0.025003433
0.001446
24.67%
1.76%


ADCY5
0.02720106
0.556833
10.50%
4.57%


EPHA5
0.027531537
0.348035
4.62%
29.40%


MPZL1
0.027615682
0.072514
1.03%
6.14%


ABCA4
0.029199146
0.741878
5.96%
36.13%


GPC6
0.02990218
0.100929
22.95%
6.15%


TAS2R16
0.030836847
0.361952
3.85%
72.28%


PTGFRN
0.031848681
0.002821
4.08%
11.19%


TGFBR1
0.032281711
0.09396
7.26%
5.44%


GRIA4
0.032638813
0.294853
31.84%
7.00%


ANO5
0.03292595
0.173622
24.39%
2.17%


GPR63
0.033174637
0.023425
30.21%
10.90%


TMEFF2
0.033210008
0.019234
41.02%
16.98%


TSPAN5
0.035010843
0.052429
26.50%
21.62%


IMPG2
0.03890453
0.366464
6.37%
15.96%


GPR173
0.041864014
0.11082
26.11%
7.01%


IGF1R
0.042444353
0.037877
4.58%
9.60%


CLSTN2
0.042626103
0.072209
37.69%
9.79%


GPR3
0.043933031
0.26419
2.25%
13.32%


LDLRAD3
0.045160096
0.018361
10.73%
12.48%


SLC39A8
0.045735119
0.068626
21.31%
13.59%


RNF150
0.045853947
0.077915
8.40%
17.20%
















TABLE 6







Surface proteins associated with the SCLC-N subtype from the Sato dataset











Surface Protein
ANOVA p value
N vs A
N vs P
N vs I














CHRNA9
5.05448E−08
0.120157
45.912%
72.111%


GRM8
3.96474E−07
0.355071
80.993%
76.876%


SEZ6
1.03337E−06
0.139193
76.746%
75.267%


LRFN5
1.81258E−06
0.158124
66.122%
55.978%


UMODL1
1.82838E−06
0.38338
34.606%
43.204%


SLC17A6
3.22336E−06
0.524894
73.828%
67.211%


ADRA2A
6.51148E−06
0.115274
60.917%
56.850%


LYPD1
9.67515E−06
0.100733
54.238%
45.481%


CHRNA3
9.68903E−06
0.21799
64.120%
48.008%


SLCO4C1
2.61247E−05
0.185723
26.358%
18.216%


FZD6
3.18865E−05
0.140046
13.137%
16.090%


DLK1
0.000116332
0.193184
62.136%
47.937%


PTCHD1
0.000228436
0.632619
63.818%
66.797%


SEMA6A
0.001402726
0.289802
50.996%
32.395%


LRP12
0.001655218
0.108132
17.170%
29.620%


CLSTN2
0.00193009
0.144353
52.121%
50.970%


NRG1
0.003235572
0.154046
60.232%
25.135%


DCC
0.003547465
0.566922
46.824%
63.911%


GPR161
0.003619516
0.21023
18.249%
17.966%


ADAM23
0.005311949
0.204287
63.098%
25.644%


SSTR2
0.006876376
0.190847
30.143%
29.927%


DSCAML1
0.007401821
0.133409
38.334%
54.470%


NRP1
0.007847671
0.525123
32.142%
32.762%


TRHDE
0.007956922
0.492265
56.800%
44.898%


GRAMD1B
0.008010425
0.159664
36.605%
30.847%


TMEM106A
0.008322271
0.414556
32.818%
40.949%


RPRM
0.008765948
0.139974
27.699%
34.039%


LY6H
0.008792535
0.253085
57.908%
44.754%


TNFRSF19
0.009987767
0.192521
35.433%
14.841%


CLRN1
0.010076298
0.285813
52.537%
55.581%


GPR55
0.01070931
0.646909
47.699%
34.856%


NTNG2
0.010800069
0.455904
55.852%
39.647%


EPHB2
0.011331235
0.235891
28.950%
24.949%


SGCD
0.011746661
0.350728
45.133%
48.681%


MMP16
0.014956634
0.334138
50.321%
61.710%


OR8G2
0.015622399
0.105404
50.108%
59.996%


PLXNB1
0.018092138
0.145416
37.690%
57.022%


CNR1
0.020145322
0.217248
50.401%
45.292%


PCDHAC1
0.022162682
0.107299
20.347%
55.591%


CD200R1
0.023823591
0.514934
29.122%
72.538%


PRIMA1
0.025581156
0.254529
40.877%
25.621%


MRGPRX1
0.025819972
0.421503
20.543%
12.984%


THSD7B
0.026001554
0.193007
69.592%
35.961%


DRD4
0.026572063
0.139979
36.941%
40.366%


CDHR1
0.031047336
0.50565
71.178%
38.867%


GRIA2
0.032074602
0.368383
83.751%
86.154%


SLC19A2
0.032547901
0.106657
11.397%
13.372%


SEMA5B
0.037498693
0.243647
42.878%
31.330%


GPR12
0.038568437
0.117854
35.447%
33.159%


EPHA6
0.041171946
0.348497
60.615%
50.138%


ASTN1
0.041246289
0.316287
55.840%
52.046%


GPR88
0.04132599
0.462697
54.393%
63.525%


ALK
0.042289593
0.31447
40.233%
40.512%


EFNB3
0.050148985
0.130481
49.443%
27.884%


BVES
0.053667518
0.27505
26.212%
33.684%


PTK7
0.05449027
0.19632
14.300%
23.241%


CLDN4
0.056211309
0.136289
20.372%
13.782%


TRIL
0.062735791
0.356276
32.099%
24.340%


GPR26
0.068259231
0.706576
46.731%
60.279%


LRTM2
0.070396159
0.312631
45.241%
50.649%


NLGN4X
0.071490795
0.211887
32.272%
58.343%


PCNXL2
0.074558267
0.138128
19.956%
23.921%


TACR1
0.078481263
0.430424
55.460%
38.901%


GRM2
0.080083393
0.236109
58.405%
44.184%


SCNN1B
0.080376427
0.290862
55.831%
31.538%


SLC5A4
0.08070531
0.17415
38.647%
37.976%


MEGF10
0.085450419
0.438442
36.192%
49.937%


CHRNA1
0.087817204
0.181296
28.089%
46.130%


APLP1
0.093640889
0.113433
63.459%
52.045%


ROR2
0.096618214
0.397502
39.646%
50.793%


SCNN1G
0.096629118
0.357045
53.447%
38.709%


MCHR1
0.099118137
0.296733
43.637%
56.272%


LRP4
0.100891439
0.117016
34.838%
26.299%


FZD10
0.101992191
0.256895
44.522%
18.144%


CNTNAP5
0.10602115
0.333789
40.073%
45.894%


FZD7
0.106798967
0.315139
14.175%
14.988%


NPFFR2
0.108494803
0.484079
51.538%
46.733%


DLL1
0.110675906
0.105097
12.264%
27.898%


DUOXA1
0.119642284
0.460531
28.932%
48.096%


CNTN1
0.136886879
0.264896
43.750%
29.543%


TAS2R7
0.138565531
0.270276
49.610%
50.050%


KIAA1324
0.141632729
0.162504
16.513%
42.199%


F3
0.147728305
0.285252
25.133%
10.791%


GABRG3
0.152392437
0.279615
40.861%
31.331%


GPR125
0.156687696
0.150356
11.711%
20.317%


GPR143
0.174935715
0.374312
10.405%
22.707%


SLC16A1
0.178516379
0.210151
24.273%
25.377%


CSPG5
0.179218288
0.204093
36.023%
37.678%


GPR158
0.192363478
0.208089
43.456%
51.035%


GABRD
0.217250984
0.621264
73.978%
55.365%


GABBR2
0.234181726
0.270761
51.035%
49.768%


OR2C3
0.236689791
0.180238
20.191%
45.481%


SLC4A4
0.251108889
0.114065
31.605%
26.837%


TSPAN1
0.252406369
0.182981
50.202%
18.189%


GPR162
0.254149923
0.119056
47.981%
22.067%


GPRC5D
0.265890768
0.127619
36.879%
10.294%


SLC24A2
0.270254978
0.347414
48.070%
50.961%


RXFP3
0.271016239
0.264443
28.202%
26.946%


ROR1
0.275779075
0.304678
23.880%
37.387%


ENPP1
0.283169434
0.192028
38.926%
45.657%


OR1J4
0.290985808
0.300929
18.488%
45.087%


CDH4
0.291596488
0.27611
18.370%
59.757%


FAM174B
0.297106361
0.104782
18.327%
12.588%


AGER
0.304827
0.295823
39.246%
40.755%


TSPAN5
0.305897682
0.175816
30.716%
13.622%


FNDC5
0.317906978
0.292368
52.050%
45.160%


SLC12A2
0.318871853
0.18774
18.953%
14.405%


TMEFF2
0.340686347
0.364396
47.881%
48.679%


TAS1R2
0.357917894
0.425702
29.500%
33.763%


SLC44A3
0.375565664
0.141601
13.061%
10.402%


PCDHA2
0.377575079
0.154232
43.069%
28.105%


FFAR1
0.380611634
0.303569
28.179%
44.525%


MST1R
0.390798181
0.117365
14.891%
19.384%


IL23R
0.394638216
0.333865
24.822%
42.711%


PRLHR
0.406872394
0.372499
44.210%
44.449%


OPRM1
0.446154303
0.121851
38.802%
30.008%


CHRNB2
0.451283795
0.121364
23.267%
32.050%


SV2C
0.473484792
0.221116
26.873%
41.279%


TMEM255A
0.477567647
0.181819
17.251%
31.592%


BAI2
0.487715326
0.179821
23.929%
28.985%


TSHR
0.50492401
0.170709
32.340%
58.390%


GJB5
0.50950575
0.360938
51.067%
21.608%


TMEM114
0.518438848
0.233104
23.751%
27.489%


PCDHB3
0.537684013
0.333606
16.661%
13.730%


DUOX2
0.557156536
0.403027
28.678%
23.353%


ABCA12
0.604360884
0.135086
36.284%
27.536%


SLC13A2
0.612876222
0.371814
35.208%
19.777%


SLC22A15
0.615019122
0.181757
11.823%
14.681%


SGCZ
0.635672356
0.382806
18.361%
23.228%


TACR3
0.641433487
0.184102
36.043%
17.226%


SCNN1D
0.684813576
0.297107
16.944%
14.482%


HCRTR1
0.69535971
0.148244
21.805%
37.521%


SIRPB2
0.705934206
0.352815
18.177%
25.873%


DUOX1
0.716800806
0.321059
29.171%
17.478%


C11orf87
0.736573623
0.105579
44.340%
52.865%


PCDHA3
0.739183518
0.191675
30.937%
20.869%


EDA
0.745140252
0.130576
22.578%
13.102%


ELFN2
0.754601024
0.171733
13.515%
12.772%


ADAM2
0.771326494
0.287737
28.638%
40.110%


HRH4
0.772160105
0.179724
22.041%
35.437%


NALCN
0.775858453
0.253893
15.739%
23.483%


ASIC5
0.817348593
0.240306
17.544%
21.065%


OR2W1
0.818607943
0.204991
13.862%
25.608%


UPK3A
0.849783625
0.238744
26.503%
20.476%


GLRA2
0.915505273
0.14121
17.162%
23.684%


CHRNA5
1.27891E−11
0.107333
4.726%
17.538%


GFRA1
1.01361E−09
0.437949
62.453%
59.433%


IGSF9
1.05941E−09
0.081147
5.303%
18.822%


SUCO
 1.7538E−09
0.006319
2.667%
5.183%


QSOX2
4.81129E−08
0.015085
23.385%
21.711%


NETO2
6.18953E−07
0.101151
2.041%
8.087%


CELSR3
8.74373E−07
0.030931
35.137%
37.436%


NRXN1
9.86924E−07
0.057663
68.892%
56.752%


NLGN1
2.29956E−06
0.083058
65.490%
50.420%


SLC6A3
 2.5439E−06
0.006027
53.750%
35.221%


NFASC
2.14888E−05
0.021436
46.811%
52.966%


GRIK3
2.77401E−05
0.089955
56.445%
45.232%


DRD2
6.23064E−05
0.037653
26.987%
33.380%


GRIK2
8.96329E−05
0.075612
73.445%
60.604%


SLC26A6
0.000174847
0.228561
34.337%
29.550%


LMBRD2
0.000258161
0.00234
7.877%
11.539%


SLC7A14
0.000344826
0.008064
68.080%
67.113%


LHFPL4
0.000348227
0.048872
52.622%
62.477%


FAM171B
0.000740595
0.034657
26.799%
23.189%


NEGR1
0.000824165
0.210725
53.127%
43.838%


LRIG2
0.001169129
0.082719
8.313%
20.367%


SEMA6D
0.0012735
0.040362
50.591%
34.111%


TMEM67
0.001575966
0.099503
23.407%
23.525%


CADM1
0.002123513
0.027474
24.056%
14.192%


SLC22A17
0.003569576
0.059665
49.628%
40.694%


OR1D2
0.004206712
7.29E−05
13.936%
28.752%


EFNA5
0.004523034
0.077912
30.287%
27.034%


KIAA1324L
0.004582258
0.090634
14.271%
6.425%


SLC24A3
0.005248239
0.174392
34.976%
25.743%


TMEM145
0.006607062
0.015526
30.501%
33.812%


STS
0.006752526
0.077968
23.221%
7.572%


TTYH3
0.00758668
0.147819
19.115%
4.698%


PLXNA3
0.00877675
0.069302
16.423%
22.207%


IGSF9B
0.009159819
0.066643
40.401%
20.370%


FZD8
0.010714137
0.089724
22.144%
20.530%


CLSTN1
0.011222174
0.085149
17.772%
15.478%


PCDHB15
0.012801464
0.008644
34.701%
24.854%


CRB2
0.013313783
0.013022
45.575%
40.953%


OR12D2
0.0135988
0.195798
23.328%
23.286%


ADCY3
0.016815836
0.124477
7.248%
7.985%


SLC2A11
0.016939645
0.161686
17.921%
34.713%


SDC2
0.017142998
0.196627
20.358%
20.772%


GPR153
0.018102302
0.060658
22.565%
29.072%


ELFN1
0.018211234
0.041309
22.816%
8.376%


EFNB1
0.018798692
0.166495
24.622%
21.840%


CLSTN3
0.019026418
0.150045
22.445%
26.636%


TRABD2B
0.019362447
0.235516
58.989%
46.049%


FZD1
0.020353875
0.087526
15.726%
2.555%


TMEM62
0.024359108
0.178813
12.545%
9.872%


NGFR
0.024698937
0.201476
53.037%
25.619%


MUC4
0.025668431
0.259347
10.987%
1.052%


PTPRU
0.029043504
0.025649
20.275%
18.220%


GPR98
0.029427265
0.076611
25.721%
2.844%


CASD1
0.030340316
0.053706
13.113%
16.993%


PTPRK
0.031622952
0.100806
5.618%
11.728%


LGR4
0.037668939
0.017517
16.978%
5.782%


EBP
0.043128127
0.103045
14.244%
14.328%


SEMA5A
0.048368106
0.112467
26.387%
17.440%


SHISA9
0.049409959
0.090641
3.616%
26.685%


C14orf132
0.04949203
0.01393
29.133%
24.324%
















TABLE 7







Surface proteins associated with the SCLC-P subtype from the George et al. dataset











Surface Protein
ANOVA P value
P vs N
P vs I
P vs A














EFNA4
 8.4107E−11
0.665145
42.38%
76.47%


TNFSF8
2.83139E−09
0.822427
29.54%
76.55%


CD46
5.37238E−09
0.330505
21.80%
17.81%


SMO
6.58432E−09
0.138195
23.32%
62.86%


ART3
2.90097E−08
0.98914
96.86%
98.78%


ANO7
3.85277E−08
0.894624
73.08%
88.78%


OLR1
5.43841E−08
0.759019
16.04%
65.49%


ITGB4
6.66957E−08
0.720817
65.15%
76.48%


AGTR1
7.26116E−08
0.922769
80.24%
90.16%


GJC3
1.19386E−07
0.675332
79.11%
42.66%


OR2T33
1.39955E−07
0.979554
88.94%
96.48%


EFNA1
1.52055E−07
0.394795
29.10%
22.96%


MICA
2.36218E−07
0.486327
14.22%
66.29%


IL1RL2
2.77546E−07
0.844712
50.71%
81.16%


OR2W3
 3.9506E−07
0.94874
80.54%
95.40%


OR2T8
 4.6941E−07
0.986425
97.90%
96.02%


TMEM63A
4.99873E−07
0.459291
21.80%
38.99%


TLR5
2.23372E−06
0.505671
10.88%
40.05%


TNFRSF21
4.34983E−06
0.388026
23.79%
14.33%


SLC2A10
7.30936E−06
0.429897
25.45%
50.62%


TMEM87A
8.43103E−06
0.23469
13.97%
16.86%


OMG
9.95594E−06
0.838163
80.60%
87.79%


NOTCH1
1.17007E−05
0.245943
18.54%
48.25%


TLR9
1.19364E−05
0.666505
29.82%
63.49%


TMPRSS5
2.16647E−05
0.682055
72.61%
78.22%


ADRB1
2.52632E−05
0.79476
64.06%
59.85%


SLC11A1
2.61715E−05
0.610752
12.36%
37.17%


PVRL4
2.68139E−05
0.632457
32.75%
56.31%


FAM171A1
2.97092E−05
0.294072
27.96%
15.16%


ABCB9
3.13633E−05
0.509671
51.18%
42.12%


DSG1
3.20907E−05
0.94698
91.97%
88.74%


HTR3E
3.29423E−05
0.997206
89.60%
99.09%


TAS1R3
3.47021E−05
0.760305
16.46%
65.48%


GAS1
3.58406E−05
0.467904
10.81%
58.01%


EPHA1
5.58326E−05
0.537752
24.02%
53.60%


CLEC5A
5.65009E−05
0.589582
12.12%
61.60%


ITGB6
8.66066E−05
0.692233
33.36%
39.12%


IL13RA1
9.60468E−05
0.303483
11.93%
13.26%


CD9
9.68695E−05
0.258285
16.13%
15.78%


OR14A16
0.000103109
0.961317
98.01%
99.51%


TEX101
0.000137167
0.86682
91.40%
34.75%


PTPRJ
0.000140474
0.277882
25.66%
37.68%


EPHB4
0.00015882
0.216584
17.54%
43.25%


KIAA0922
0.000170286
0.34579
18.62%
21.31%


FOLH1
0.000178323
0.542073
53.28%
72.90%


EPHB3
0.000224589
0.340999
39.45%
31.73%


ITGB5
0.000241464
0.326944
11.45%
25.41%


CLEC17A
0.000284055
0.845813
14.15%
81.27%


CHPT1
0.000361697
0.252501
15.30%
27.59%


AQP5
0.000440324
0.568598
53.40%
70.14%


LILRA2
0.000448315
0.817182
24.72%
78.33%


IL1RAP
0.000452298
0.669933
51.78%
71.24%


CHRM1
0.000454436
0.808455
82.09%
89.84%


LRIT3
0.00057546
0.397658
59.39%
77.72%


SLC6A9
0.000586836
0.486214
24.42%
44.73%


LRP5
0.000608646
0.239165
27.54%
20.39%


GPR110
0.000740268
0.795993
44.62%
85.39%


RNF43
0.000793841
0.383204
37.91%
57.82%


GPR143
0.000814447
0.213691
52.06%
42.03%


SLC6A7
0.000838794
0.627173
20.99%
72.61%


KCNMB3
0.001025188
0.511001
58.81%
41.27%


PRLR
0.001144253
0.888585
61.88%
94.68%


DSC2
0.001261101
0.487046
45.61%
63.42%


ATP2B4
0.001790531
0.10117
10.46%
26.99%


BACE2
0.001864832
0.414236
14.77%
12.43%


LRP6
0.001951906
0.115569
23.77%
15.84%


CD1E
0.002157992
0.759057
17.91%
77.03%


TNFSF11
0.002210775
0.679738
32.97%
68.24%


NRG4
0.002285591
0.398112
51.25%
52.91%


IL1RAPL2
0.002505288
0.457987
95.43%
88.32%


IL1RL1
0.002745563
0.764687
31.62%
73.26%


CNTN6
0.002751463
0.935146
77.71%
73.55%


OR2A7
0.00289799
0.432388
58.76%
65.25%


SLC29A2
0.002907563
0.296952
28.61%
12.92%


VTCN1
0.003312723
0.77516
62.99%
88.59%


SLC46A2
0.003323087
0.704155
13.31%
43.70%


EPHA4
0.003346467
0.440623
27.09%
14.41%


TRPV5
0.003567806
0.670506
70.53%
77.68%


EGF
0.003757905
0.556532
54.25%
89.67%


SLC12A8
0.00377477
0.639211
37.13%
58.14%


AQP2
0.004139175
0.82412
90.21%
87.42%


HFE2
0.004236521
0.786573
78.33%
77.85%


JAG1
0.004751604
0.219891
20.70%
17.58%


ANO6
0.004763639
0.23775
17.03%
11.49%


CEACAM19
0.004826399
0.50418
57.14%
29.05%


TREM1
0.005602779
0.644712
22.52%
26.77%


EVC2
0.005611979
0.405536
34.36%
40.37%


PCSK5
0.005693818
0.583504
42.85%
46.11%


SLC43A3
0.006162496
0.211633
15.76%
18.03%


TYRP1
0.006263061
0.760874
45.57%
44.20%


AGER
0.0066642
0.722123
14.66%
46.37%


BTC
0.007271929
0.645059
44.81%
56.34%


ERBB3
0.007379771
0.262827
33.67%
32.52%


MSLN
0.008068245
0.745137
29.16%
47.69%


GPR133
0.008127868
0.565386
30.80%
43.01%


SLC16A4
0.008452332
0.357789
15.24%
44.01%


NGFR
0.008472324
0.204603
13.17%
55.54%


PKHD1
0.008499116
0.866847
69.66%
45.70%


ITGA8
0.008556682
0.497222
11.06%
45.40%


LYVE1
0.008799947
0.587227
24.74%
46.19%


AMN
0.009052556
0.60465
28.56%
53.72%


KCNS1
0.009065972
0.722646
70.64%
80.52%


F2RL1
0.009251378
0.302104
26.28%
31.68%


TRPV6
0.01019293
0.145089
58.54%
86.59%


CHRNA7
0.010193192
0.230165
41.52%
72.70%


ANO2
0.010456449
0.133929
57.11%
65.11%


SLC16A5
0.010880559
0.348931
15.95%
38.28%


CHODL
0.010930067
0.671464
81.38%
74.88%


ROS1
0.011061816
0.742415
17.58%
29.67%


SLC9A2
0.01119155
0.825633
77.12%
54.51%


AQP4
0.011337328
0.6693
21.99%
37.02%


ELFN2
0.011558687
0.13072
35.27%
86.35%


SGCA
0.01188718
0.645452
40.43%
29.40%


TTYH1
0.011952592
0.847065
89.14%
89.74%


CORIN
0.012523347
0.562165
38.78%
44.19%


LPAR3
0.012837212
0.559451
54.49%
82.84%


SLC6A16
0.013156814
0.437973
62.00%
66.96%


ADORA1
0.013572428
0.148568
35.58%
61.66%


CD177
0.013943537
0.80316
80.76%
36.40%


ADRA2B
0.014117225
0.193016
30.92%
57.33%


TSPAN2
0.015405045
0.158347
24.13%
39.67%


FGFRL1
0.015601802
0.452219
29.65%
53.08%


GJA3
0.015961745
0.915415
81.06%
86.61%


MME
0.016403426
0.676529
46.78%
26.60%


RRH
0.01684885
0.350216
56.50%
52.34%


ENPP6
0.01703951
0.742891
50.38%
67.09%


MUC13
0.017125072
0.89308
79.58%
18.22%


DSC3
0.017909978
0.429529
53.45%
83.21%


DCHS2
0.018051482
0.545891
88.85%
86.04%


EFNB2
0.018374811
0.208394
12.40%
21.32%


OR1G1
0.019567153
0.800716
64.39%
86.33%


GPRC5A
0.020114473
0.526023
22.32%
31.99%


SCN7A
0.020505778
0.64189
29.04%
34.32%


ESYT3
0.020876712
0.354858
40.51%
12.29%


ADRB3
0.020966445
0.614002
24.08%
68.18%


ERBB2
0.021055046
0.280321
22.63%
22.99%


ADCY6
0.02117691
0.168773
31.19%
20.17%


OR7A5
0.021286953
0.950561
80.72%
95.35%


GPR156
0.022083402
0.231931
42.06%
64.35%


SCTR
0.023375499
0.62339
29.68%
24.92%


SLC7A10
0.026205032
0.721705
84.47%
81.12%


GPRC5D
0.026497893
0.188734
42.94%
37.86%


SLC1A1
0.026903816
0.349672
10.61%
27.55%


SLC24A4
0.028137202
0.528737
67.10%
89.70%


ACE2
0.028432856
0.479573
21.69%
46.59%


GUCY2C
0.028712571
0.305401
18.38%
57.20%


GPR17
0.030094261
0.876818
83.58%
93.97%


PLP1
0.030391865
0.598853
67.18%
81.10%


LRP8
0.030965801
0.1222
34.17%
27.74%


CCR3
0.033322703
0.774373
51.33%
78.62%


NPY2R
0.034661438
0.959179
97.39%
97.85%


ANO3
0.035055085
0.682266
53.81%
58.82%


SLCO6A1
0.036341673
0.725141
71.48%
44.17%


OR51I1
0.037933366
0.818566
82.86%
71.72%


MMP17
0.038688354
0.446805
38.26%
54.76%


TYRO3
0.040249495
0.125142
19.95%
33.37%


NPY1R
0.041073669
0.676799
12.45%
78.71%


MRGPRD
0.041485825
0.341437
71.93%
76.06%


CLDN10
0.042522253
0.514514
76.49%
48.08%


NOTCH3
0.043919721
0.203597
15.43%
23.51%


KCNMB4
0.044449222
0.319162
32.24%
26.41%


OXGR1
0.045050137
0.689548
43.03%
62.11%


EPHB6
0.045424814
0.254378
12.66%
55.93%


OR1E1
0.045916035
0.888355
67.73%
84.42%


CX3CR1
0.048647041
0.776186
38.40%
77.43%


OR7C1
0.049394983
0.740652
63.17%
83.97%


SLC5A9
0.049668309
0.573112
31.52%
44.80%


GPC4
0.051678748
0.313392
20.86%
30.10%


GJB7
0.05273889
0.712129
61.87%
43.01%


ATP1A2
0.057053662
0.65187
62.91%
49.30%


SLC34A2
0.057359102
0.472189
11.80%
10.23%


TACSTD2
0.058819435
0.366904
17.51%
30.18%


MUC16
0.060526781
0.407618
65.55%
86.69%


SLC19A3
0.060674687
0.685987
35.54%
31.08%


PTH1R
0.06247867
0.49763
23.42%
18.05%


VSIG2
0.062792439
0.357679
38.39%
40.58%


ROR1
0.063145223
0.175749
41.48%
42.48%


PTK7
0.064276357
0.19172
16.76%
21.59%


TAS2R38
0.064796129
0.852551
93.97%
79.30%


SLC6A4
0.065880531
0.844789
32.53%
56.72%


PROM2
0.066147525
0.215337
42.47%
39.03%


DSG2
0.066454771
0.194862
28.70%
21.48%


HTR3B
0.066612063
0.477303
85.44%
71.38%


AVPR2
0.067733761
0.275832
48.53%
49.11%


TAS2R9
0.068395293
0.463287
76.01%
74.39%


TM4SF4
0.070625087
0.922386
89.76%
84.08%


SHISA6
0.070637439
0.452698
87.07%
92.28%


TMEM171
0.072804998
0.575858
28.52%
17.58%


MEGF10
0.073549936
0.257342
79.53%
96.08%


IL13RA2
0.075093846
0.679916
39.52%
64.57%


TMEM211
0.07532478
0.849341
89.72%
71.53%


S1PR3
0.07964697
0.270132
15.51%
18.27%


SLC39A2
0.081436028
0.758829
75.78%
97.87%


OR2M3
0.081772548
0.702289
86.93%
76.87%


ITGB8
0.083510372
0.183599
31.49%
32.20%


DPCR1
0.083941913
0.67573
36.31%
68.62%


ABCC9
0.085480661
0.176252
21.87%
16.19%


ATP13A5
0.085632442
0.382861
56.91%
80.27%


SLC10A2
0.085821319
0.884712
80.44%
87.16%


ABCB4
0.086819783
0.544165
35.97%
68.09%


PTGFRN
0.087535731
0.150178
19.58%
14.59%


SLC2A4
0.087649817
0.543777
38.05%
26.55%


SLCO2A1
0.088181013
0.116896
11.41%
29.48%


NLGN3
0.092107476
0.268587
53.37%
51.79%


CHRNE
0.092608577
0.345935
15.86%
45.25%


ABCA8
0.093124763
0.588744
48.62%
55.18%


PTPRQ
0.094850636
0.701677
18.98%
35.27%


HTR2A
0.095218297
0.572068
23.28%
58.67%


FGFR4
0.097040066
0.587395
36.66%
38.46%


FLRT3
0.097754914
0.388623
26.86%
43.47%


NRG2
0.09799727
0.536332
71.87%
75.05%


MAG
0.098341934
0.594878
72.86%
78.35%


P2RX2
0.099264374
0.571596
18.61%
71.53%


CEACAM1
0.099670836
0.487904
55.32%
33.66%


GABRP
0.099691256
0.322992
37.31%
62.97%


EMR3
0.099973368
0.719821
33.57%
50.23%


EFNA3
0.100561442
0.224619
32.69%
28.55%


TAS2R1
0.102303043
0.618894
53.75%
70.86%


SVOPL
0.10469247
0.691319
58.68%
29.67%


GPR126
0.105320886
0.824585
49.19%
32.83%


OR2C3
0.105426763
0.93233
87.34%
96.90%


LRRN4CL
0.105470732
0.50418
39.22%
54.38%


LPAR4
0.105903885
0.725048
76.72%
88.79%


TAS2R4
0.107228562
0.160054
63.62%
50.39%


OR2L2
0.107945954
0.890086
100.00%
63.35%


MPZ
0.115877849
0.350074
33.52%
25.02%


OR2AK2
0.120352195
0.85132
82.30%
54.54%


BTNL9
0.127231925
0.115219
11.28%
43.09%


OR2H2
0.127823089
0.577927
60.73%
54.18%


UPK1A
0.127948226
0.581606
68.03%
43.60%


NPY5R
0.130569764
0.786431
12.13%
88.92%


TAS2R10
0.131962692
0.434925
69.51%
64.23%


MTNR1A
0.136531947
0.77608
46.03%
50.89%


MMP16
0.137405514
0.343624
55.40%
27.58%


TAS1R2
0.137648238
0.968373
98.39%
96.85%


CDH17
0.137679582
0.792077
75.06%
76.23%


OR10H1
0.140328417
0.675839
78.70%
86.57%


TMPRSS11E
0.141515309
0.869983
82.81%
69.78%


OR52N2
0.145823719
0.822447
36.49%
26.20%


ZP4
0.149279396
1
92.86%
97.83%


GJB3
0.149663808
0.492994
46.99%
55.77%


MFSD6L
0.151785406
0.473599
46.92%
20.73%


LPPR5
0.155375697
0.331811
88.30%
88.33%


MC5R
0.155724755
0.199239
50.79%
71.24%


CDH16
0.156400295
0.997076
99.06%
97.74%


OR3A1
0.159340672
0.766853
72.53%
72.42%


ITGB3
0.160963176
0.23081
34.70%
40.06%


SLC5A4
0.161854327
0.396068
50.95%
61.50%


SLC26A8
0.163162981
0.483082
55.01%
33.53%


CLDN16
0.164648344
0.426791
44.67%
67.09%


NPR3
0.165148184
0.487012
10.71%
27.82%


GABRA6
0.165706626
0.793245
86.08%
71.01%


CD300LD
0.165804434
0.958912
64.88%
93.86%


LHCGR
0.166864269
0.179474
64.50%
86.48%


GHRHR
0.169093244
0.11812
71.63%
87.84%


MUSK
0.175886446
0.656954
10.24%
52.42%


AVPR1A
0.17732047
0.270305
35.14%
50.57%


CDH19
0.177565353
0.896903
63.29%
85.95%


CLDN2
0.178639236
0.656958
43.46%
44.38%


TRPV4
0.181421521
0.177181
28.21%
66.97%


SLC1A6
0.187838755
0.884619
94.00%
87.71%


OPCML
0.188996811
0.114824
63.15%
61.82%


PCDHGA11
0.191438613
0.5688
70.61%
62.14%


PCDHGB7
0.191500813
0.420732
19.72%
40.33%


OR56A1
0.193811563
0.899266
96.75%
91.92%


OR2D2
0.194279947
0.710616
34.58%
70.56%


OR5AK2
0.194720213
0.843427
83.52%
68.30%


TAS2R30
0.197744614
0.702948
89.07%
79.87%


SLC3A1
0.198821818
0.368173
44.28%
29.66%


EDNRB
0.199593812
0.37187
26.10%
41.12%


OR52E6
0.20203476
1
39.14%
15.56%


TRHR
0.206396211
0.206114
18.56%
79.22%


CEACAM8
0.207601332
0.445245
68.62%
85.69%


SCN2B
0.208183103
0.443652
40.18%
61.08%


GPR87
0.210507679
0.71056
79.26%
72.67%


NIPAL4
0.210619893
0.477055
23.27%
41.40%


PCDH1
0.215677745
0.179956
27.49%
16.78%


ZP2
0.221450708
0.844645
66.81%
38.44%


LPL
0.225272333
0.213236
21.72%
13.14%


TAS2R14
0.231893619
0.159452
36.82%
24.55%


RGR
0.235820069
0.572266
67.41%
94.45%


GRIA4
0.239230762
0.952162
75.07%
58.06%


SLC22A1
0.239271045
0.333878
43.18%
42.43%


OR13A1
0.243147239
0.385063
45.19%
12.82%


OR3A3
0.248306294
0.562802
92.37%
92.85%


TAS2R20
0.253720488
0.18062
30.82%
20.27%


TREH
0.257881966
0.884718
77.11%
54.76%


LYPD2
0.266284276
0.118249
52.31%
77.30%


OR10AD1
0.266518291
0.414722
60.90%
37.05%


SLC6A15
0.266704162
0.57333
41.10%
38.48%


SPACA1
0.269350373
0.945545
100.00%
74.77%


IL22RA1
0.270446327
0.247689
33.30%
33.17%


TGFA
0.270467452
0.350554
31.84%
35.48%


XPNPEP2
0.271584399
0.544586
40.62%
55.07%


FFAR1
0.273068174
0.6556
65.33%
62.51%


OR51B4
0.281462593
0.927919
69.49%
21.91%


SELE
0.28581219
0.503158
18.06%
35.70%


HLA-DRB5
0.289245803
0.307817
10.35%
24.63%


ITGA6
0.290825792
0.133514
13.24%
15.19%


DUOXA1
0.290944834
0.275387
31.60%
31.21%


LEPR
0.295103641
0.368354
24.64%
23.25%


CDH3
0.301911808
0.253595
22.64%
20.82%


IGDCC4
0.303287665
0.17724
15.81%
46.68%


OR5M11
0.308950386
0.916373
39.38%
73.52%


TAS2R8
0.31169874
0.739599
55.64%
76.01%


OR56A3
0.324780124
0.941395
55.34%
25.53%


TPO
0.325197567
0.83885
83.14%
38.48%


OR6K3
0.326247755
0.897422
47.56%
52.44%


FSHR
0.332841152
0.553428
100.00%
92.10%


HTR2C
0.335918418
0.999735
99.97%
72.20%


SLCO1B3
0.336276389
0.86063
92.82%
69.90%


HTR3D
0.337826954
0.459008
88.42%
39.63%


PCDHGA2
0.341933737
0.276588
51.88%
26.31%


PMEPA1
0.347625064
0.161026
20.53%
16.49%


RHAG
0.349959661
0.526784
83.06%
61.50%


MDGA2
0.35062656
0.970358
89.32%
63.82%


MRGPRG
0.350733511
0.284351
94.91%
75.73%


TAS1R1
0.364489067
0.347182
57.30%
66.01%


SLC5A8
0.371037101
0.609705
13.17%
21.11%


OR7G2
0.373781402
0.775875
100.00%
29.43%


GPR128
0.374950878
0.998037
99.72%
55.47%


EREG
0.383464698
0.315331
10.39%
69.81%


SLC39A5
0.39030688
0.386952
53.11%
42.58%


OR56A4
0.390513457
0.860972
100.00%
50.01%


SLC10A5
0.391236381
0.199345
30.43%
10.24%


TM4SF20
0.394075952
0.209688
55.41%
25.14%


BTN1A1
0.398177117
0.496319
46.37%
14.84%


GPR22
0.398560689
0.826058
93.32%
39.56%


SCARA5
0.39886845
0.57999
56.65%
60.70%


TNFRSF25
0.400610662
0.153979
20.21%
16.25%


MUC4
0.407044062
0.272589
24.35%
44.32%


PCDHB7
0.409713081
0.319223
35.63%
15.31%


PCDH7
0.434676508
0.508357
27.30%
21.02%


TDGF1
0.444145245
0.560496
35.33%
28.94%


RTN4RL2
0.44922469
0.176964
15.00%
26.77%


SORCS1
0.449766671
0.789279
75.16%
62.12%


NTRK2
0.454201266
0.205316
29.43%
52.05%


OR52N1
0.454661384
0.849011
67.95%
64.44%


OR7E24
0.456797167
0.869033
51.89%
58.91%


TMEM27
0.466431493
0.193446
19.46%
22.74%


SLC26A4
0.47014402
0.283031
40.83%
52.24%


OR10Q1
0.477575038
0.479528
100.00%
32.02%


GABRG2
0.478414967
0.699959
37.19%
30.08%


BTNL3
0.480748272
0.613497
21.03%
41.83%


TMEM213
0.483184799
0.402734
57.32%
49.02%


UMOD
0.49405328
0.737087
54.73%
56.20%


TMPRSS13
0.496987784
0.301886
33.55%
44.43%


SLC6A8
0.500550185
0.117882
10.01%
19.14%


ERVV-1
0.50134262
0.2678
61.26%
44.17%


CACHD1
0.508789618
0.16718
13.01%
18.37%


OR2C1
0.512670511
0.137443
32.18%
34.31%


OR3A2
0.531951762
0.271244
86.86%
88.31%


SLC1A7
0.552627356
0.126664
50.58%
65.17%


SLC5A11
0.573269145
0.211991
87.84%
30.69%


OR2M4
0.580555576
0.73969
100.00%
34.32%


VIPR2
0.592772318
0.487689
51.39%
27.96%


GPR20
0.594023087
0.345519
16.94%
26.54%


SLC17A8
0.603554458
0.358808
61.62%
59.02%


TPSG1
0.604243563
0.506422
43.40%
14.99%


ABCA13
0.613374042
0.363266
30.31%
53.52%


OR2T3
0.622433332
0.571684
100.00%
27.56%


SLC22A12
0.623032751
0.169417
100.00%
24.19%


OR11L1
0.624516845
0.407419
59.54%
78.07%


OR2K2
0.633368729
0.366968
44.71%
51.31%


KIR3DL3
0.659474269
0.661364
39.74%
15.36%


SLC18A3
0.6599718
0.306886
37.11%
40.94%


OR10A3
0.67529466
0.788284
62.84%
18.54%


CNTN1
0.679674951
0.145236
36.97%
19.45%


OR11H12
0.703757044
0.230856
74.21%
47.76%


PTGER3
0.710831509
0.394932
61.96%
42.77%


SERINC5
0.721823022
0.112287
19.21%
12.95%


MLNR
0.724905932
0.17268
39.04%
16.80%


DUOX1
0.727206229
0.122774
18.37%
21.26%


LRRC4
0.742301207
0.123438
10.33%
19.47%


OR2A2
0.754863653
0.489595
34.11%
58.86%


ERVFRD-1
0.783008795
0.355158
31.97%
25.50%


GRM5
0.787467035
0.291893
55.92%
23.65%


GPM6A
0.798661537
0.446923
41.10%
26.42%


PCDH15
0.80956288
0.414102
49.67%
41.97%


CDH6
0.819645372
0.173842
22.98%
11.76%


GPR78
0.875975682
0.394652
58.66%
61.84%


SLC22A13
0.906218245
0.109789
17.26%
20.63%


LY6K
0.9128643
0.219513
23.59%
27.02%


RXFP4
0.918452229
0.211565
11.51%
30.11%


OR5K1
0.939867811
0.221892
56.54%
46.71%


CLDN1
0.963511597
0.111213
13.19%
11.12%


IL27RA
3.80835E−10
0.491909
1.57%
38.05%


TMEM37
2.07883E−08
0.401771
2.69%
38.32%


FZD7
1.05725E−07
0.291174
5.62%
56.74%


TNFRSF1A
2.97304E−07
0.293602
5.05%
20.43%


SIRPB2
1.66205E−06
0.738437
7.51%
69.80%


TFPI
6.13469E−06
0.476096
8.02%
24.64%


PTGDR
6.70351E−06
0.656201
0.24%
61.19%


CD70
7.94973E−06
0.778936
0.47%
67.60%


UNC5C
3.31841E−05
0.679531
7.70%
57.95%


CD55
3.34123E−05
0.369519
8.42%
15.47%


PDGFRA
9.46902E−05
0.48919
1.73%
35.02%


ICAM4
0.000118391
0.685901
1.99%
56.94%


AOC3
0.000250065
0.417545
2.29%
10.73%


CX3CL1
0.000260353
0.311673
6.99%
32.06%


GPR125
0.000292712
0.019715
21.19%
16.00%


LTBR
0.000322781
0.230382
5.91%
8.51%


EMP1
0.000423485
0.276759
7.15%
24.47%


PROM1
0.000556949
0.358625
56.74%
3.99%


RNFT1
0.000595944
0.157005
1.32%
5.40%


CRIM1
0.000752526
0.211906
0.79%
24.63%


QSOX1
0.000949294
0.225639
7.44%
12.53%


NOTCH2
0.001391497
0.432679
9.91%
35.44%


LDLR
0.002098538
0.30669
23.44%
1.44%


SLC29A1
0.002665488
0.197281
15.85%
4.54%


TMEM87B
0.002787639
0.150347
0.88%
1.18%


NRP1
0.003486853
0.189763
5.00%
34.02%


TM7SF3
0.004471624
0.150418
5.20%
3.64%


DUOX2
0.004501498
0.063127
47.16%
61.35%


LYPD3
0.004916422
0.36759
35.87%
9.05%


IGF1R
0.005824442
0.001382
18.15%
23.42%


DAGLB
0.006306386
0.101116
2.85%
18.77%


ATP1A1
0.006719033
0.138506
8.71%
5.99%


PPAP2B
0.006922599
0.215878
4.79%
15.20%


SLC12A2
0.007080979
0.050994
19.62%
22.26%


ABCC4
0.007336235
0.419182
7.37%
40.77%


SLC11A2
0.007926953
0.216816
12.87%
8.52%


SHISA9
0.007978787
0.001578
40.78%
9.21%


TMEM9B
0.008107124
0.112142
1.90%
0.63%


GRPR
0.008826539
0.09859
76.15%
68.85%


OR52N4
0.008933724
0.790776
6.85%
67.48%


HEG1
0.009239977
0.17681
0.66%
27.88%


LRRN2
0.009827145
0.081034
24.82%
42.49%


FURIN
0.009833891
0.165856
5.20%
6.86%


CDCP1
0.009930141
0.323386
17.32%
9.31%


ROBO3
0.010179135
0.016396
14.70%
61.69%


KCNMB1
0.010785151
0.339065
2.12%
30.07%


IGSF9
0.011837538
0.03483
1.96%
27.93%


ADAM15
0.011971108
0.296194
9.59%
15.63%


IL17RB
0.012038765
0.093433
30.02%
12.59%


P2RY1
0.012285131
0.264869
6.51%
51.61%


FGFR1
0.013687141
0.464362
15.19%
3.87%


ENPP5
0.014027223
0.162987
27.72%
7.02%


GPR55
0.015085835
0.072386
5.22%
58.55%


GPR157
0.016995435
0.552128
3.58%
32.33%


PKD2
0.017914637
0.0393
6.18%
18.66%


MFI2
0.018053005
0.0917
34.51%
13.46%


ADAM32
0.020247857
0.64185
9.50%
46.15%


GLDN
0.021536127
0.503465
53.98%
3.46%


MANSC4
0.021762601
0.499754
1.05%
55.22%


CD109
0.022506005
0.031266
27.38%
50.34%


CALHM2
0.024631579
0.114388
3.25%
23.65%


TMEM62
0.026593448
0.193535
6.37%
9.31%


S1PR2
0.027717445
0.210772
15.84%
9.68%


MUC1
0.034007566
0.370313
14.97%
5.45%


AQP1
0.03425542
0.240582
4.53%
22.90%


SEMA5A
0.035410634
0.073182
21.71%
42.09%


LAYN
0.036306834
0.005031
2.33%
23.91%


TM9SF4
0.036561803
0.076365
2.75%
0.55%


ICAM5
0.037135955
0.43688
1.74%
28.60%


FAT1
0.041493222
0.233061
14.15%
5.17%


GPR116
0.042591638
0.227676
0.72%
20.74%


ADAM10
0.044380072
0.109811
9.08%
10.06%


CDON
0.045400463
0.088132
27.52%
24.83%


CD58
0.049115226
0.244785
4.97%
16.26%


GABRE
0.049254216
0.087662
31.34%
62.00%


NOX4
0.049597451
0.431235
2.21%
33.10%
















TABLE 8







Surface proteins associated with the SCLC-P subtype from the cell line dataset












ANOVA P





Surface Protein
value
P vs N
P vs I
P vs A














OR2W3
1.84063E−09
0.973307
78.97%
90.63%


TNFRSF25
3.18647E−08
0.403317
35.77%
15.18%


P2RY8
1.69851E−06
0.886062
100.00%
94.18%


ANO9
2.00245E−06
0.609042
92.17%
10.81%


CDCP1
3.27424E−06
0.561207
66.07%
14.00%


OR2T8
 6.0221E−06
0.927161
85.65%
84.59%


IL17RB
2.00076E−05
0.184279
19.91%
13.25%


SIGIRR
2.27068E−05
0.699622
68.09%
15.97%


NIPAL1
3.47959E−05
0.583635
57.00%
22.38%


OR2A1
4.98952E−05
0.949456
67.14%
84.51%


ART3
8.81977E−05
0.55051
58.96%
45.47%


PCSK5
0.000193993
0.4293
71.49%
40.80%


GJC3
0.000224967
0.297753
25.50%
13.12%


NRG2
0.000241036
0.104315
32.85%
58.77%


MPZL2
0.000303634
0.420672
68.20%
15.96%


IL13RA1
0.000321744
0.385055
27.47%
21.82%


OR2AJ1
0.000451239
0.887388
72.04%
87.04%


ACE2
0.000500139
0.422543
63.73%
38.24%


OR2L8
0.000551402
0.80432
52.51%
83.54%


OR2AK2
0.000569755
0.758023
73.85%
79.80%


HTR1E
0.000596264
0.217146
87.73%
79.00%


CD8A
0.000633729
0.823627
85.03%
82.00%


OR2A7
0.000801993
0.920764
70.45%
68.49%


TAS2R38
0.000848049
0.839025
100.00%
52.91%


CLEC5A
0.001010686
0.490292
62.28%
14.91%


NRP1
0.001075071
0.374064
12.26%
11.35%


CD8B
0.001192305
0.616522
87.57%
66.30%


TAS2R8
0.001258191
0.50259
26.49%
20.55%


ERBB3
0.001304319
0.419577
43.11%
22.79%


PPAP2C
0.001484947
0.697998
52.35%
25.32%


OR10W1
0.001670769
0.838678
56.47%
94.68%


EPHA1
0.001699042
0.371204
24.11%
59.20%


GPR141
0.001776037
0.850228
100.00%
83.30%


CRB3
0.001848833
0.666753
67.25%
16.84%


TAS2R9
0.001858952
0.53866
13.89%
12.22%


GJB7
0.001915966
0.360237
31.48%
18.53%


ITGA8
0.00249817
0.515019
39.38%
63.52%


OR2L3
0.00338085
0.808428
65.83%
82.10%


OR6V1
0.003486184
0.379756
16.40%
18.61%


DCHS2
0.003868332
0.551525
40.71%
53.84%


OR1N1
0.003946122
0.716867
86.87%
63.89%


BACE2
0.003948012
0.520011
29.78%
13.29%


PVR
0.003952176
0.140649
16.24%
22.99%


OR1S1
0.003978803
0.991257
71.42%
90.88%


OR1N2
0.004171406
0.682637
86.09%
56.31%


OR2A2
0.004429299
0.995638
68.50%
63.58%


OR2L2
0.005055368
0.824659
61.11%
77.99%


TAS2R3
0.005721531
0.242471
28.24%
13.37%


OR1B1
0.005829807
0.694422
89.24%
59.70%


OR2L5
0.00646865
0.890388
67.95%
75.11%


TMEM27
0.006509446
0.230813
37.03%
15.62%


FOLH1
0.006676013
0.625949
39.07%
67.97%


RELT
0.007030806
0.149871
67.44%
20.00%


OR9Q2
0.007379378
0.990776
100.00%
85.83%


SCN4A
0.007459589
0.606443
66.83%
66.40%


CLDN1
0.007493518
0.720816
22.10%
23.10%


ABCG5
0.007626799
0.249168
19.37%
11.07%


OR1L1
0.007730612
0.628269
92.37%
61.76%


GJB2
0.008920645
0.921522
36.79%
51.62%


OR5B21
0.009408114
0.935063
50.68%
75.83%


TLR5
0.011131903
0.201083
49.00%
28.05%


OR1L3
0.011147399
0.681512
70.15%
45.38%


FGFRL1
0.011434613
0.37889
19.30%
56.73%


ANO7
0.011733181
0.627077
70.57%
60.74%


FAT1
0.012132693
0.339811
17.16%
14.90%


OR1Q1
0.013140994
0.565595
74.42%
44.35%


CEACAM19
0.013216645
0.304763
46.49%
32.64%


OR9A4
0.013839863
0.647544
100.00%
34.65%


OR2A14
0.015508627
0.993415
81.58%
67.65%


TAS2R10
0.016026464
0.326119
15.83%
12.88%


GPR110
0.016469961
0.726944
59.84%
60.86%


CX3CL1
0.017536946
0.117163
100.00%
71.11%


TAS2R4
0.0185871
0.201529
29.12%
14.53%


XKR3
0.018628148
0.545371
18.87%
70.91%


EPHB3
0.018940533
0.502897
29.63%
47.52%


TMPRSS5
0.018969675
0.589436
71.78%
30.85%


OR9Q1
0.018983602
0.917247
81.20%
81.27%


TLR2
0.019100789
0.470826
51.75%
53.64%


OR9A2
0.019317845
0.516833
31.23%
28.47%


DSG1
0.019795728
0.567852
54.76%
55.28%


OR13A1
0.021116533
0.716623
84.64%
47.81%


FAT3
0.021138231
0.289766
23.34%
25.15%


OR1L8
0.022372362
0.643219
80.77%
51.71%


IL4R
0.023899289
0.335102
30.77%
58.12%


ENPP6
0.025088121
0.335612
21.96%
75.90%


EFNB2
0.025356024
0.169393
22.74%
26.45%


FGFR4
0.0262064
0.296085
37.36%
53.94%


SLC9A2
0.027190369
0.365608
41.31%
19.11%


CDH3
0.027397592
0.453031
51.62%
30.17%


CR2
0.028556562
0.642956
68.14%
62.41%


ADRA1A
0.028845367
0.426984
85.82%
73.90%


OR1S2
0.02916823
0.717935
100.00%
83.34%


MME
0.030756491
0.591549
14.03%
36.32%


KLRB1
0.032475047
0.213607
15.92%
10.26%


SLC10A2
0.03275455
0.851805
70.74%
75.16%


DSC2
0.033233433
0.520117
46.48%
28.57%


TAS2R7
0.033841624
0.614803
26.32%
33.24%


OR13C9
0.034277568
0.740651
100.00%
28.60%


PDGFRA
0.034416122
0.451549
10.86%
46.23%


OR2A25
0.03552652
0.938721
100.00%
71.03%


OR2A12
0.035687425
0.994012
60.25%
62.80%


IL23R
0.036369788
0.613067
58.45%
64.06%


OR9A1P
0.038328013
0.69407
100.00%
48.42%


OR1J4
0.038914619
0.549154
67.58%
46.38%


MMP17
0.04021141
0.281181
22.52%
51.55%


SLC46A3
0.041716091
0.389513
10.14%
29.11%


HLA-DPB1
0.043641859
0.395253
56.66%
67.43%


SUCNR1
0.047035846
0.660814
91.66%
65.69%


HLA-DMA
0.049805633
0.336833
11.35%
39.34%


OR1J2
0.050489198
0.664251
67.92%
53.01%


OR9G4
0.050824372
0.91413
100.00%
85.55%


CEACAM1
0.052876583
0.346306
21.52%
11.56%


CRHR2
0.055144286
0.264782
63.08%
29.91%


ERVMER34-1
0.055572169
0.318853
33.42%
41.85%


MTNR1A
0.056140081
0.777653
76.36%
64.45%


OR1J1
0.056598819
0.712029
47.77%
53.37%


SLC17A8
0.05829662
0.679933
45.27%
41.92%


CNTNAP3
0.058407089
0.161318
39.24%
29.89%


OR4M2
0.059603738
0.528109
100.00%
75.41%


RGMA
0.061505925
0.272183
21.14%
41.97%


TRPV6
0.06204423
0.413929
43.54%
64.49%


CACNG7
0.066494282
0.2808
10.98%
82.33%


UPK1A
0.066974912
0.663818
40.32%
75.89%


SLCO2A1
0.06741531
0.576558
42.03%
13.55%


MFI2
0.072748757
0.215102
30.66%
22.15%


GABRR2
0.07317984
0.47354
34.99%
40.99%


TNFRSF1A
0.073812744
0.364976
10.21%
13.39%


OR56A1
0.07399119
0.858549
53.00%
34.91%


MST1R
0.074404792
0.591335
58.89%
15.83%


OR2L13
0.07695085
0.757735
81.87%
73.75%


IL1RAPL2
0.0776838
0.523302
58.36%
46.99%


CYBB
0.078629877
0.342058
57.60%
30.36%


PCDHB4
0.084692394
0.302877
25.12%
16.26%


SPACA1
0.085012316
0.584819
34.07%
74.13%


SLC12A8
0.08538709
0.326941
38.88%
35.42%


GPRC5D
0.085529285
0.465035
38.48%
24.62%


LYPD3
0.085802705
0.759723
58.79%
54.25%


AQP4
0.089780677
0.549586
59.14%
38.39%


ESYT3
0.091559678
0.178229
21.46%
15.31%


VTCN1
0.095112743
0.185368
33.51%
46.82%


ERVV-2
0.096038814
0.666382
55.12%
70.28%


IL18R1
0.096127678
0.551192
73.42%
64.50%


PCDHB16
0.098000564
0.331829
16.51%
15.08%


LRRN2
0.098105712
0.127241
39.40%
35.39%


GRIK2
0.098857286
0.203627
32.25%
19.54%


NRG4
0.099399089
0.260411
18.13%
20.67%


CD86
0.100551892
0.663328
59.42%
11.47%


OR5G3
0.102371633
0.676355
100.00%
67.27%


PCDHB11
0.103815249
0.26072
11.17%
16.28%


KCNMB4
0.105038502
0.222219
22.01%
22.40%


CNR1
0.10571149
0.213543
35.83%
31.06%


F2RL1
0.106186666
0.484344
54.69%
35.26%


GFRAL
0.107140783
0.170322
29.31%
48.29%


GPRC5B
0.108411012
0.10721
23.37%
10.41%


GJB6
0.109506084
0.862423
50.38%
61.87%


PCDHB6
0.112838679
0.364807
20.99%
15.03%


SLC22A15
0.113416061
0.378399
51.89%
35.40%


PCDHB5
0.114159032
0.334816
17.97%
19.27%


TRPV4
0.114643774
0.146926
26.99%
42.94%


TNFSF4
0.115249636
0.371655
17.33%
43.20%


DSG2
0.116000019
0.202068
39.80%
20.91%


KEL
0.120910405
0.365646
19.53%
38.30%


PTPRT
0.130093482
0.368033
72.16%
31.30%


SUSD3
0.133668009
0.783583
85.95%
47.18%


TENM4
0.134065874
0.226163
32.49%
20.84%


CHRM2
0.13554
0.371524
49.51%
20.81%


SLC26A1
0.138435991
0.390587
39.94%
52.26%


ITGB6
0.139238334
0.594235
52.04%
24.87%


FPR3
0.139804913
0.502996
44.66%
35.31%


ADRB1
0.141201256
0.607753
22.55%
42.52%


ERVV-1
0.145860715
0.507579
36.44%
65.81%


DSC3
0.146403903
0.648925
28.03%
34.75%


TNFSF8
0.14698994
0.618329
80.13%
31.95%


CD55
0.150135424
0.211569
16.98%
11.83%


SLCO1B7
0.150952106
0.915267
57.51%
69.94%


OR52I1
0.154537609
0.513911
50.16%
20.58%


GLRA2
0.156600032
0.14043
19.23%
21.63%


CD96
0.157863716
0.477956
52.90%
44.88%


OR2M7
0.15876197
0.916036
39.01%
52.33%


PRLR
0.159286417
0.420592
28.09%
53.15%


ANO2
0.16030019
0.252646
63.13%
40.91%


CD69
0.164815239
0.690481
55.14%
55.37%


ADAM20
0.166413187
0.243452
15.92%
14.82%


MET
0.169015296
0.235704
14.02%
14.11%


OR2T33
0.174236616
0.812728
57.23%
62.11%


OR5K2
0.174666738
0.422613
73.39%
17.10%


SLC7A4
0.17803141
0.2785
100.00%
32.07%


LILRB1
0.181261011
0.723975
42.58%
70.18%


TNFRSF21
0.182948506
0.154049
23.81%
13.26%


IL1R2
0.185112377
0.627093
29.48%
68.51%


SLC26A8
0.19056878
0.337852
34.50%
18.91%


NCMAP
0.19327846
0.607444
100.00%
43.91%


CDH8
0.194710737
0.354918
50.62%
16.22%


ATRNL1
0.195716156
0.245131
23.42%
12.15%


OR2K2
0.196488959
0.721186
77.89%
54.47%


TMEM132C
0.202964813
0.633432
91.89%
47.15%


OR5B2
0.203401678
0.810152
65.45%
74.87%


TLR9
0.20361623
0.3674
72.90%
19.20%


OR14A16
0.203932798
0.771262
50.32%
67.38%


TNFRSF10A
0.204795169
0.65951
44.10%
46.49%


OR6C76
0.207984379
0.9901
80.75%
65.14%


SLC37A2
0.209902696
0.292212
21.10%
50.60%


TNFRSF14
0.213815918
0.645521
49.63%
47.81%


SLC22A9
0.217506966
0.220773
71.16%
47.72%


SPN
0.217712541
0.339599
49.88%
62.67%


SLC36A2
0.220665533
0.326637
77.16%
69.33%


OR5H6
0.224152204
0.795929
100.00%
67.57%


TRPV5
0.224234664
0.510244
27.48%
56.10%


SLC5A1
0.224586241
0.432877
61.43%
10.40%


CLDN24
0.230121474
0.158046
12.00%
54.84%


LPAR5
0.230286127
0.158757
25.14%
59.51%


CORIN
0.235163153
0.339445
25.11%
26.74%


FLT3
0.236239688
0.507759
54.60%
48.73%


VSIG10L
0.239025236
0.287458
27.07%
50.65%


SLC26A9
0.244667472
0.20879
55.73%
20.72%


PCDH20
0.24473481
0.406825
69.21%
24.93%


IL22RA1
0.247480624
0.528809
48.70%
41.01%


HTR1F
0.25262321
0.426215
38.01%
39.52%


SCTR
0.269360584
0.585706
41.15%
53.18%


AREG
0.285365133
0.988205
40.33%
34.77%


TMPRSS11E
0.287289737
0.757176
50.76%
35.24%


GPR27
0.287369334
0.129887
15.05%
41.52%


OR2M3
0.287883414
0.723642
49.61%
25.37%


CHRM3
0.292760552
0.429913
35.99%
28.84%


OR5212
0.293589602
0.565417
100.00%
25.71%


AMICA1
0.294366502
0.430957
54.26%
61.89%


CNTNAP3B
0.304664468
0.162365
37.98%
27.46%


MMP16
0.305192815
0.148228
32.67%
21.30%


DSC1
0.30666097
0.465046
29.64%
37.02%


EPHA6
0.307795383
0.117628
33.80%
21.89%


SLC40A1
0.308943972
0.314302
12.16%
25.02%


PTPRJ
0.314666079
0.141104
15.58%
14.29%


OR11H4
0.317603218
0.560032
29.95%
35.99%


CDH4
0.318696407
0.389524
46.11%
20.95%


OR2M2
0.322368988
0.708985
74.12%
62.75%


CLDN10
0.327363727
0.159067
16.77%
25.90%


P2RY10
0.333403021
0.665451
77.17%
77.98%


ULBP2
0.337577227
0.29396
35.12%
22.53%


OR2T12
0.342472629
0.714293
75.25%
61.56%


PVRL3
0.353586641
0.250931
10.89%
19.79%


OR2M5
0.354120997
0.779831
44.43%
50.29%


EPHA3
0.362160887
0.138787
23.92%
33.99%


NMBR
0.362182681
0.541793
29.88%
28.24%


OR56B4
0.369114629
0.558478
58.38%
30.35%


OPRM1
0.372173832
0.186038
64.22%
32.52%


SLC5A4
0.376301607
0.129465
20.37%
22.08%


OPCML
0.389676505
0.294599
69.53%
35.03%


PCDHA1
0.391064646
0.157543
35.28%
10.59%


GPR116
0.394508978
0.247755
27.35%
34.25%


KLRF1
0.399078459
0.674108
19.83%
47.89%


SLC6A14
0.4026801
0.566357
52.21%
40.86%


HTR2C
0.409046112
0.498029
59.44%
51.72%


NPSR1
0.414882712
0.461735
60.16%
37.20%


OR5H2
0.420245553
0.905735
71.84%
66.85%


SLC6A19
0.421923475
0.536126
78.46%
16.05%


HBEGF
0.422130674
0.127216
10.82%
17.99%


RNF43
0.423679314
0.396023
26.70%
32.10%


SLC22A13
0.425250729
0.510741
16.86%
32.17%


ABCA9
0.4277513
0.275948
31.58%
27.72%


MFAP3L
0.428727582
0.199564
11.18%
24.09%


IFNLR1
0.433412386
0.294
20.30%
13.23%


FZD10
0.437181281
0.622028
47.63%
24.64%


UNC93A
0.438775001
0.649639
82.06%
19.41%


PROM2
0.441833696
0.393812
54.47%
37.29%


SLCO1B3
0.442776927
0.854388
42.64%
61.95%


SLC28A2
0.444899935
0.217122
25.65%
12.37%


TAS1R1
0.45291952
0.626463
43.90%
20.96%


OR4F21
0.454580119
0.210305
28.56%
24.89%


OR2A5
0.470985473
0.837936
100.00%
63.44%


SLC22A20
0.471884901
0.31203
13.44%
13.14%


ABCG2
0.480513416
0.329798
23.97%
42.04%


SLC4A5
0.481157567
0.128431
13.80%
11.15%


PCDH19
0.489035885
0.189855
28.68%
25.74%


SEMA5A
0.500223818
0.364455
23.62%
38.59%


VIPR2
0.510572731
0.660258
51.81%
33.31%


LTK
0.519512543
0.311795
13.06%
38.57%


LY75
0.522290382
0.249467
31.45%
12.70%


EFNA3
0.529633845
0.27612
16.80%
26.97%


EPHB6
0.539794027
0.597071
40.31%
50.22%


ERBB4
0.56107755
0.172151
13.10%
17.25%


CA14
0.571308258
0.128152
26.81%
12.06%


CNTN5
0.581581196
0.300722
27.49%
29.98%


OR2M4
0.582020963
0.580173
66.24%
36.75%


FCER1A
0.591025159
0.493507
100.00%
67.56%


OR5H15
0.593724479
0.689702
55.59%
66.75%


KLRG1
0.596205981
0.142958
27.45%
20.35%


OR13H1
0.598162745
0.51299
22.13%
31.26%


PCDHA4
0.60134538
0.218153
23.26%
15.97%


PCDHGA4
0.602655137
0.163238
10.30%
11.58%


LYVE1
0.61113917
0.268007
15.56%
14.62%


CDH13
0.613502521
0.342099
40.25%
18.34%


CD93
0.627459193
0.224708
100.00%
12.24%


EMB
0.629582122
0.247293
10.10%
13.93%


TNFRSF17
0.630768688
0.245416
45.29%
13.44%


CTLA4
0.642812168
0.393482
26.78%
58.56%


SELE
0.6433245
0.390103
54.55%
35.02%


OR11H1
0.649357164
0.269127
32.41%
38.72%


PTGER3
0.665517257
0.197934
39.76%
15.31%


IL1RAPL1
0.688183296
0.231912
41.10%
35.67%


GPR157
0.69036096
0.537657
39.32%
51.47%


OR2F2
0.696878987
0.401806
45.07%
62.41%


DYNAP
0.706197838
0.567356
15.43%
36.68%


OR4D2
0.720626162
0.14698
43.04%
39.72%


FLT1
0.729697246
0.194547
15.15%
23.07%


OXGR1
0.743841162
0.288636
25.39%
33.57%


HTR3B
0.779009395
0.278209
29.90%
45.18%


OTOA
0.785937295
0.267347
16.95%
18.12%


PTGER2
0.793703486
0.121655
15.34%
25.18%


SLCO1A2
0.802250978
0.196178
17.31%
10.80%


OR6B1
0.802485941
0.46091
72.71%
52.28%


NOX4
0.821136337
0.266074
45.25%
20.04%


MSR1
0.828371516
0.151105
41.81%
24.54%


C5AR1
0.832412178
0.310529
16.58%
32.90%


MUC13
0.834813066
0.322597
19.84%
16.00%


SLCO1B1
0.836752168
0.260668
20.64%
11.76%


MDGA2
0.836864692
0.210291
24.66%
16.08%


NPY5R
0.867710216
0.388816
58.16%
41.80%


IGSF1
0.872718716
0.121582
16.61%
19.65%


HLA-DMB
0.89272369
0.20179
29.71%
17.38%


IL18RAP
0.907294485
0.425764
54.57%
31.49%


OR56B1
0.926460274
0.397007
27.69%
39.20%


OR2F1
0.943961981
0.443042
41.18%
41.24%


DUOX2
0.959949085
0.184136
19.80%
13.30%


SGCZ
0.969958844
0.14357
32.02%
10.60%


RAETIG
0.973088186
0.139034
16.11%
14.57%


EPCAM
2.02382E−18
0.345566
44.27%
0.08%


MPZL3
4.99593E−16
0.534769
76.83%
9.06%


DLL1
1.74009E−10
0.427292
44.74%
1.01%


CDH1
7.07699E−10
0.523184
58.95%
6.24%


KIT
6.69101E−09
0.378968
31.12%
5.66%


ENPP4
1.95292E−08
0.189435
11.85%
2.46%


SLC10A5
2.96282E−08
0.292874
28.00%
7.67%


P2RX4
2.27518E−07
0.193772
6.62%
1.20%


TMEM87A
1.22819E−06
0.135133
6.80%
11.55%


ENPP5
1.15581E−05
0.319918
45.40%
9.41%


GRM7
5.91371E−05
0.468273
50.67%
2.29%


SMO
6.68432E−05
0.088063
26.67%
63.85%


MEGF9
7.56124E−05
0.12105
18.55%
7.64%


TPBG
8.56861E−05
0.424973
4.17%
2.82%


F2R
0.000113079
0.149416
2.29%
53.20%


LPPR1
0.000118726
0.045147
57.69%
32.92%


CD37
0.000139435
0.143309
7.38%
59.39%


SLC15A2
0.000255311
0.239744
15.61%
2.70%


FREM2
0.000256065
0.338356
31.55%
8.91%


ITGB8
0.000279081
0.298247
26.47%
4.82%


SLC29A1
0.000295873
0.046854
0.65%
14.91%


GPR160
0.000380265
0.192355
23.31%
6.96%


KLRK1
0.000413482
0.995288
50.03%
9.98%


TMEM87B
0.000510537
0.112924
10.02%
1.40%


LPHN3
0.000698088
0.060092
46.51%
4.75%


BACE1
0.000810086
0.065745
9.24%
0.71%


ALCAM
0.001043198
0.246204
20.28%
7.57%


NCR3LG1
0.001245492
0.08902
26.24%
5.19%


PKHD1L1
0.001307845
0.29306
45.18%
8.13%


TMEM123
0.001447703
0.102344
11.43%
4.56%


TMEM182
0.001478348
0.051119
17.60%
3.19%


PLET1
0.001595024
0.171932
14.69%
5.60%


SLC6A16
0.001833695
0.0162
26.65%
48.39%


LINGO2
0.001895523
0.19192
55.82%
1.39%


KIAA0922
0.001914469
0.158753
9.78%
11.92%


HEPACAM2
0.002317196
0.164385
51.46%
7.43%


SLC12A2
0.00242017
0.045658
4.79%
10.35%


SLC1A1
0.003394852
0.191851
19.87%
1.43%


CCKBR
0.003725192
0.342195
90.32%
3.31%


CD160
0.00389868
0.170698
6.32%
2.52%


NOTCH1
0.004020153
0.147541
4.23%
40.57%


SVOPL
0.004081823
0.341754
34.83%
3.91%


SLC23A1
0.004213537
0.25089
7.30%
7.41%


SUCO
0.004675952
0.07198
1.44%
3.00%


ITGB4
0.004906184
0.514201
8.75%
55.46%


ANO6
0.005524992
0.172207
3.00%
6.65%


GP1BA
0.005945809
0.002759
41.14%
17.46%


RNFT1
0.006873387
0.099814
2.44%
8.05%


ENTPD3
0.007279018
0.165306
20.28%
1.10%


TMPRSS11D
0.009674279
0.175342
28.07%
2.94%


UGT8
0.012270284
0.11394
32.92%
6.71%


GNRHR2
0.012379872
0.081632
5.38%
0.92%


SLC22A23
0.013490751
0.160706
14.88%
9.74%


NUP210
0.013666093
0.092027
15.09%
5.60%


P2RY1
0.013698663
0.034256
10.70%
47.88%


SLC7A2
0.014618404
0.053093
53.75%
12.30%


VSIG2
0.01579597
0.092862
36.95%
37.47%


ZP2
0.016556352
0.078104
58.40%
52.67%


BRS3
0.01697724
0.042971
59.71%
0.74%


FGFR3
0.020297633
0.083726
7.22%
25.79%


MXRA8
0.020404014
0.462705
7.14%
67.07%


SLC16A6
0.02390724
0.030914
3.61%
16.38%


CD46
0.026096598
0.07699
6.34%
6.70%


IL20RA
0.026755353
0.560022
45.79%
2.92%


TMX3
0.027176233
0.063082
5.61%
2.68%


ASTN2
0.027524861
0.040549
20.44%
2.51%


SLC22A4
0.029046522
0.119051
0.70%
2.14%


SLCO5A1
0.030227009
0.050288
30.43%
6.75%


TGOLN2
0.03273918
0.083115
2.38%
3.33%


ITGA2
0.034090169
0.308722
5.49%
18.58%


CLDN2
0.035184898
0.416548
14.58%
7.96%


SLC41A1
0.03927828
0.120731
2.92%
15.18%


TMEM25
0.039486944
0.125839
14.06%
5.13%


CNNM4
0.042901454
0.02802
6.38%
9.24%


TGFA
0.045427395
0.410837
39.09%
9.43%


PCDHB13
0.047145464
0.20157
2.20%
3.73%


CLEC2D
0.048823542
0.176045
6.71%
7.68%


GPR55
0.04916716
0.439132
100.00%
4.48%


MFSD8
0.049379748
0.059857
3.94%
1.37%
















TABLE 9







Surface proteins associated with the SCLC-P subtype from the Sato dataset











Surface Protein
ANOVA p value
P vs N
P vs I
P vs A














ART3
 1.2998E−05
0.662148
70.204%
62.747%


PROM1
2.76663E−05
0.25483
57.251%
14.357%


NOTCH1
4.87508E−05
0.123338
17.436%
19.492%


TNFSF4
0.000199207
0.244973
25.491%
19.693%


PRLR
0.000840064
0.260746
46.405%
52.358%


MME
0.001908314
0.473581
24.432%
50.273%


OR2B3
0.004715832
0.586817
29.496%
26.796%


LDLRAD4
0.005285089
0.258651
21.737%
14.572%


CCR5
0.005464222
0.408635
10.927%
21.751%


TIGIT
0.012805575
0.49146
13.370%
19.357%


MFI2
0.012826303
0.156787
27.083%
25.959%


TEX101
0.013201621
0.527416
21.996%
13.154%


FAP
0.022727492
0.242762
18.279%
16.091%


JAG1
0.023646265
0.192893
12.006%
18.315%


CDH22
0.027697679
0.341067
52.483%
29.156%


CD6
0.030125671
0.543197
14.206%
27.522%


PRTG
0.035274209
0.189406
22.644%
29.456%


BTN3A1
0.040328712
0.186453
12.742%
14.610%


ERVFRD-1
0.04249732
0.437423
58.257%
44.479%


SVOPL
0.043554717
0.547867
29.708%
36.161%


HLA-DQB1
0.044608653
0.538001
41.789%
53.641%


SLC28A3
0.058109964
0.166732
11.442%
49.439%


GPR32
0.059841001
0.326674
48.851%
11.051%


PKHD1L1
0.060329735
0.73797
21.830%
25.166%


LGR5
0.06858935
0.160077
62.650%
15.182%


VCAM1
0.070368953
0.358085
17.366%
25.644%


CXCR3
0.085582802
0.327426
10.335%
22.699%


LRRC15
0.090682069
0.306011
13.012%
23.493%


IL20RA
0.111415007
0.596385
37.625%
41.667%


TNFRSF4
0.129959253
0.459243
18.426%
39.519%


VTCN1
0.151308506
0.226516
20.306%
37.608%


C3orf80
0.15220129
0.302032
17.846%
27.087%


P2RY10
0.157726973
0.446814
18.430%
42.652%


GABRP
0.171236688
0.234794
48.794%
42.461%


SIRPG
0.172099411
0.669871
11.428%
26.020%


TLR1
0.233778951
0.248104
13.499%
23.407%


DRD3
0.265995847
0.54176
40.561%
33.405%


LY75
0.268294766
0.281054
11.438%
20.845%


GLRA1
0.290102441
0.174587
52.418%
16.091%


EPHA4
0.304526498
0.249193
19.504%
18.679%


VLDLR
0.308025733
0.259313
13.836%
11.308%


SIGLEC10
0.359314534
0.32217
12.112%
12.512%


TNFRSF9
0.368884213
0.246724
15.606%
17.552%


CCRL2
0.380422323
0.41643
10.540%
21.366%


EFNA3
0.394772627
0.225541
21.263%
18.815%


FCRL4
0.457873258
0.405458
17.592%
16.385%


CORIN
0.508566636
0.395145
30.486%
28.618%


NOX4
0.514923909
0.139361
23.313%
17.446%


CEACAM1
0.546893035
0.424365
10.824%
17.432%


AMN
0.554657767
0.365207
28.224%
33.180%


BTLA
0.576763569
0.303658
14.473%
21.401%


CDH17
0.586890385
0.506942
35.203%
19.240%


ZPLD1
0.628796415
0.135294
10.391%
29.853%


SUCNR1
0.631460481
0.336939
15.209%
18.889%


GSG1
0.633640739
0.269539
33.426%
34.495%


CCR3
0.675585655
0.363197
13.957%
23.492%


TRHR
0.68036082
0.133491
10.296%
12.604%


TAS2R8
0.834484916
0.400714
23.592%
12.855%


HEPACAM2
2.17258E−11
0.097628
53.731%
0.744%


KCNMB3
3.76264E−09
0.38387
2.573%
5.931%


KIT
6.26736E−08
0.087065
42.303%
9.946%


EPCAM
8.43294E−08
0.035613
0.017%
0.734%


SLC44A1
3.48196E−07
0.078006
5.172%
6.303%


CHPT1
1.69432E−06
0.216974
5.321%
17.991%


TMEM87A
 3.1838E−06
0.145235
1.119%
11.110%


TMX3
 4.2271E−06
0.049912
5.689%
0.692%


FZD3
4.80862E−06
0.132925
11.171%
1.990%


EFNA4
3.69156E−05
0.154554
1.872%
44.668%


ACVR2B
5.85767E−05
0.090462
17.760%
4.970%


ICOS
0.000618045
0.411374
7.269%
51.703%


SLC5A3
0.000720572
0.091042
9.897%
2.103%


TNFRSF25
0.000813338
0.130748
23.393%
1.481%


DSG2
0.000887054
0.17887
2.184%
16.799%


BTN3A3
0.001043248
0.278059
22.301%
27.320%


SLAMF7
0.001190124
0.466535
6.076%
22.392%


BTN2A2
0.001547106
0.066278
7.428%
9.763%


IL27RA
0.001800748
0.644602
9.623%
39.850%


TNFSF13B
0.001949925
0.346322
8.821%
18.479%


HLA-E
0.001990978
0.149901
2.007%
14.554%


RNFT1
0.002140771
0.108749
3.437%
5.442%


TMEM123
0.002288474
0.035826
2.558%
4.067%


HIAT1
0.00290717
0.007914
2.513%
1.009%


CD84
0.005249768
0.336669
6.300%
17.497%


PDGFRA
0.005478881
0.355302
12.580%
25.318%


SLC12A8
0.005777932
0.305535
5.688%
39.048%


RNF43
0.005791168
0.10495
1.723%
28.760%


CD40LG
0.006348126
0.634674
8.149%
31.415%


MILR1
0.007520632
0.359341
16.872%
39.426%


LILRA4
0.007791151
0.294002
13.465%
35.727%


IL15RA
0.008020583
0.221492
2.696%
15.234%


TMEM108
0.008314283
0.115159
36.188%
4.178%


BTN2A1
0.010034365
0.056814
15.270%
8.897%


FPR3
0.011425995
0.276224
3.203%
14.234%


GPC4
0.01154952
0.24206
6.118%
26.140%


SIGLEC8
0.013371752
0.550992
19.753%
22.763%


BTN3A2
0.014909281
0.193761
16.264%
24.178%


C16orf52
0.015057781
0.067421
7.449%
1.318%


CD80
0.016477818
0.25146
8.800%
5.681%


CD96
0.017797972
0.381662
8.632%
26.825%


TLR7
0.018041997
0.517391
1.441%
22.758%


TNFRSF17
0.018050766
0.559379
5.926%
37.133%


CLEC5A
0.020084646
0.377996
0.631%
47.287%


SLC10A3
0.021207072
0.066508
1.616%
18.374%


CRTAM
0.021898481
0.584179
9.660%
20.736%


LRP1B
0.024412537
0.333244
78.679%
45.629%


GPR171
0.02441676
0.473553
1.048%
29.203%


IL18R1
0.024602517
0.537454
9.455%
30.993%


ADORA3
0.02718111
0.334552
10.534%
41.849%


ITGB7
0.031076277
0.459
28.290%
38.349%


FCGR2B
0.033423689
0.373126
7.167%
12.491%


SLC43A3
0.036494082
0.098964
17.614%
15.471%


PTGER1
0.037929605
0.282717
7.504%
11.009%


MPZL3
0.040723592
0.188717
1.284%
4.597%


HLA-C
0.045437467
0.07974
2.116%
10.147%


CXCR6
0.045599702
0.359267
22.747%
29.545%


HAVCR2
0.049116133
0.298879
12.792%
34.416%
















TABLE 10







Surface proteins associated with the SCLC-I subtype


from the George et al. dataset











Surface
ANOVA





Protein
p value
I vs N
I vs P
I vs A














SLAMF6
 2.0489E−14
83.15%
52.34%
70.83%


HLA-DOB
8.40165E−13
68.03%
23.50%
53.58%


VNN2
1.10838E−12
82.20%
44.26%
62.27%


IL15RA
1.68281E−11
66.66%
27.77%
50.91%


CD180
1.80221E−11
68.23%
33.79%
58.50%


CD38
2.43721E−11
72.74%
40.18%
56.98%


EVI2B
4.76043E−11
60.28%
24.38%
47.72%


HAVCR2
5.12432E−11
56.33%
24.39%
44.74%


CD84
5.79077E−11
75.16%
42.13%
69.38%


CCRL2
 7.2792E−11
71.71%
36.02%
55.07%


CLEC12A
7.86442E−11
83.14%
43.21%
70.31%


GPR65
8.06116E−11
71.95%
32.19%
61.57%


P2RY10
8.30508E−11
78.01%
47.92%
68.33%


SIGLEC8
1.09725E−10
75.90%
48.17%
63.12%


SLAMF1
 1.3785E−10
77.14%
43.32%
64.24%


CD6
1.51793E−10
73.31%
43.59%
61.77%


CD96
1.63341E−10
74.93%
40.55%
62.12%


TMEM150B
1.72326E−10
74.06%
35.42%
59.69%


CD86
2.11085E−10
71.44%
40.10%
58.35%


PDCD1LG2
2.11378E−10
70.19%
40.35%
58.80%


S1PR4
2.41467E−10
72.20%
31.30%
60.31%


TNFSF13B
2.72077E−10
69.87%
34.27%
51.78%


CD48
3.15615E−10
59.36%
26.28%
43.26%


CD97
3.35334E−10
60.69%
28.88%
49.28%


SEMA4A
3.98484E−10
65.90%
21.09%
58.06%


SIGLEC14
4.04895E−10
77.99%
33.06%
58.28%


CLEC7A
4.37288E−10
67.40%
27.08%
62.62%


FCRL5
4.61194E−10
82.65%
43.09%
72.34%


SLAMF7
4.83623E−10
61.39%
33.32%
47.06%


CD53
5.25442E−10
52.99%
25.06%
41.56%


TLR8
 5.4449E−10
75.93%
42.60%
66.11%


ITGAX
5.50841E−10
57.54%
23.53%
50.63%


PILRA
5.65337E−10
56.54%
30.80%
49.61%


LY9
6.62498E−10
81.47%
43.18%
66.66%


CD300LF
6.82801E−10
63.97%
35.65%
50.65%


GPR171
6.89105E−10
78.14%
41.29%
59.99%


CCR5
7.96872E−10
70.44%
39.09%
61.44%


HLA-DMA
8.65142E−10
39.67%
15.03%
29.81%


SIGLEC7
1.09414E−09
68.42%
38.66%
58.99%


CD33
1.11754E−09
71.71%
31.20%
61.52%


EVI2A
1.12892E−09
69.84%
23.16%
54.93%


ICOS
1.13456E−09
76.36%
43.86%
63.09%


HLA-DMB
 1.3426E−09
43.05%
19.42%
34.63%


CD52
1.37278E−09
44.74%
13.23%
32.50%


CEACAM21
1.38519E−09
70.34%
35.60%
67.69%


ITGAL
1.42536E−09
68.25%
37.67%
58.94%


HLA-DOA
1.42768E−09
54.89%
25.47%
45.14%


CD2
1.52338E−09
62.65%
29.09%
48.37%


CXCR6
1.54737E−09
72.14%
36.93%
53.34%


CD80
1.57981E−09
69.61%
47.19%
57.54%


P2RY13
1.64544E−09
70.69%
35.02%
61.92%


CD5
1.66421E−09
73.72%
48.40%
62.63%


TNFRSF17
1.69606E−09
76.86%
43.38%
62.56%


AMICA1
1.76006E−09
64.84%
27.46%
56.14%


SIGLEC9
1.87646E−09
67.54%
30.70%
59.15%


IL18RAP
1.87988E−09
81.56%
41.86%
67.76%


CD37
1.88527E−09
60.25%
23.07%
49.57%


CCR1
1.96273E−09
58.07%
26.96%
46.26%


SLC1A3
1.98011E−09
63.13%
36.42%
69.71%


TNFRSF9
2.03278E−09
70.70%
51.48%
65.47%


GPR174
2.04938E−09
75.64%
37.31%
64.35%


LILRB1
 2.0837E−09
73.98%
41.14%
64.29%


FCRL3
2.16991E−09
81.56%
55.75%
70.41%


TRAT1
2.28791E−09
77.68%
41.67%
57.98%


PTAFR
2.34959E−09
69.70%
33.29%
63.81%


PDCD1
2.50224E−09
73.30%
39.80%
61.43%


DPEP2
2.56288E−09
69.85%
25.38%
56.00%


CD19
2.57633E−09
84.60%
58.66%
72.71%


TIGIT
2.65466E−09
70.79%
37.24%
54.95%


PTPRC
2.70821E−09
61.71%
31.26%
49.42%


IL12RB1
2.80163E−09
69.06%
49.59%
58.58%


IFNAR2
3.15989E−09
32.28%
12.09%
16.47%


CD4
3.20309E−09
59.32%
30.52%
47.89%


FCGR1A
3.20713E−09
65.89%
27.17%
47.96%


CD3G
3.22345E−09
72.35%
32.31%
58.83%


SPN
3.41185E−09
69.27%
20.65%
66.77%


SELPLG
3.46916E−09
61.50%
29.76%
50.56%


CRTAM
3.54528E−09
73.66%
43.76%
59.94%


CSF2RB
3.66491E−09
62.28%
34.16%
54.27%


KLRB1
4.01281E−09
68.44%
19.72%
49.09%


TREM2
4.10337E−09
57.59%
13.36%
47.72%


IL2RG
4.37455E−09
56.39%
26.84%
43.19%


FPR3
4.51633E−09
51.16%
23.59%
41.35%


IL7R
4.72697E−09
66.87%
27.59%
54.52%


IL6R
4.76571E−09
71.47%
19.88%
59.72%


CD244
4.86836E−09
76.78%
44.67%
65.83%


FCRL2
4.87908E−09
84.74%
45.76%
68.67%


HLA-DRA
5.19295E−09
28.51%
10.30%
21.97%


CD27
5.30164E−09
64.15%
34.91%
48.06%


SLAMF8
5.46295E−09
55.90%
29.68%
44.05%


TLR2
5.65819E−09
58.78%
13.70%
47.53%


KLRK1
5.67699E−09
68.45%
27.81%
54.95%


VNN1
5.91542E−09
77.04%
47.28%
74.73%


BTN3A3
6.75949E−09
45.96%
10.20%
40.78%


SIGLEC10
7.09795E−09
74.41%
54.78%
59.94%


LPAR5
7.15917E−09
66.34%
30.43%
60.49%


CD79A
7.28226E−09
68.55%
41.55%
54.44%


CYBB
7.43534E−09
50.62%
23.26%
45.78%


LILRB3
7.55178E−09
67.34%
35.78%
57.41%


SELL
 7.602E−09
70.89%
42.56%
60.71%


ITGB2
7.98337E−09
53.23%
27.03%
44.31%


IL2RB
8.46731E−09
62.64%
37.10%
51.24%


GPNMB
8.74489E−09
41.54%
16.42%
33.77%


LILRB5
8.82366E−09
70.26%
33.34%
64.94%


LAIR1
9.24736E−09
57.93%
27.07%
47.15%


TLR7
9.90723E−09
66.60%
34.48%
61.77%


IL10RA
1.04823E−08
52.92%
28.25%
45.80%


PTCRA
1.05765E−08
77.67%
44.69%
66.83%


CD69
1.09854E−08
69.62%
26.38%
54.66%


BTLA
1.12215E−08
80.35%
57.52%
70.30%


IGSF6
1.42487E−08
51.11%
32.39%
45.74%


CD28
1.56819E−08
66.31%
50.44%
64.11%


TLR6
1.64202E−08
68.10%
32.24%
58.62%


CD79B
1.65147E−08
70.32%
39.13%
60.77%


FLVCR2
1.74986E−08
61.62%
24.72%
61.91%


CXCR3
1.88085E−08
70.31%
51.83%
64.47%


IL2RA
1.90577E−08
65.31%
41.64%
49.39%


SIRPG
2.06264E−08
77.69%
48.60%
61.76%


GLIPR1
2.06265E−08
50.89%
19.99%
38.23%


CMKLR1
2.09689E−08
67.64%
38.13%
61.77%


SIRPA
2.33553E−08
42.57%
10.02%
49.47%


FASLG
2.98975E−08
74.10%
42.34%
62.51%


LILRA6
3.07924E−08
64.72%
27.01%
55.29%


ICAM3
3.13145E−08
49.22%
27.61%
40.97%


CD68
3.15674E−08
41.96%
19.38%
32.34%


SLC15A3
3.21496E−08
47.63%
17.63%
33.84%


LILRB2
3.40809E−08
66.57%
33.84%
54.00%


IL21R
3.53519E−08
74.08%
53.86%
66.33%


MS4A6A
3.55458E−08
52.47%
21.52%
40.34%


HLA-DPB1
4.62258E−08
38.92%
18.02%
31.78%


CCR2
4.90605E−08
73.47%
47.05%
67.86%


ITGB7
5.18847E−08
56.49%
36.44%
47.69%


SLC17A9
5.22376E−08
59.55%
24.59%
42.20%


CD74
5.89811E−08
29.88%
13.21%
22.43%


GPR132
 6.0616E−08
59.76%
42.91%
62.90%


CD300C
6.06254E−08
65.62%
34.25%
59.30%


CD3D
6.07523E−08
64.84%
34.19%
46.67%


GPR18
6.85491E−08
76.57%
51.70%
65.17%


FCGR1B
6.94693E−08
75.07%
39.92%
60.42%


LRRC25
7.27699E−08
59.15%
34.35%
45.84%


FCGR2A
 7.7703E−08
45.19%
14.35%
34.99%


CXCL16
 7.7909E−08
47.98%
17.01%
38.67%


SIRPB1
 7.9852E−08
77.34%
22.01%
69.69%


CCR4
8.58863E−08
73.03%
43.61%
68.09%


SLC47A1
1.16018E−07
44.09%
28.31%
61.89%


CD200R1
1.18058E−07
71.15%
31.27%
56.01%


FCGR3A
1.22443E−07
51.83%
23.22%
38.61%


LAG3
1.30277E−07
49.93%
40.94%
43.91%


SIGLEC1
1.31718E−07
60.56%
31.75%
54.07%


C3AR1
1.40605E−07
51.68%
23.33%
41.57%


NCR3
1.48023E−07
76.23%
48.12%
67.49%


CYSLTR1
1.50401E−07
63.99%
20.11%
55.17%


CD226
1.52294E−07
67.39%
43.16%
56.67%


SLC37A2
1.53783E−07
54.44%
27.67%
53.23%


VCAM1
1.64606E−07
55.58%
27.17%
47.12%


HLA-DQA1
1.69908E−07
44.45%
18.49%
39.29%


FCRL6
1.83468E−07
66.99%
45.54%
63.45%


CD1B
1.86058E−07
82.55%
51.56%
81.07%


HLA-DPA1
2.02404E−07
38.54%
15.02%
29.25%


CD7
2.08808E−07
65.34%
36.98%
46.83%


GPR183
2.13468E−07
55.32%
14.67%
38.78%


SLC2A9
2.31902E−07
54.77%
22.86%
42.88%


P2RX1
2.38536E−07
69.10%
37.58%
65.96%


CD14
2.64212E−07
47.87%
21.59%
35.09%


MPEG1
2.85089E−07
47.79%
26.15%
37.94%


BTN3A1
2.86212E−07
41.14%
10.50%
33.62%


SLC6A12
3.14038E−07
65.20%
49.93%
70.78%


MS4A1
3.19834E−07
84.56%
48.96%
68.67%


HLA-DRB1
3.23095E−07
35.56%
12.43%
27.58%


CLEC12B
3.60286E−07
80.14%
38.48%
80.54%


P2RY8
3.66932E−07
61.14%
26.35%
58.14%


CD22
3.88315E−07
83.86%
44.82%
74.78%


CR1
4.07631E−07
74.29%
47.59%
70.77%


FCGR2B
4.12418E−07
72.23%
33.70%
57.18%


MRC1
5.15829E−07
76.75%
24.80%
61.36%


SLC46A3
5.17993E−07
47.42%
11.22%
40.55%


MSR1
5.37688E−07
54.65%
21.26%
47.91%


GPR141
5.93184E−07
72.74%
38.06%
68.40%


HLA-F
7.44915E−07
40.21%
17.95%
33.64%


CD40LG
7.59849E−07
75.62%
39.77%
63.81%


CD274
7.68211E−07
64.26%
45.06%
51.94%


SLCO2B1
7.72444E−07
52.65%
27.47%
47.05%


ITGAM
8.53209E−07
66.32%
29.99%
61.49%


HLA-DQB1
1.06577E−06
47.90%
15.89%
44.25%


TNFRSF1B
1.17968E−06
43.41%
25.94%
38.64%


TLR10
 1.1797E−06
84.76%
49.94%
71.99%


TLR1
1.24504E−06
56.51%
23.91%
42.70%


GYPC
1.54539E−06
45.92%
15.50%
38.38%


MMP25
1.62565E−06
59.73%
41.45%
54.94%


TMEM106A
 1.6803E−06
48.20%
20.02%
39.41%


TRPV2
1.70835E−06
41.99%
27.93%
35.63%


CXCR5
1.78382E−06
79.94%
48.27%
69.34%


TNFRSF4
1.86433E−06
46.04%
19.92%
36.95%


NFAM1
1.96793E−06
51.99%
34.12%
52.55%


CD300A
2.01384E−06
45.49%
28.39%
32.29%


RHBDF2
2.14921E−06
45.46%
21.34%
36.56%


P2RY6
2.37473E−06
66.51%
39.46%
52.37%


SLC2A5
 2.5299E−06
59.27%
21.91%
54.89%


TMEM26
2.67638E−06
54.26%
42.84%
49.87%


MFSD7
2.77692E−06
49.38%
14.60%
40.74%


CCR8
3.01745E−06
70.08%
49.68%
60.91%


FCRL1
3.04241E−06
89.43%
65.60%
80.86%


EMB
3.21177E−06
42.78%
18.43%
43.72%


TNFRSF8
 3.2862E−06
67.45%
48.20%
64.49%


CLEC2D
3.36044E−06
40.47%
18.69%
50.70%


CSF2RA
3.46349E−06
63.54%
42.71%
66.91%


CD163
3.57333E−06
56.37%
25.46%
48.79%


ADCY7
3.83263E−06
40.11%
22.48%
41.89%


ICAM1
4.07088E−06
43.01%
12.45%
27.30%


SUSD3
4.32085E−06
54.21%
22.25%
40.81%


TNFRSF13B
4.52712E−06
77.23%
48.44%
69.06%


BTN3A2
4.77524E−06
41.86%
11.41%
33.89%


IL1R1
4.81042E−06
48.07%
12.41%
35.98%


BTN2A2
5.21307E−06
40.02%
20.07%
43.54%


LY75
 5.2498E−06
56.23%
24.32%
41.26%


CSF1
5.39237E−06
47.67%
25.46%
46.20%


LILRA5
6.25423E−06
68.43%
25.32%
48.48%


CCR7
6.57438E−06
61.96%
40.88%
53.70%


IL1R2
6.59636E−06
80.57%
76.21%
74.88%


FCRL4
6.65091E−06
91.45%
69.44%
85.13%


SECTM1
8.18885E−06
49.89%
26.48%
35.57%


ITGAE
8.40917E−06
32.33%
10.40%
16.67%


GPR114
8.49098E−06
69.54%
51.83%
57.62%


P2RY12
8.59531E−06
76.77%
38.26%
72.21%


TNFRSF14
8.85907E−06
27.17%
14.42%
16.31%


SIT1
9.05091E−06
57.64%
35.78%
43.08%


IGFLR1
9.13735E−06
32.55%
23.56%
26.08%


SIGLEC5
9.26414E−06
65.93%
54.83%
64.56%


MEP1A
1.14997E−05
68.03%
29.53%
72.27%


GPR15
1.24945E−05
77.03%
38.22%
71.99%


UNC93B1
1.33021E−05
30.30%
10.53%
20.11%


ADORA3
1.46671E−05
53.72%
30.14%
57.04%


ADAM8
1.48264E−05
54.48%
26.24%
37.66%


MR1
1.51261E−05
53.64%
15.66%
44.40%


PTGER4
1.53174E−05
56.08%
25.44%
42.22%


FAS
 1.5901E−05
49.21%
26.79%
46.37%


AQP9
1.76825E−05
71.52%
14.35%
49.20%


SLC12A3
1.96002E−05
72.81%
61.48%
71.42%


VSIG10L
2.28557E−05
51.54%
29.87%
49.65%


SLC40A1
2.51598E−05
30.08%
17.39%
24.45%


TNFRSF18
2.58362E−05
58.20%
29.59%
53.59%


HLA-DQB2
2.58684E−05
48.71%
28.82%
47.26%


TLR3
2.90136E−05
58.10%
14.88%
43.45%


TGFBR2
3.26298E−05
38.64%
11.16%
34.37%


P2RX7
3.59739E−05
61.65%
54.30%
56.68%


ITGAD
3.72153E−05
85.15%
40.41%
67.95%


CSF1R
4.03411E−05
45.95%
24.19%
38.39%


CD1D
4.26485E−05
59.23%
32.18%
49.17%


XCR1
5.54676E−05
79.11%
54.65%
76.04%


LILRA1
5.69984E−05
66.82%
41.35%
59.53%


KIR3DL1
5.81227E−05
89.65%
80.94%
75.57%


EMR2
5.84273E−05
68.15%
10.27%
66.38%


CD8B
6.94531E−05
51.36%
28.04%
65.09%


TMEM140
7.26214E−05
24.11%
14.36%
20.25%


GPR84
7.29165E−05
63.61%
42.80%
55.83%


HLA-DQA2
7.38048E−05
47.14%
36.66%
44.75%


ENTPD1
7.54083E−05
27.10%
20.45%
38.74%


LILRA4
8.71569E−05
62.17%
46.58%
55.78%


CTLA4
0.000108268
70.11%
40.83%
38.14%


GPR34
0.000133066
52.05%
25.35%
44.91%


CR2
0.000147094
88.33%
47.00%
74.57%


CEACAM4
0.000222012
60.09%
40.71%
55.50%


IL3RA
0.000222018
36.92%
25.30%
37.17%


GGT1
0.000228935
45.05%
26.02%
40.66%


FPR1
0.000251402
58.07%
29.81%
45.35%


ATP1A4
0.00025478
81.26%
52.62%
85.12%


GP1BA
0.000270596
55.79%
41.63%
62.82%


FOLR2
0.000275979
46.80%
28.68%
39.22%


CPM
0.000280529
53.62%
31.81%
44.24%


FCGRT
0.000306889
19.04%
11.01%
23.37%


KIR3DL2
0.000307374
79.16%
57.65%
74.23%


OSTM1
0.000310326
20.12%
10.29%
18.85%


CRLF2
0.000311888
78.15%
23.11%
81.39%


KIR2DL3
0.000314959
88.50%
65.54%
63.34%


NCR1
0.000316966
76.30%
60.02%
67.58%


MFSD2A
0.000320659
38.77%
37.18%
11.39%


ADRB2
0.000335867
58.23%
18.87%
48.44%


CDH11
0.000336463
34.61%
12.12%
28.96%


CLEC1A
0.000407114
39.57%
13.63%
45.47%


GPR161
0.000476523
15.95%
14.47%
51.73%


SLC29A3
0.000479328
34.04%
25.87%
34.32%


CNR2
0.000483208
70.16%
60.56%
70.03%


CCR6
0.000497955
63.03%
35.28%
52.50%


TNFSF4
0.000502367
43.05%
21.95%
44.87%


SCARF1
0.000509252
44.83%
24.71%
45.88%


PLXDC2
0.000510073
36.97%
16.58%
35.60%


KLRC1
0.000516275
86.58%
57.26%
53.41%


AXL
0.000517776
41.12%
18.20%
36.67%


CD1C
0.000539098
66.68%
18.75%
64.49%


SLC38A5
0.000552214
51.02%
17.13%
43.23%


IL9R
0.00057445
41.17%
32.66%
70.34%


KCNA3
0.000578449
26.41%
47.26%
54.24%


PTGER2
0.000585255
59.39%
36.43%
48.74%


SLC16A6
0.00061927
26.64%
18.33%
52.08%


SLC2A14
0.000630181
56.86%
17.42%
77.35%


DPP4
0.000668206
49.59%
14.30%
43.92%


SLC2A6
0.000702092
35.42%
47.33%
28.85%


ILAR
0.00071199
35.84%
14.71%
36.55%


SLC2A3
0.000761924
30.92%
10.89%
25.42%


TMIGD2
0.000874526
53.95%
58.88%
61.89%


CHRNA6
0.001107356
76.82%
35.67%
68.42%


ACVRL1
0.001131442
33.96%
12.05%
33.08%


SELP
0.001357549
58.69%
15.73%
49.17%


HFE
0.001374258
52.60%
12.01%
44.34%


KIR2DL4
0.001433465
87.86%
39.81%
56.35%


FPR2
0.001710602
72.46%
45.59%
52.64%


PTGIR
0.001858841
42.31%
11.48%
25.24%


GPR25
0.002113398
55.44%
40.36%
57.82%


GPR31
0.002152634
72.19%
51.40%
79.69%


IL31RA
0.002201478
59.85%
39.16%
73.59%


FAP
0.00224563
38.08%
10.25%
26.50%


EMR1
0.00232614
77.04%
50.07%
67.34%


HCAR3
0.002438521
63.30%
35.35%
41.75%


FLT3
0.002458482
70.14%
46.12%
54.61%


ITGA4
0.002477499
32.80%
14.23%
31.39%


HLA-G
0.002606559
50.00%
26.50%
55.48%


KIR2DS4
0.002665903
77.92%
55.01%
75.58%


SUCNR1
0.002967653
74.23%
12.13%
23.35%


DPEP1
0.003052523
58.76%
37.01%
66.21%


ABCA6
0.003078104
52.19%
10.72%
44.27%


CD300E
0.003196233
56.76%
17.16%
51.67%


TSPAN33
0.003331691
21.37%
19.20%
35.25%


HEPACAM
0.003396402
35.45%
39.38%
86.07%


VSTM1
0.003398374
82.60%
42.51%
57.88%


TLR4
0.003544398
54.48%
29.70%
33.53%


PIK3IP1
0.004121404
24.75%
18.38%
14.20%


SIDT1
0.004231394
50.33%
34.16%
32.55%


ALPP
0.005265665
76.73%
29.75%
70.52%


ENG
0.005443173
24.33%
12.68%
24.92%


ICAM2
0.005643045
37.41%
21.80%
14.41%


LRP10
0.005665413
22.05%
10.72%
11.98%


KLRC3
0.005849581
73.21%
40.32%
28.55%


MYOF
0.006175117
33.29%
12.36%
30.62%


GPR68
0.006417327
32.13%
30.75%
39.46%


S1PR1
0.006676834
29.22%
13.12%
26.73%


CLMP
0.00668654
40.35%
10.68%
47.81%


HCAR2
0.006754245
50.86%
20.17%
49.09%


SLC28A3
0.007405939
32.97%
33.32%
83.21%


FCGR3B
0.007501269
49.97%
21.56%
50.60%


ADAM19
0.00784852
13.08%
16.14%
29.94%


SIGLEC6
0.008217117
73.67%
13.29%
69.79%


CLEC9A
0.008600165
73.55%
18.08%
53.08%


CD40
0.010588927
33.25%
19.23%
20.22%


RAMP3
0.010713307
31.56%
15.49%
27.07%


LRRC3B
0.010915448
64.58%
68.48%
77.56%


CYSLTR2
0.011086624
40.48%
34.20%
38.41%


KLRC2
0.011660162
79.89%
31.98%
23.46%


PLXNC1
0.011819309
17.19%
37.67%
37.53%


TSPAN4
0.012634994
25.08%
26.26%
18.13%


HTR2B
0.012971039
43.95%
15.14%
43.83%


ALPPL2
0.013258468
87.82%
26.61%
86.32%


TNFSF18
0.014089112
51.13%
43.48%
52.69%


GPR1
0.014149687
77.95%
53.47%
91.14%


HEPH
0.014584616
45.69%
14.43%
31.02%


ART4
0.016075366
64.98%
12.39%
54.73%


TMEM158
0.016971813
17.84%
43.98%
20.77%


GPR155
0.018031969
40.02%
37.62%
37.00%


OR4C6
0.01906316
89.60%
81.29%
54.61%


EFNA2
0.022332929
10.03%
59.65%
75.45%


CD163L1
0.024429535
35.12%
14.29%
38.33%


SLC22A2
0.026703114
58.18%
61.27%
94.41%


EDAR
0.028623147
48.77%
32.68%
79.09%


SPNS3
0.030240964
47.63%
34.39%
56.12%


CD82
0.031670685
20.63%
18.57%
27.18%


GPBAR1
0.031808223
53.16%
43.66%
22.55%


KIR2DL1
0.033881652
72.08%
77.67%
64.43%


FGFR3
0.03601052
10.85%
23.25%
56.31%


DPEP3
0.036810148
55.54%
51.38%
69.85%


ABCB1
0.037449053
42.34%
33.34%
47.50%


APCDD1
0.038885148
20.45%
33.79%
14.00%


SIDT2
0.039726648
19.41%
15.55%
12.19%


ITGA11
0.041348494
36.32%
16.69%
30.65%


LRRC15
0.044608166
62.33%
29.44%
43.40%


SSTR3
0.045237944
24.52%
71.22%
61.35%


SLC43A2
0.04579749
20.01%
12.15%
15.42%


CD8A
0.048186112
50.12%
53.07%
48.81%


FCAMR
0.048672388
89.94%
70.70%
80.27%


SEMA4D
0.049671578
13.78%
15.77%
11.34%


PCDH11Y
0.05249787
55.00%
61.40%
72.57%


CD83
0.053170623
21.81%
14.61%
12.71%


HRH2
0.05425675
30.56%
15.85%
50.20%


OR9K2
0.055346648
50.14%
100.00%
72.80%


ACE
0.057091438
23.59%
16.05%
19.58%


KLRF1
0.0624496
49.67%
14.42%
21.97%


HBEGF
0.063083869
26.82%
12.85%
22.82%


AREG
0.063379385
59.46%
11.05%
48.78%


IL17RA
0.069735707
16.60%
15.60%
18.15%


FAM26E
0.076139775
34.14%
14.07%
24.37%


CLEC4M
0.076825144
84.98%
67.86%
53.74%


SLC14A1
0.078179092
26.35%
35.35%
66.22%


STAB2
0.080166637
61.02%
58.90%
49.80%


KEL
0.081362044
25.76%
22.89%
41.76%


GPR150
0.085508538
53.96%
33.70%
22.25%


GHR
0.086428647
50.68%
39.88%
75.13%


THBD
0.0889064
31.42%
10.05%
12.78%


MAS1L
0.089717898
90.73%
41.49%
72.12%


CA12
0.092735208
42.57%
15.66%
44.36%


CTNS
0.095491713
20.76%
11.87%
12.29%


ANPEP
0.095821779
33.92%
16.74%
31.87%


FLT3LG
0.099824876
26.64%
23.49%
18.55%


GPR82
0.106862956
30.15%
45.56%
42.85%


IL23R
0.10892897
51.72%
30.38%
57.90%


GPR151
0.114981165
75.93%
87.60%
51.46%


PCDH11X
0.11793424
18.31%
91.98%
48.10%


FCER1A
0.129568313
52.45%
14.65%
67.52%


FCAR
0.137064204
37.35%
53.89%
62.14%


ANTXR2
0.138531686
24.23%
24.79%
25.13%


SDC1
0.142896081
17.67%
18.48%
11.30%


RAET1G
0.143670101
21.34%
28.99%
46.24%


LIM2
0.145921766
68.41%
72.52%
60.71%


LRRN4
0.152287624
51.00%
17.34%
26.10%


TMEM204
0.160249453
21.96%
10.99%
15.89%


OR10G2
0.162520657
84.20%
89.46%
35.19%


F2RL3
0.163598915
28.96%
25.29%
25.86%


OR6S1
0.165047248
67.09%
94.81%
73.91%


PCDHGA12
0.168434817
23.20%
15.87%
46.95%


PARM1
0.173585911
24.09%
26.04%
12.02%


CD1A
0.187558898
34.09%
13.56%
60.83%


SIGLEC12
0.188071133
51.48%
41.93%
44.17%


TMEFF2
0.191127136
31.05%
62.28%
10.41%


SIGLEC15
0.191489067
32.80%
65.06%
24.43%


SIGLEC11
0.198069651
45.66%
17.01%
49.12%


OR52D1
0.203182103
85.29%
20.00%
73.48%


ADAM7
0.218058488
65.43%
75.61%
88.53%


PRND
0.21958522
19.64%
45.17%
69.95%


DDR2
0.220941876
29.15%
17.37%
34.66%


LRRC52
0.223360079
70.15%
35.54%
35.83%


CD248
0.225295624
19.59%
15.38%
16.88%


NRP2
0.226983312
17.46%
26.93%
25.77%


OR5AU1
0.230862414
52.98%
81.82%
56.11%


HTR7
0.231150739
50.54%
13.38%
67.83%


TREML2
0.236355659
60.54%
16.68%
35.74%


SLCO1B1
0.23811508
80.02%
97.52%
49.43%


OR51B5
0.247380328
94.86%
72.58%
69.40%


ALPI
0.248773362
62.79%
100.00%
91.77%


OR11H6
0.252091671
62.39%
100.00%
70.28%


OR4N2
0.269899128
83.72%
63.78%
89.22%


OR4M2
0.277627911
84.31%
62.19%
100.00%


ITGA1
0.297561615
11.24%
10.41%
15.12%


SSTR4
0.301516412
62.14%
91.83%
84.42%


SORCS3
0.30598007
15.56%
92.47%
12.11%


ICOSLG
0.308851901
15.47%
25.06%
16.39%


ITLN1
0.32944986
59.45%
25.32%
77.42%


OR9A4
0.342397173
59.73%
33.38%
73.64%


EPHA5
0.375869842
52.30%
64.02%
54.66%


TNFRSF10C
0.37873391
32.63%
28.83%
10.65%


PCDHA4
0.400014956
30.91%
73.41%
14.42%


PTGFR
0.411624358
19.46%
40.61%
50.59%


CNTNAP4
0.411697707
52.50%
72.17%
54.19%


OR10C1
0.420933008
53.34%
100.00%
57.06%


SLAMF9
0.429164603
41.21%
22.82%
12.79%


OR1E2
0.438456241
87.23%
34.19%
66.34%


LY6D
0.444188916
12.69%
19.90%
66.86%


HRH1
0.445940141
29.53%
22.48%
21.70%


LRP2
0.453436945
51.77%
41.99%
28.99%


CD101
0.453721123
29.37%
20.81%
25.74%


PLB1
0.459993867
24.60%
32.48%
16.06%


SLC6A19
0.473661425
42.74%
94.78%
62.75%


P2RY14
0.474983931
27.51%
11.39%
26.45%


ASGR1
0.476297454
22.57%
22.52%
11.36%


PRSS41
0.525049211
85.27%
87.12%
59.26%


ERVV-2
0.533637306
44.35%
73.25%
40.47%


CLEC1B
0.536328757
51.51%
47.43%
48.59%


ACHE
0.543275241
22.41%
37.72%
26.09%


SUSD2
0.554481684
22.06%
10.61%
10.54%


TM4SF18
0.565251826
15.14%
14.23%
27.96%


LPPR1
0.587730816
40.02%
21.26%
18.01%


OR10J3
0.588745272
62.98%
100.00%
18.60%


MUC15
0.607910314
46.90%
46.41%
13.02%


OR11G2
0.627970732
31.28%
100.00%
60.46%


CEACAM6
0.644987142
15.24%
28.56%
12.57%


MAS1
0.657858756
11.04%
78.07%
18.14%


OR52E4
0.658683792
80.82%
27.43%
49.82%


OR1L8
0.670604998
19.29%
46.31%
13.57%


LRRC38
0.671819613
46.01%
55.67%
35.07%


SCN10A
0.673755981
40.92%
26.29%
40.05%


RAET1L
0.699603878
20.71%
58.98%
40.36%


USH2A
0.704907869
35.06%
87.97%
27.88%


PHEX
0.708815533
14.96%
17.62%
25.27%


LY6G6D
0.730040354
11.19%
50.33%
39.54%


CLEC4G
0.737227214
37.27%
53.92%
22.23%


GRID2
0.739784265
57.21%
22.35%
47.45%


GRIN3B
0.749536105
21.78%
34.50%
12.92%


SLC34A1
0.757860005
17.97%
30.88%
51.28%


GLP2R
0.790996461
11.82%
34.33%
46.60%


TMIGD1
0.827554573
53.42%
51.05%
46.69%


CNTNAP3
0.931090379
13.25%
15.57%
16.86%


OR5V1
0.969185091
48.09%
24.79%
30.25%


HLA-E
2.88005E−09
27.48%
7.86%
20.92%


IL18R1
4.43558E−09
69.21%
9.27%
64.20%


GPR137B
4.23233E−08
25.19%
0.04%
22.24%


RNF149
5.54774E−08
21.62%
5.38%
17.17%


BST2
5.80782E−08
39.21%
8.78%
23.70%


CSF3R
6.05325E−07
65.07%
7.53%
45.69%


EMP3
9.52059E−07
28.36%
8.98%
26.96%


HLA-B
2.06027E−06
20.48%
5.68%
15.10%


KLRG1
2.11931E−06
44.42%
1.32%
45.70%


C5AR1
5.32274E−06
46.82%
7.56%
38.22%


SEMA7A
9.19462E−06
55.11%
9.25%
44.94%


SSPN
1.34226E−05
55.84%
0.73%
43.29%


CD44
1.41112E−05
36.61%
4.37%
48.78%


FCGR2C
1.52087E−05
66.73%
7.85%
61.92%


BST1
1.72928E−05
41.62%
5.00%
34.79%


VASN
3.53555E−05
36.74%
6.15%
20.72%


CNTN2
7.12044E−05
2.23%
80.14%
68.63%


IFNGR1
0.000134821
17.09%
6.22%
10.21%


OTOA
0.000136446
63.84%
3.69%
57.64%


NAGPA
0.000140162
27.25%
8.52%
19.70%


SLC39A8
0.000171504
44.02%
3.70%
28.51%


ABCC3
0.000257432
47.97%
8.33%
46.07%


OSMR
0.000282849
43.26%
2.31%
35.46%


PIEZO1
0.000286913
33.28%
4.50%
32.78%


MPZL1
0.000372352
16.14%
0.71%
14.32%


HLA-C
0.00039901
18.48%
3.34%
12.32%


TMEM150A
0.000447531
33.23%
7.75%
17.85%


SLC41A2
0.000472854
9.54%
40.29%
6.68%


IFNGR2
0.000478988
12.59%
4.66%
1.74%


HLA-A
0.000493636
18.13%
6.57%
10.88%


ACP2
0.000547946
20.59%
8.52%
12.85%


LPAR6
0.000648364
37.34%
0.60%
37.86%


MFSD5
0.001016103
20.69%
10.02%
6.42%


RNF130
0.001069597
9.34%
3.07%
14.16%


PLAUR
0.001308991
31.56%
8.17%
21.49%


SLC6A11
0.00136016
1.69%
54.06%
89.45%


HM13
0.001389185
12.67%
3.33%
3.36%


LAMP3
0.001608543
34.39%
9.59%
7.20%


SPPL2A
0.002034623
15.46%
6.93%
12.87%


PSEN2
0.002203809
24.28%
11.57%
6.05%


M6PR
0.002212382
12.05%
1.34%
6.23%


MMP14
0.00227536
13.27%
4.88%
21.98%


MPZL2
0.002618202
25.80%
0.15%
28.43%


TNFRSF10A
0.002652269
39.18%
4.47%
39.36%


CD59
0.004884834
19.06%
0.68%
3.24%


MRC2
0.005121681
29.09%
6.18%
22.18%


PROCR
0.005162919
22.38%
1.75%
29.40%


CD63
0.005308545
11.81%
4.59%
6.44%


ADAM9
0.005410379
18.21%
4.09%
7.40%


RPRM
0.006224452
4.85%
45.62%
3.38%


MRGPRF
0.006327273
50.89%
9.61%
46.35%


OR56B1
0.006634671
79.41%
5.25%
82.89%


CD302
0.006691516
30.25%
8.64%
4.49%


ABCA1
0.006722944
14.83%
4.77%
31.22%


ITM2B
0.007028054
10.38%
2.15%
6.28%


ITGA5
0.007467691
23.83%
4.99%
20.93%


GPA33
0.008626779
84.23%
7.89%
83.48%


TCIRG1
0.010323314
22.33%
6.69%
15.04%


F2R
0.01097726
15.75%
3.70%
19.37%


SLC31A1
0.012409667
13.91%
7.82%
8.51%


ABCA9
0.013132101
44.70%
2.49%
41.00%


CALCRL
0.014087908
33.78%
1.70%
21.77%


MYADM
0.015217168
26.50%
0.97%
1.61%


RECK
0.015625369
8.76%
16.91%
31.17%


LINGO3
0.018052603
8.62%
70.63%
18.43%


MXRA8
0.0181563
24.65%
7.89%
17.18%


NCSTN
0.018785421
6.80%
0.43%
0.92%


FRRS1
0.01931061
36.23%
2.11%
38.38%


PLA2R1
0.019413426
41.93%
4.22%
38.90%


LY6E
0.021661514
20.04%
9.83%
16.19%


PRNP
0.022136049
25.41%
7.09%
19.59%


NPC1
0.022850945
12.00%
5.32%
12.99%


PKD1L1
0.025432154
20.04%
2.45%
44.08%


CD93
0.031807592
19.54%
1.39%
23.40%


RNF13
0.03288098
13.52%
4.90%
3.07%


FFAR3
0.035469445
59.77%
7.83%
44.34%


PPAP2A
0.035890417
16.16%
3.05%
15.66%


STAB1
0.036106728
25.31%
7.64%
23.96%


RTN4RL1
0.036943614
3.64%
8.55%
57.38%


TTYH3
0.037151495
1.22%
11.13%
9.71%


FGFR2
0.042451549
3.97%
23.92%
51.89%


CLEC14A
0.045282141
20.89%
7.13%
19.54%


TEK
0.049971964
29.29%
4.41%
37.31%
















TABLE 11







Surface proteins associated with the SCLC-I subtype from the cell line dataset











Surface Protein
ANOVA P value
I vs N
I vs P
I vs A














PDGFRB
9.70855E−13
41.82%
87.73%
89.46%


SCARF2
1.14401E−06
28.00%
55.46%
87.84%


AXL
1.41233E−06
42.54%
60.57%
47.87%


S1PR3
1.00165E−05
34.43%
50.87%
76.36%


MRC2
1.16913E−05
40.41%
66.21%
64.45%


GPR124
1.53035E−05
24.18%
16.47%
33.93%


SSPN
3.15744E−05
47.13%
20.08%
73.38%


GPR176
4.11096E−05
18.82%
28.91%
39.70%


ITGA11
5.90876E−05
51.71%
99.77%
64.24%


EMP3
6.40989E−05
29.27%
73.47%
61.72%


ELFN1
 7.084E−05
20.66%
99.69%
59.94%


OR2W1
7.51498E−05
47.62%
53.74%
90.16%


ABCC10
8.64139E−05
16.88%
24.08%
15.80%


SIRPG
0.000125124
54.50%
20.54%
87.91%


CD248
0.000140839
51.80%
88.49%
80.94%


ERBB2
0.000158538
31.30%
17.83%
28.08%


IL15RA
0.000180892
86.00%
24.09%
65.39%


EPHB4
0.000183815
36.27%
35.64%
58.50%


NOTCH3
0.000184805
51.42%
28.11%
54.94%


VCAM1
0.000185193
75.66%
12.66%
73.35%


TMEM63B
0.000202062
11.31%
11.86%
13.46%


GAS1
0.000229798
63.61%
28.89%
84.65%


EMP1
0.000251881
56.89%
39.27%
67.12%


DAG1
0.000268459
14.58%
10.17%
10.80%


SIRPB1
0.000285131
41.23%
34.75%
73.19%


ITGA5
0.000291127
14.15%
39.97%
38.83%


GJA3
0.000343217
70.40%
71.58%
89.41%


HLA-E
0.000345515
53.04%
44.15%
73.70%


CCR10
0.000404984
21.44%
58.04%
54.58%


TP53I13
0.000464936
11.36%
33.85%
53.00%


EMR2
0.000465156
35.27%
35.02%
66.99%


SLC2A3
0.000480693
14.22%
50.21%
59.18%


LY6E
0.000548484
23.98%
77.93%
59.03%


BTNL9
0.000576928
48.11%
57.89%
80.48%


BTN2A3P
0.00062003
23.96%
16.19%
49.19%


EPHA2
0.000630155
25.40%
20.37%
53.25%


SLC1A6
0.000699746
63.96%
45.32%
83.48%


TMEM26
0.00074033
62.21%
99.65%
84.53%


CHRNG
0.000779166
26.61%
69.85%
71.18%


HLA-C
0.000829317
67.10%
20.53%
39.03%


SECTM1
0.001033177
99.40%
59.17%
71.79%


GYPC
0.001048073
20.53%
99.05%
93.07%


PTPRQ
0.001228831
46.76%
71.68%
37.91%


SIRPA
0.0012998
23.00%
19.42%
53.09%


CSPG4
0.001382179
16.05%
64.93%
56.40%


VASN
0.001678081
49.90%
62.89%
45.92%


CD36
0.001802107
44.34%
57.34%
43.04%


ELFN2
0.001814298
13.24%
26.98%
68.75%


SLC16A5
0.001827075
88.43%
55.60%
76.18%


MALRD1
0.001941222
50.13%
37.60%
58.76%


LRRC15
0.002610256
53.05%
76.41%
81.17%


CD97
0.002967346
35.16%
38.68%
53.52%


EDNRA
0.002984467
61.85%
31.26%
56.19%


IL1R1
0.003251884
79.09%
22.85%
63.05%


SLC38A4
0.003300738
31.52%
31.04%
21.41%


OLR1
0.003597158
69.69%
22.47%
78.10%


OR2J3
0.003661151
53.38%
45.61%
73.72%


LY6K
0.003696562
76.50%
81.73%
68.27%


CSF2RA
0.003860425
40.84%
50.18%
68.11%


MICA
0.004093527
82.55%
50.87%
76.35%


GJA1
0.004139472
34.81%
44.90%
39.66%


HFE
0.004759886
58.52%
44.98%
39.99%


FSHR
0.004852942
27.62%
99.42%
72.48%


OR2J2
0.005516914
49.92%
46.85%
78.53%


ZPLD1
0.00554278
26.30%
87.74%
62.18%


SIGLEC10
0.005610828
59.09%
10.73%
57.72%


LPHN2
0.005757306
23.37%
28.32%
22.89%


CRLF2
0.006602335
74.81%
88.17%
75.13%


NLGN2
0.007183664
11.51%
15.52%
22.20%


NT5E
0.007910095
46.08%
23.07%
32.38%


FAM26E
0.008056667
81.74%
85.99%
69.92%


CALCR
0.008328862
69.39%
34.94%
40.61%


SCNN1D
0.008695163
31.70%
35.19%
45.85%


GPNMB
0.009107969
42.84%
43.29%
35.71%


TMEM150A
0.009184623
21.96%
28.47%
41.19%


SLC6A7
0.009465125
19.01%
99.21%
71.82%


NIPAL4
0.010403691
11.82%
53.50%
39.59%


AGTR1
0.011008851
65.46%
21.84%
64.33%


ADAM19
0.011294672
12.43%
16.75%
18.07%


CACNG8
0.011445992
69.51%
43.60%
82.00%


CDH10
0.011463268
22.18%
77.86%
36.14%


HLA-DRA
0.011810381
90.27%
64.96%
74.19%


FZD2
0.011825025
40.01%
75.15%
46.91%


MMP14
0.011895604
43.04%
41.58%
61.49%


ITGB5
0.011906104
25.09%
15.21%
45.53%


LRRC4B
0.012282734
50.44%
86.50%
68.81%


ATP1A2
0.01356725
40.87%
75.14%
70.15%


HLA-B
0.015591244
68.55%
28.55%
54.29%


SEMA7A
0.016400864
13.93%
14.32%
49.75%


F2RL2
0.016703706
44.63%
36.55%
66.00%


NAGPA
0.016942233
10.82%
28.27%
26.65%


SLC2A10
0.017091586
51.60%
54.82%
65.32%


MICB
0.017256735
62.98%
57.16%
57.14%


ZP3
0.017350621
25.93%
39.64%
37.85%


LRFN3
0.017451257
11.83%
43.72%
28.58%


HYAL2
0.017616091
35.96%
49.22%
28.55%


IL31RA
0.018781884
46.13%
68.78%
60.05%


OR7A5
0.019891214
32.52%
99.35%
76.26%


SUSD5
0.019979736
28.91%
45.10%
41.66%


EGFR
0.020072443
43.36%
44.48%
24.78%


GHR
0.021406512
59.67%
32.33%
50.02%


TEK
0.021476624
33.06%
60.81%
45.15%


HCRTR2
0.022721512
44.85%
56.05%
70.83%


CD180
0.024188886
86.84%
99.44%
46.09%


LPAR4
0.025833382
61.07%
12.43%
68.02%


SLC43A2
0.028164393
15.56%
49.17%
17.98%


PTGDR
0.028701973
67.64%
27.36%
27.10%


CEACAM8
0.032014126
52.16%
99.48%
64.33%


CD163
0.03389116
11.84%
15.55%
60.96%


HLA-F
0.034348946
51.77%
52.74%
59.52%


SLC12A9
0.035177737
22.62%
25.00%
38.24%


HTR1B
0.035875203
77.67%
99.42%
75.68%


PCDH7
0.038481146
41.72%
43.17%
32.77%


HLA-H
0.04201114
78.24%
50.87%
61.85%


LMAN2
0.042283864
11.64%
22.53%
15.98%


CD109
0.043629781
39.60%
49.60%
42.38%


HLA-DRB1
0.043948828
99.34%
72.03%
73.64%


RHBDF2
0.046645232
12.81%
28.73%
49.67%


GPER1
0.04742007
13.13%
39.53%
41.14%


XPNPEP2
0.049087924
59.32%
99.34%
74.80%


IL6R
0.049745524
54.93%
15.57%
57.60%


TMEM161A
0.050201605
19.59%
35.40%
37.79%


CACNG4
0.05073865
17.62%
71.93%
18.62%


CELSR1
0.051217298
28.36%
14.10%
10.73%


CSF1
0.051958401
38.68%
26.49%
53.37%


ZAN
0.052351116
11.67%
72.23%
43.70%


MFSD5
0.053591241
18.80%
24.83%
17.04%


S1PR5
0.053635072
30.73%
22.83%
47.94%


ELTD1
0.058172278
40.56%
57.07%
68.80%


TTYH3
0.064064238
16.47%
17.10%
14.58%


LRP10
0.064141968
20.58%
17.03%
22.91%


CHRNE
0.069609585
22.06%
20.42%
26.67%


SLC26A6
0.071529916
11.20%
31.98%
15.40%


NPY6R
0.072231424
25.59%
76.42%
46.99%


ULBP3
0.072772617
34.55%
17.67%
47.19%


CXCR5
0.073347916
27.46%
18.95%
32.42%


GPIHBP1
0.07686716
82.68%
51.07%
68.18%


GABRE
0.07851393
14.17%
39.09%
52.18%


BTN3A3
0.079711513
23.74%
13.99%
25.87%


OR11A1
0.080154435
14.49%
56.48%
67.08%


GRIN2B
0.082424733
16.96%
32.50%
44.93%


TGFBR3
0.083141392
25.41%
12.89%
22.76%


S1PR2
0.084817954
26.85%
99.06%
61.04%


SPRN
0.086293416
70.70%
99.18%
66.86%


DPEP3
0.086424214
33.32%
69.13%
72.82%


TMEM179B
0.086534095
14.21%
12.08%
10.21%


CD70
0.087034742
88.22%
17.81%
73.03%


S1PR1
0.08969823
19.82%
99.70%
33.44%


EVC2
0.089894424
53.35%
36.67%
39.32%


PCDH11Y
0.090602169
55.66%
99.69%
32.42%


SLC2A6
0.091936867
17.91%
48.87%
19.90%


PTAFR
0.098445711
33.11%
44.85%
39.69%


P2RX7
0.102272577
23.50%
53.02%
28.38%


ADAM18
0.104336724
84.11%
24.64%
49.22%


BST2
0.104466458
90.31%
61.70%
71.82%


BTNL3
0.105508382
57.74%
63.97%
77.52%


UPK3B
0.107067928
48.51%
35.35%
24.50%


MR1
0.108011944
56.39%
32.77%
39.47%


CALY
0.110304713
65.48%
99.28%
48.57%


KCNMB1
0.110447558
64.76%
53.40%
69.55%


NPR3
0.111672739
60.72%
32.32%
35.24%


PTCHD3
0.111985187
31.80%
58.61%
55.01%


GPR108
0.119031557
27.66%
52.58%
30.36%


MRVI1
0.121894675
19.91%
13.06%
34.23%


TMEM95
0.126037075
42.49%
67.41%
69.99%


FAP
0.127343392
28.33%
66.10%
38.01%


BCAN
0.127394461
34.65%
80.21%
26.67%


SLC52A2
0.127746183
15.00%
27.59%
28.44%


SIDT2
0.128965846
13.44%
11.07%
10.23%


IL3RA
0.131274959
29.56%
57.02%
32.51%


LRFN4
0.131499594
27.62%
16.19%
37.23%


DPCR1
0.138274816
29.90%
48.99%
38.89%


FCRL5
0.138531663
36.22%
99.20%
63.34%


MYADM
0.142338163
40.96%
32.08%
43.94%


SDC1
0.143847536
21.00%
18.25%
20.56%


CDH6
0.146632816
42.00%
76.80%
26.39%


TSPAN4
0.147567311
18.66%
28.91%
30.74%


OR8B4
0.149381345
87.90%
62.52%
67.17%


OR8B12
0.150200686
48.66%
77.61%
76.50%


OR8B8
0.150658993
87.02%
99.35%
68.61%


SLC14A2
0.156210262
19.95%
58.56%
14.06%


GHSR
0.156234158
71.26%
19.08%
54.68%


SLC6A13
0.164696133
60.61%
74.74%
40.26%


KLRC1
0.165423349
70.79%
11.45%
40.18%


OR1F2P
0.167047968
34.59%
80.15%
52.00%


IL7R
0.168491361
67.99%
99.41%
70.50%


PTPRC
0.169864738
42.59%
25.65%
28.29%


UNC93B1
0.170029747
50.14%
13.72%
37.99%


PLXNB2
0.17020525
10.05%
10.74%
10.67%


SLC26A2
0.171178969
11.76%
10.61%
11.28%


SIGLEC7
0.174623553
55.62%
98.98%
78.48%


RXFP1
0.175323639
58.44%
52.19%
40.28%


HTR6
0.181627387
15.43%
99.11%
39.39%


MMP25
0.185402559
22.21%
16.96%
30.63%


SLCO1C1
0.193949469
45.99%
54.07%
44.47%


KIR3DL1
0.194145863
44.82%
77.27%
67.27%


NPY2R
0.209153189
46.30%
45.28%
67.38%


THY1
0.210844572
18.36%
19.04%
44.53%


IGSF8
0.212197037
29.16%
24.02%
17.22%


TMEM219
0.212203145
21.10%
22.50%
18.22%


MCOLN1
0.219563384
10.47%
23.21%
17.28%


PTPRR
0.225118894
41.96%
31.59%
33.56%


LRRC3B
0.226893135
13.85%
78.36%
54.04%


SLC7A10
0.228337953
15.75%
37.57%
29.84%


IL1RL2
0.231235711
33.38%
77.33%
63.99%


IL27RA
0.238484435
18.83%
43.82%
38.56%


OR13G1
0.243162251
77.09%
78.16%
66.47%


TLR7
0.249528057
46.12%
56.71%
46.49%


ENPEP
0.251772489
47.95%
10.97%
37.35%


FGFR1
0.265314907
11.64%
21.89%
17.16%


OR14K1
0.265862673
91.17%
99.19%
54.88%


PCDHGA3
0.267301318
26.59%
21.80%
21.68%


DSG3
0.267594902
50.64%
42.01%
41.91%


GPR1
0.273842346
22.84%
70.37%
24.36%


SLC10A3
0.277025033
14.69%
15.82%
18.76%


TGFBR2
0.278270861
27.44%
40.77%
29.32%


OR7C1
0.279025692
61.63%
99.14%
67.90%


ABCB11
0.281867014
12.42%
39.31%
38.80%


OR6J1
0.284944765
18.47%
50.76%
60.28%


TFPI
0.291695477
12.54%
16.98%
31.45%


CLCA2
0.292814974
51.42%
45.41%
25.99%


TM4SF5
0.299823016
24.97%
98.70%
61.73%


OR8A1
0.302696206
73.58%
80.33%
67.47%


OR3A2
0.306415526
89.65%
99.05%
67.27%


CD40
0.308489803
68.74%
11.91%
40.40%


GPC1
0.312044176
12.15%
24.86%
13.06%


SLC51B
0.320090119
65.92%
98.93%
53.99%


PCDHGA8
0.321583365
22.02%
10.43%
20.96%


OR8B2
0.322781396
66.66%
63.56%
63.86%


HLA-DOB
0.325697853
58.00%
47.99%
53.49%


FCRL2
0.329327269
28.22%
59.81%
65.65%


GDPD2
0.330216847
30.99%
36.13%
20.08%


MC1R
0.333798247
11.38%
23.30%
19.40%


BDKRB2
0.335990089
32.48%
82.83%
46.24%


TYRP1
0.340270627
28.06%
24.09%
19.40%


SLC6A2
0.340516161
54.47%
98.88%
66.54%


GRIA3
0.349815304
23.36%
19.76%
33.49%


GABRR1
0.351236381
48.31%
22.01%
38.96%


FCRL4
0.352669005
41.45%
66.92%
62.88%


HLA-A
0.354772295
17.19%
10.20%
17.68%


ROS1
0.365755385
30.56%
12.12%
42.04%


SLC5A7
0.367674471
16.57%
83.78%
37.48%


GPA33
0.371405824
30.27%
98.81%
55.27%


MYOF
0.385629323
21.19%
41.11%
21.06%


ADAM2
0.395455857
55.32%
72.58%
36.43%


CD151
0.39706503
31.10%
16.38%
25.88%


OR52E6
0.404255084
67.86%
79.46%
14.39%


FCGR2C
0.404723052
27.46%
32.10%
47.30%


SHISA4
0.404857855
36.58%
35.62%
36.20%


ERVFRD-1
0.411868828
10.96%
11.62%
11.12%


NLGN4Y
0.414016011
55.61%
54.26%
30.85%


CALCRL
0.416735924
28.36%
10.24%
23.47%


TMPRSS11B
0.419430434
44.65%
66.33%
38.57%


ACKR2
0.420171485
39.10%
10.84%
15.55%


ITLN1
0.431710976
42.83%
99.00%
39.89%


LPAR1
0.437577179
40.17%
23.56%
24.92%


GPRC5A
0.443911646
25.96%
36.66%
42.75%


RHO
0.449401165
35.23%
70.26%
50.31%


CD82
0.451520502
33.50%
54.70%
17.28%


ASGR2
0.453889237
38.09%
17.99%
60.73%


BTN1A1
0.457469508
17.26%
75.38%
36.90%


VSTM4
0.470409176
46.10%
29.19%
37.90%


SIGLEC5
0.471798433
33.14%
98.80%
50.91%


CR1
0.472408291
21.88%
34.07%
31.65%


TNFSF18
0.47248415
39.04%
99.11%
50.55%


ITGAD
0.477965365
35.44%
76.09%
41.32%


CSF1R
0.482231444
25.84%
61.18%
29.47%


PCDHGA12
0.487188389
18.84%
10.66%
12.80%


ITGAX
0.492293391
33.77%
62.72%
44.85%


HRH1
0.496070302
13.78%
77.21%
14.54%


LTB4R2
0.499245999
33.67%
32.50%
29.70%


ABCA1
0.501257794
15.16%
15.98%
10.10%


PCDH18
0.50445456
12.44%
43.11%
12.32%


OR1C1
0.504532204
74.30%
99.04%
58.03%


TPSG1
0.513791919
15.34%
57.52%
36.54%


TECTB
0.524070714
35.21%
56.48%
61.23%


MS4A15
0.55496264
98.39%
33.58%
22.56%


HLA-DQB1
0.560863505
66.88%
33.66%
58.50%


CLEC7A
0.566991408
61.95%
23.70%
25.62%


CCR3
0.578683946
31.30%
60.27%
55.63%


SLC10A6
0.580091405
19.54%
39.67%
34.23%


OR8D1
0.596270694
24.63%
79.33%
43.53%


SLC10A4
0.602488524
12.23%
15.04%
15.86%


CCRL2
0.604393418
43.96%
98.88%
21.95%


ASIC5
0.608054386
54.30%
81.59%
40.83%


ADRA2C
0.616104389
15.05%
33.74%
29.29%


CLEC9A
0.617473862
38.03%
35.89%
48.96%


DUOXA1
0.619770714
13.09%
36.92%
36.36%


OR10D3
0.620509038
34.29%
71.33%
45.38%


OR8D2
0.632808285
64.17%
58.19%
59.91%


CLEC12A
0.633663241
40.08%
98.80%
46.02%


MEP1A
0.647686397
20.07%
98.50%
22.15%


GJB4
0.648355542
21.58%
98.41%
42.69%


FZD9
0.64889927
50.45%
48.65%
47.69%


SLC44A2
0.649439099
12.58%
12.55%
12.01%


OR14A2
0.660245293
60.97%
99.10%
41.17%


OR8B3
0.663064669
35.02%
58.48%
47.13%


IL13RA2
0.667080328
31.79%
30.27%
34.08%


MILR1
0.674176317
41.25%
34.83%
18.69%


SORCS1
0.695659133
27.17%
63.09%
20.35%


GPR149
0.697360216
44.76%
27.14%
23.83%


CLEC1A
0.69855076
16.16%
98.34%
39.08%


OR8G1
0.700029247
48.42%
59.96%
45.23%


ITGAL
0.700284334
15.57%
57.11%
11.69%


KIR2DL4
0.711538473
73.52%
55.15%
55.76%


OR8G5
0.726783101
55.19%
39.67%
46.27%


OR2AT4
0.730479448
57.56%
29.53%
35.85%


CCR2
0.738631773
23.19%
98.17%
25.66%


CNTNAP4
0.752168179
18.26%
35.49%
25.87%


SLC22A3
0.754846789
26.52%
58.93%
31.07%


OR4D1
0.755277997
33.10%
64.97%
37.15%


OR6F1
0.755553415
75.53%
97.76%
26.49%


GPM6A
0.755936769
16.72%
14.76%
22.54%


UPK3A
0.758561782
27.49%
98.19%
25.25%


MUC21
0.784791847
60.17%
32.54%
45.31%


ASGR1
0.789223379
15.16%
50.12%
22.04%


MUSK
0.794634299
28.41%
23.46%
17.41%


PCDH15
0.802189331
12.88%
38.54%
17.19%


NPFFR2
0.803972336
18.04%
64.73%
15.18%


GRIN3B
0.805884492
34.69%
14.30%
28.02%


VNN1
0.807570724
47.83%
59.74%
36.35%


CD74
0.814203565
34.46%
29.95%
26.52%


GRM6
0.818292499
25.79%
61.95%
41.09%


BOC
0.820910863
12.71%
12.06%
13.40%


KIR2DL1
0.823617205
71.14%
53.01%
31.27%


EREG
0.824067105
43.12%
61.54%
30.64%


SLC22A2
0.829422311
38.37%
65.89%
32.44%


CNTN6
0.833575047
26.98%
13.27%
16.50%


ADORA2A
0.834148243
12.33%
50.83%
30.69%


LRRC32
0.849594703
18.03%
11.26%
37.22%


OR1E2
0.851206648
71.67%
98.19%
49.96%


HLA-DRB5
0.857348426
50.84%
97.96%
45.82%


FCRL1
0.863158359
44.76%
98.03%
31.54%


ABCC3
0.89599808
11.50%
28.19%
12.20%


CDH19
0.897963086
31.79%
38.89%
26.58%


OR52B6
0.908122928
39.77%
21.13%
17.03%


SLC17A1
0.915852827
24.27%
16.53%
32.31%


AQP8
0.91910142
14.67%
37.05%
29.28%


TM4SF4
0.919889102
39.50%
36.56%
40.08%


OR8K3
0.927735573
50.61%
55.79%
31.66%


FCGR2A
0.96423416
11.89%
17.21%
15.01%


SLC22A25
0.971153274
11.53%
35.59%
16.21%


SLC19A3
0.973316054
10.44%
30.64%
12.49%


KITLG
1.22912E−09
33.22%
8.72%
1.73%


EPOR
3.64388E−07
37.77%
52.03%
1.36%


LRP1
1.43654E−05
22.89%
9.74%
22.90%


SLC1A3
1.70439E−05
0.47%
52.15%
58.29%


CRIM1
 2.3671E−05
10.46%
3.26%
19.75%


PIEZO1
3.72517E−05
6.01%
11.45%
17.13%


SCAP
4.45561E−05
2.45%
8.05%
13.10%


DDR2
6.74876E−05
2.63%
28.27%
31.13%


SLC38A2
7.23319E−05
10.61%
7.33%
4.92%


CNTNAP1
7.33744E−05
8.44%
11.28%
16.73%


GPR126
0.000115686
56.76%
7.36%
40.95%


TMEM67
0.000207487
13.84%
6.96%
1.98%


TCTN2
0.000294838
12.12%
7.00%
1.70%


HEG1
0.000324881
1.32%
13.80%
26.29%


CD276
0.000332245
5.66%
9.27%
15.55%


SLC41A2
0.000375485
5.29%
28.71%
3.36%


OSMR
0.000429575
17.80%
2.08%
15.09%


ATP13A1
0.000649164
2.17%
11.47%
11.98%


FAT4
0.001200168
8.87%
29.26%
30.85%


TMEM63A
0.001200493
33.38%
5.87%
22.36%


ADAM9
0.001366603
12.74%
5.63%
9.12%


BTN2A1
0.001550834
11.85%
8.34%
13.02%


SERINC1
0.001952639
5.37%
4.67%
0.33%


DLK2
0.00209582
6.12%
22.46%
21.41%


OPRL1
0.002200766
0.01%
6.60%
53.82%


FAM189B
0.002623661
1.29%
13.06%
13.27%


ANPEP
0.002631649
7.72%
57.25%
56.01%


TCTN3
0.003283122
8.06%
8.80%
9.73%


BTN2A2
0.003593958
5.87%
5.53%
23.92%


PLA2R1
0.003601681
31.45%
1.46%
45.84%


EFNA4
0.004659915
52.46%
3.85%
54.17%


ITGB1
0.005116504
10.13%
4.32%
6.51%


SPPL2A
0.0079037
6.19%
6.57%
4.24%


ATG9A
0.00823111
3.26%
5.11%
11.31%


BMPR1A
0.008696054
6.96%
6.18%
7.15%


SLC39A14
0.010300373
5.92%
13.63%
11.43%


PPAP2A
0.010349324
2.84%
7.97%
6.97%


TIMD4
0.010952103
9.98%
72.04%
56.92%


BTN3A1
0.011807557
21.66%
4.62%
21.92%


ABCB9
0.012872125
3.69%
16.39%
20.94%


PSEN2
0.013607372
1.57%
44.97%
16.40%


NOTCH2
0.015085852
23.85%
9.53%
28.46%


FAS
0.015303925
41.01%
7.09%
37.76%


TM9SF4
0.015507074
2.08%
4.85%
6.30%


TSPAN3
0.015549376
0.03%
4.22%
4.12%


PRND
0.016101818
4.40%
66.53%
65.83%


IGF2R
0.016362752
9.92%
5.44%
3.71%


TMEM104
0.017780302
1.39%
22.68%
4.67%


FAIM2
0.0194138
5.67%
79.10%
16.13%


NPR2
0.020748914
5.84%
26.26%
6.55%


TREH
0.021038328
35.00%
8.77%
6.40%


ADCY3
0.023753612
0.57%
3.65%
5.53%


SLC19A1
0.024259375
5.18%
18.97%
25.28%


TNFRSF10D
0.024866438
41.92%
9.94%
52.01%


UPK2
0.027646553
0.52%
40.88%
72.80%


ECE1
0.027824102
4.17%
14.54%
0.41%


TENM3
0.029749637
19.17%
5.48%
2.74%


STT3B
0.030311224
6.09%
5.49%
5.80%


LRIG2
0.030916383
0.57%
0.97%
3.72%


NCSTN
0.035326878
8.01%
11.55%
10.17%


CACHD1
0.036374936
1.32%
2.27%
12.48%


SLC15A3
0.037803739
9.28%
28.53%
25.09%


AMN
0.038022559
3.05%
12.27%
9.08%


AMIGO2
0.040462608
42.52%
33.54%
1.11%


LRP5
0.04064938
11.33%
0.99%
15.79%


NPC1
0.040734377
4.41%
10.32%
4.47%


PLXDC2
0.041556302
48.29%
9.83%
34.02%


HLA-DPA1
0.041968046
32.97%
4.78%
61.81%


APLP2
0.042589097
10.07%
4.84%
4.06%


NLGN3
0.042745598
1.92%
1.58%
18.82%


SLC17A5
0.044873172
8.75%
5.89%
5.21%


LAMP1
0.046646461
10.03%
8.94%
3.99%


OR52W1
0.048413228
75.90%
21.33%
5.51%
















TABLE 12







Surface proteins associated with the SCLC-I subtype from the Sato dataset











Surface Protein
ANOVA p value
I vs N
I vs P
I vs A














ULBP2
0.000401771
33.616%
21.160%
30.038%


LAMP3
0.000500427
27.061%
18.820%
23.810%


IL1R2
0.001123023
48.534%
16.083%
59.376%


FREM2
0.001290176
27.403%
29.302%
21.104%


ABCC4
0.001291636
10.574%
21.181%
30.267%


CEACAM6
0.001572035
28.896%
48.775%
24.840%


CTLA4
0.00235198
59.992%
12.364%
34.041%


LPAR6
0.004382294
29.854%
13.805%
26.729%


TMEM116
0.008232977
15.832%
18.672%
11.796%


SLC6A14
0.010025829
38.415%
23.327%
44.788%


QRFPR
0.010389646
22.644%
58.781%
28.888%


ITGB6
0.010994872
13.902%
11.241%
39.858%


SLC26A9
0.011576247
19.328%
51.036%
13.183%


SLC44A5
0.012341309
26.223%
23.536%
22.349%


CDH26
0.012561895
31.647%
14.247%
14.401%


ROS1
0.014075255
50.362%
23.774%
22.464%


TMPRSS13
0.016875706
29.883%
25.000%
46.376%


MPZL2
0.016942684
20.914%
27.805%
32.087%


IL1RAP
0.019303137
37.041%
16.450%
54.210%


NIPAL4
0.019309994
36.139%
48.262%
44.384%


SLC2A1
0.028160352
15.621%
10.434%
13.744%


GPR110
0.030651959
23.740%
37.659%
39.189%


MUC1
0.032222447
18.344%
14.318%
11.590%


CD109
0.038542669
11.875%
17.350%
22.645%


CDH3
0.043188459
25.570%
45.250%
47.256%


CLCA2
0.043321363
42.009%
73.048%
58.739%


GJB6
0.047670625
51.153%
52.840%
80.502%


SLC51A
0.054500968
51.515%
36.209%
49.467%


ZAN
0.063702876
19.138%
39.480%
10.196%


PVRL3
0.065439262
14.855%
33.512%
30.180%


SLC7A5
0.072533224
29.273%
18.383%
18.077%


CLDN1
0.073714631
32.382%
27.791%
36.580%


AVPR2
0.075099561
50.256%
30.796%
50.875%


ENTPD3
0.076708202
18.680%
36.303%
23.105%


GJB2
0.078372255
58.528%
26.796%
53.764%


LPAR3
0.081401485
11.129%
30.020%
39.629%


ADAM20
0.091064095
46.719%
28.273%
24.993%


CEACAM7
0.094983069
37.838%
47.755%
10.661%


OR51M1
0.10617364
28.967%
38.831%
27.455%


SDC1
0.108283365
23.959%
27.889%
28.630%


TMC7
0.127266725
28.041%
10.121%
15.949%


DSG3
0.138965552
59.627%
55.316%
74.495%


CLDN6
0.140494484
53.224%
33.893%
30.715%


PANX2
0.146302225
18.780%
30.390%
28.326%


EGF
0.147163821
50.558%
10.109%
42.195%


ATP13A5
0.16067304
22.588%
26.785%
39.892%


PCDHB5
0.184159617
27.607%
38.288%
41.172%


ABCA13
0.189178704
21.495%
48.736%
40.243%


UPK1B
0.199342196
31.540%
30.963%
27.315%


LYPD3
0.202574616
34.065%
26.625%
42.489%


OXGR1
0.206375308
58.893%
26.740%
26.748%


TACSTD2
0.208454138
18.494%
22.452%
35.639%


PCDH20
0.211076831
15.426%
44.983%
16.357%


GPRC5A
0.213072322
13.133%
30.278%
44.221%


SLC46A2
0.217209365
46.731%
43.778%
35.347%


EFNB2
0.22377892
10.721%
16.446%
19.745%


TREM1
0.223947474
33.399%
21.515%
32.476%


ERVMER34-1
0.229064798
19.235%
14.167%
16.286%


GFRA3
0.232751993
35.323%
28.622%
27.143%


CALCR
0.233111903
45.738%
40.242%
37.457%


CLDN20
0.238970005
14.562%
20.459%
26.028%


TMPRSS11D
0.239442354
23.926%
31.485%
30.009%


ACE2
0.240101964
47.376%
36.245%
36.245%


PTPRO
0.250845719
21.768%
22.274%
18.421%


SLC52A3
0.269986489
36.261%
13.813%
46.402%


LYPD6B
0.272299557
37.875%
40.037%
33.835%


PTPRZ1
0.291648271
23.355%
45.840%
24.104%


SLCO1B3
0.298279793
68.423%
12.303%
40.314%


TYRP1
0.302111078
24.148%
32.252%
36.444%


GPR87
0.310279746
26.904%
53.279%
54.040%


F2RL2
0.332184561
37.288%
41.031%
26.633%


MSLN
0.343970634
46.256%
18.829%
33.190%


HLA-DQB2
0.350158887
20.153%
15.104%
18.533%


SLAMF9
0.353137509
14.036%
23.481%
11.639%


GPR68
0.353981958
47.305%
19.060%
20.809%


VN1R3
0.362208892
44.630%
39.140%
31.468%


UNC93B1
0.369803275
16.255%
14.871%
28.872%


EPHA1
0.377588291
21.526%
16.347%
21.495%


HTR2B
0.383339042
51.236%
22.463%
24.653%


SLITRK1
0.414452608
53.002%
56.783%
21.849%


EMR1
0.414508571
44.855%
14.646%
17.070%


OR7A5
0.429503421
44.713%
15.734%
36.237%


SLC34A2
0.43388428
10.692%
35.292%
13.931%


HTR2C
0.448988824
38.674%
33.834%
48.501%


MUC15
0.464271203
28.149%
38.156%
53.016%


GPR45
0.472734149
42.147%
26.431%
21.258%


CNTN5
0.479426869
58.117%
25.530%
24.467%


ADORA2B
0.490531691
16.395%
25.203%
21.145%


NRG4
0.505959614
33.911%
31.350%
32.512%


OR2F2
0.521732819
39.682%
12.472%
15.795%


TMEM171
0.52708684
31.488%
12.212%
18.162%


RXFP1
0.54822571
32.665%
27.142%
30.082%


MDGA2
0.554126454
42.113%
36.030%
41.024%


OR6B1
0.565764307
15.997%
37.251%
10.699%


MUC16
0.574609577
51.836%
32.324%
43.961%


FFAR4
0.586185845
30.353%
22.593%
35.908%


VNN3
0.609937374
48.825%
40.015%
42.229%


CR1
0.610551241
44.176%
11.561%
22.088%


LRRN4
0.620032487
43.633%
26.532%
28.864%


GNRHR
0.734837204
14.775%
32.424%
26.310%


ACKR4
0.740067283
18.813%
22.240%
12.871%


TMPRSS11B
0.756391224
23.647%
27.261%
36.061%


OR5V1
0.764212185
37.067%
14.598%
20.162%


PRSS8
0.803107736
15.101%
10.536%
13.219%


MEP1B
0.804628935
36.581%
22.287%
11.916%


SLC22A11
0.885014214
35.337%
26.901%
13.936%


ABCC10
1.00807E−07
14.767%
1.216%
2.741%


DCBLD1
 1.1404E−06
31.620%
4.903%
14.499%


F11R
1.36563E−06
9.197%
2.673%
6.087%


ADAM17
1.60763E−05
12.457%
4.381%
7.925%


ITGAE
1.73594E−05
7.132%
0.502%
3.595%


MICA
1.92641E−05
28.382%
5.300%
25.966%


SEMA4C
5.72638E−05
14.299%
6.514%
5.206%


EPHA2
0.000198743
41.813%
26.823%
46.253%


GPR107
0.00023609
9.022%
4.047%
6.809%


SLC11A2
0.000340249
12.708%
7.690%
7.153%


TSPAN31
0.000343171
23.140%
3.247%
4.969%


LAMP1
0.000384984
9.557%
2.627%
6.110%


ABCA1
0.000407256
14.279%
2.386%
13.243%


SLC12A7
0.000429879
6.601%
3.175%
1.590%


CD46
0.000586389
6.835%
2.602%
6.828%


DSC2
0.000621513
16.234%
3.214%
38.646%


SLC31A1
0.000940061
26.990%
6.241%
21.250%


CD274
0.000951345
40.294%
3.023%
21.822%


PCDH1
0.001082683
15.109%
27.859%
28.287%


TMEM9
0.001377575
1.684%
5.723%
6.547%


EMP2
0.001477302
4.856%
12.404%
2.868%


ATRAID
0.001636825
12.721%
6.131%
10.313%


CXCL16
0.003528987
35.088%
3.172%
16.673%


ITGB5
0.004208038
11.972%
4.089%
17.520%


ZDHHC5
0.004653623
7.929%
6.247%
7.814%


SLC37A3
0.005332971
3.113%
5.188%
2.832%


RNF149
0.005531618
14.775%
4.299%
14.857%


SLAMF8
0.005551306
49.786%
0.477%
21.436%


SLC33A1
0.005647423
7.888%
2.271%
2.174%


TSPAN13
0.006210859
1.847%
7.745%
0.906%


THBD
0.006315115
26.931%
21.150%
21.213%


P2RY6
0.006366337
50.048%
6.705%
27.836%


CDH1
0.006482738
9.663%
7.428%
7.370%


C3AR1
0.007003309
34.122%
1.010%
17.107%


GPR157
0.007599707
19.989%
2.341%
22.021%


SLC39A4
0.007876928
14.161%
4.295%
4.092%


EFNA1
0.007891944
20.804%
0.404%
24.316%


CDCP1
0.007958915
1.822%
1.423%
6.232%


TNFSF15
0.009410143
14.459%
1.449%
11.172%


LPAR5
0.010109622
33.939%
7.455%
35.447%


TSPAN33
0.01063962
17.422%
7.100%
19.477%


CD9
0.013244926
9.064%
2.699%
17.328%


IL13RA1
0.013356457
14.127%
2.085%
13.021%


IL17RA
0.013615554
17.979%
4.282%
15.084%


LYSMD3
0.013667996
6.733%
0.769%
3.200%


MR1
0.014310513
22.268%
7.679%
35.081%


TMEM37
0.01458688
54.056%
15.680%
34.939%


MET
0.016631502
29.117%
11.653%
3.321%


SEMA4B
0.01729249
7.237%
4.817%
21.461%


LRIG3
0.019103303
1.499%
21.173%
14.097%


ADAM9
0.019713191
12.943%
6.388%
12.784%


LTBR
0.021083671
9.975%
9.724%
16.849%


LMAN2L
0.021967872
9.752%
3.135%
3.320%


SLC47A1
0.022622797
40.991%
7.648%
25.502%


DGCR2
0.023431268
12.239%
7.817%
5.004%


TLR3
0.024401176
26.580%
4.189%
30.641%


SLC12A6
0.02474767
22.363%
9.449%
26.572%


TM4SF1
0.026267868
7.239%
1.953%
17.463%


ESYT3
0.026675173
8.354%
15.233%
5.129%


BCAN
0.027012643
33.601%
8.132%
2.357%


LRRC4
0.028490024
34.757%
46.633%
38.560%


PLB1
0.029078035
32.743%
11.511%
19.376%


IFNGR1
0.034174512
10.475%
5.439%
11.688%


TM9SF2
0.034950372
5.576%
3.487%
6.981%


GLIPR1
0.035521861
32.326%
7.468%
18.401%


C14orf37
0.035801097
63.457%
13.510%
28.378%


FLVCR2
0.037917827
22.459%
8.245%
7.603%


STEAP4
0.038626049
17.663%
28.655%
22.804%


CLDN12
0.040350372
5.558%
5.867%
3.123%


TMEM9B
0.043371434
9.870%
7.121%
5.370%


ALCAM
0.045036666
3.578%
10.628%
2.237%


SCN11A
0.045107412
14.980%
9.254%
15.953%


ADCY7
0.045393791
22.209%
1.888%
16.249%


SLC5A6
0.04680909
22.261%
4.969%
15.821%


ABCC3
0.049733245
41.071%
15.109%
38.927%









Example 2—Analysis of Therapeutic Surface Targets

To investigate cell surface targets broadly, the inventors examined expression of genes that encode known targets of therapeutic monoclonal antibodies, CARs, or ADCs across each subtype in SCLC tumor and cell line data sets.


The inventors identified several surface protein-encoding genes with consistent relative expression patterns among our three data sets and with therapeutics already in development. For example, somatostatin receptor 2 (SSTR2) is a well-established target expressed in low- and intermediate-grade neuroendocrine tumors (NETs), in which somatostatin analogues, such as octreotide and lanreotide, which bind SSTR2, are routinely used therapeutically. SSTR2 is also the target of an ADC, PEN-221, already under development for less aggressive NETs26,27. While SSTR2 is not broadly expressed in all SCLCs, it was observed to be highly expressed in both SCLC-N tumors and cell lines (FIGS. 3A-3C). Further, flow cytometric analyses confirmed robust expression of SSTR2 in SCLC-N cell lines and supported the trend toward greater relative expression in SCLC-N (FIG. 3D). In addition, Western blot analysis of cell lines shows that SSTR2 is preferentially expressed in SCLC-N (FIG. 6A).


For SCLC-P and SCLC-I, MICA, the gene which encodes MHC class I polypeptide-related sequence A, was identified as highly expressed in both of these subtypes (FIGS. 4A-4C). In addition, Western blot analysis of cell lines shows that on a global scale, there is differential protein expression across the subtypes of MICA, expressed in SCLC-I and -P (FIG. 6B). MICA normally acts as the ligand for Natural Killer Group 2 (NKG2D) receptor activation, however prolonged NKG2D activation can ultimately suppress Natural Killer (NK) cell and CD8+ T-cell activity, allowing for immune evasion. MICA is the target of a molecule (IPH43) currently in preclinical development, with proposed dual mechanism of blocking MICA's interaction with NKG2D, while also designed as an ADC targeting MICA-expressing cells28. As for the remaining subtype, SCLC-A, carcinoembryonic antigen-related cell adhesion molecule 5 (CEACAM5), a cell adhesion molecule overexpressed in gastrointestinal and breast cancers as well as in NSCLC, is the target of labetuzumab govitecan, an ADC in clinical investigation for patients with refractory metastatic colorectal cancer, as well as a CAR T-cell29-32. While this molecule has not been previously described as a target for SCLC-specific therapies, the inventors observed differential expression in the datasets, with significantly higher CEACAM5 expression in SCLC-A (FIGS. 5A-5C). In addition, Western blot analysis of cell lines shows that on a global scale, there is differential protein expression across the subtypes of CEACAM5, expressed in SCLC-A (FIG. 6B).


All of the methods disclosed and claimed herein can be made and executed without undue experimentation in light of the present disclosure. While the compositions and methods of this invention have been described in terms of preferred embodiments, it will be apparent to those of skill in the art that variations may be applied to the methods and in the steps or in the sequence of steps of the method described herein without departing from the concept, spirit and scope of the invention. More specifically, it will be apparent that certain agents which are both chemically and physiologically related may be substituted for the agents described herein while the same or similar results would be achieved. All such similar substitutes and modifications apparent to those skilled in the art are deemed to be within the spirit, scope and concept of the invention as defined by the appended claims.


REFERENCES

The following references, to the extent that they provide exemplary procedural or other details supplementary to those set forth herein, are specifically incorporated herein by reference.

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  • 32. Thistlethwaite, F. C., Gilham, D. E., Guest, R. D., Rothwell, D. G., Pillai, M., Burt, D. J., Byatte, A. J., Kirillova, N., Valle, J. W., Sharma, S. K., et al. (2017). The clinical efficacy of first-generation carcinoembryonic antigen (CEACAM5)-specific CAR T cells is limited by poor persistence and transient pre-conditioning-dependent respiratory toxicity. Cancer Immunol Immunother 66, 1425-1436.

Claims
  • 1. A method for treating a subject for small cell lung cancer (SCLC), the method comprising administering a targeting agent capable of specifically binding to one or more of the proteins of Table 1, Table 2, or Table 3 to a subject determined to have SCLC-A.
  • 2. The method of claim 1, wherein the one or more proteins are one or more proteins of Table 1.
  • 3. The method of claim 1, wherein the one or more proteins are one or more proteins of Table 2.
  • 4. The method of claim 1, wherein the one or more proteins are one or more proteins of Table 3.
  • 5. The method of any of claims 1-4, wherein the targeting agent is capable of specifically binding to DLL3.
  • 6. The method of any of claims 1-4, wherein the targeting agent is capable of specifically binding to CEACAM5.
  • 7. The method of any of claims 1-4, wherein the targeting agent is capable of specifically binding to SCNN1A.
  • 8. The method of any of claims 1-7, wherein the subject was determined to have SCLC-A by detecting expression of ASCL1 from cancer cells from the subject.
  • 9. The method of any of claims 1-8, wherein the targeting agent comprises an antibody or fragment thereof.
  • 10. The method of any of claims 1-8, wherein the targeting agent is a bispecific T-cell engager.
  • 11. The method of any of claims 1-10, wherein a cell comprising the targeting agent is administered to the subject.
  • 12. The method of claim 11, wherein the cell is an immune cell.
  • 13. The method of claim 12, wherein the immune cell is a T cell.
  • 14. The method of claim 12, wherein the immune cell is an NK cell.
  • 15. The method of any of claims 11-13, wherein the targeting agent is a chimeric antigen receptor.
  • 16. The method of any of claims 11-13, wherein the targeting agent is a T cell receptor.
  • 17. The method of any of claims 1-16, wherein the targeting agent is operatively linked to a therapeutic agent.
  • 18. The method of claim 17, wherein the therapeutic agent is a chemotherapeutic.
  • 19. The method of claim 17, wherein the therapeutic agent is a toxin.
  • 20. The method of claim 17, wherein the therapeutic agent is a therapeutic nucleic acid.
  • 21. The method of any of claims 1-20, wherein the targeting agent is an antibody-drug conjugate.
  • 22. The method of any of claims 1-20, wherein the targeting agent is an antibody-oligonucleotide conjugate.
  • 23. A method for treating a subject for SCLC, the method comprising administering a targeting agent capable of specifically binding to one or more of the proteins of Table 4, Table 5, or Table 6 to a subject determined to have SCLC-N.
  • 24. The method of claim 23, wherein the one or more proteins are one or more proteins of Table 4.
  • 25. The method of claim 23, wherein the one or more proteins are one or more proteins of Table 5.
  • 26. The method of claim 23, wherein the one or more proteins are one or more proteins of Table 6.
  • 27. The method of any of claims 23-26, wherein the targeting agent is capable of specifically binding to SSTR2.
  • 28. The method of any of claims 23-26, wherein the targeting agent is capable of specifically binding to SEMA6D.
  • 29. The method of any of claims 23-26, wherein the targeting agent is capable of specifically binding to SGCD.
  • 30. The method of any of claims 23-29, wherein the subject was determined to have SCLC-N by detecting expression of NEUROD1 from cancer cells from the subject.
  • 31. The method of any of claims 23-30, wherein the targeting agent comprises an antibody or fragment thereof.
  • 32. The method of any of claims 23-30, wherein the targeting agent is a bispecific T-cell engager.
  • 33. The method of any of claims 23-32, wherein a cell comprising the targeting agent is administered to the subject.
  • 34. The method of claim 33, wherein the cell is an immune cell.
  • 35. The method of claim 34, wherein the immune cell is a T cell.
  • 36. The method of claim 34, wherein the immune cell is an NK cell.
  • 37. The method of any of claims 33-35, wherein the targeting agent is a chimeric antigen receptor.
  • 38. The method of any of claims 33-35, wherein the targeting agent is a T cell receptor.
  • 39. The method of any of claims 23-38, wherein the targeting agent is operatively linked to a therapeutic agent.
  • 40. The method of claim 39, wherein the therapeutic agent is a chemotherapeutic.
  • 41. The method of claim 39, wherein the therapeutic agent is a toxin.
  • 42. The method of claim 39, wherein the therapeutic agent is a therapeutic nucleic acid.
  • 43. The method of any of claims 23-42, wherein the targeting agent is an antibody-drug conjugate.
  • 44. The method of any of claims 23-42, wherein the targeting agent is an antibody-oligonucleotide conjugate.
  • 45. A method for treating a subject for SCLC, the method comprising administering a targeting agent capable of specifically binding to one or more of the proteins of Table 7, Table 8, or Table 9 to a subject determined to have SCLC-P.
  • 46. The method of claim 45, wherein the one or more proteins are one or more proteins of Table 7.
  • 47. The method of claim 45, wherein the one or more proteins are one or more proteins of Table 8.
  • 48. The method of claim 45, wherein the one or more proteins are one or more proteins of Table 9.
  • 49. The method of any of claims 45-48, wherein the targeting agent is capable of specifically binding to MICA.
  • 50. The method of any of claims 45-48, wherein the targeting agent is capable of specifically binding to TMEM87A.
  • 51. The method of any of claims 45-48, wherein the targeting agent is capable of specifically binding to ART3.
  • 52. The method of any of claims 45-51, wherein the subject was determined to have SCLC-P by detecting expression of POU2F3 from cancer cells from the subject.
  • 53. The method of any of claims 45-52, wherein the targeting agent comprises an antibody or fragment thereof.
  • 54. The method of any of claims 45-52, wherein the targeting agent is a bispecific T-cell engager.
  • 55. The method of any of claims 45-54, wherein a cell comprising the targeting agent is administered to the subject.
  • 56. The method of claim 55, wherein the cell is an immune cell.
  • 57. The method of claim 56, wherein the immune cell is a T cell.
  • 58. The method of claim 56, wherein the immune cell is an NK cell.
  • 59. The method of any of claims 55-57, wherein the targeting agent is a chimeric antigen receptor.
  • 60. The method of any of claims 55-57, wherein the targeting agent is a T cell receptor.
  • 61. The method of any of claims 45-60, wherein the targeting agent is operatively linked to a therapeutic agent.
  • 62. The method of any of claim 61, wherein the therapeutic agent is a chemotherapeutic.
  • 63. The method of any of claim 61, wherein the therapeutic agent is a toxin.
  • 64. The method of any of claim 61, wherein the therapeutic agent is a therapeutic nucleic acid.
  • 65. The method of any of claims 45-64, wherein the targeting agent is an antibody-drug conjugate.
  • 66. The method of any of claims 45-64, wherein the targeting agent is an antibody-oligonucleotide conjugate.
  • 67. A method for treating a subject for SCLC, the method comprising administering a targeting agent capable of specifically binding to one or more of the proteins of Table 10, Table 11, or Table 12 to a subject determined to have SCLC-I.
  • 68. The method of claim 67, wherein the one or more proteins are one or more proteins of Table 10.
  • 69. The method of claim 67, wherein the one or more proteins are one or more proteins of Table 11.
  • 70. The method of claim 67, wherein the one or more proteins are one or more proteins of Table 12.
  • 71. The method of any of claims 67-70, wherein the targeting agent is capable of specifically binding to SLAMF8.
  • 72. The method of claim 67, wherein the targeting agent is capable of specifically binding to MRC2.
  • 73. The method of claim 67, wherein the targeting agent is capable of specifically binding to PIEZO1.
  • 74. The method of any of claims 67-73, wherein the subject was determined to have SCLC-I by determining cancer cells from the subject not to express any of ASCL1, NEUROD1, or POU2F3.
  • 75. The method of any of claims 67-74, wherein the targeting agent comprises an antibody or fragment thereof.
  • 76. The method of any of claims 67-74, wherein the targeting agent is a bispecific T-cell engager.
  • 77. The method of any of claims 67-76, wherein a cell comprising the targeting agent is administered to the subject.
  • 78. The method of claim 77, wherein the cell is an immune cell.
  • 79. The method of claim 78 wherein the immune cell is a T cell.
  • 80. The method of claim 78, wherein the immune cell is an NK cell.
  • 81. The method of any of claims 77-79, wherein the targeting agent is a chimeric antigen receptor.
  • 82. The method of any of claims 77-79, wherein the targeting agent is a T cell receptor.
  • 83. The method of any of claims 67-82, wherein the targeting agent is operatively linked to a therapeutic agent.
  • 84. The method of claim 83, wherein the therapeutic agent is a chemotherapeutic.
  • 85. The method of claim 83, wherein the therapeutic agent is a toxin.
  • 86. The method of claim 83, wherein the therapeutic agent is a therapeutic nucleic acid.
  • 87. The method of any of claims 67-86, wherein the targeting agent is an antibody-drug conjugate.
  • 88. The method of any of claims 67-86, wherein the targeting agent is an antibody-oligonucleotide conjugate.
  • 89. A method for treating a subject for SCLC, the method comprising administering a DLL3-binding protein to a subject determined to have SCLC-A.
  • 90. A method for treating a subject for SCLC, the method comprising administering a CEACAM5-binding protein to a subject determined to have SCLC-A.
  • 91. A method for treating a subject for SCLC, the method comprising administering a SCNN1A-binding protein to a subject determined to have SCLC-A.
  • 92. A method for treating a subject for SCLC, the method comprising administering a SSTR2-binding protein to a subject determined to have SCLC-N.
  • 93. A method for treating a subject for SCLC, the method comprising administering a SEMA6D-binding protein to a subject determined to have SCLC-N.
  • 94. A method for treating a subject for SCLC, the method comprising administering a SGCD-binding protein to a subject determined to have SCLC-N.
  • 95. A method for treating a subject for SCLC, the method comprising administering a MICA-binding protein to a subject determined to have SCLC-P.
  • 96. A method for treating a subject for SCLC, the method comprising administering a TMEM87A-binding protein to a subject determined to have SCLC-P.
  • 97. A method for treating a subject for SCLC, the method comprising administering a ART3-binding protein to a subject determined to have SCLC-P.
  • 98. A method for treating a subject for SCLC, the method comprising administering a SLAMF8-binding protein to a subject determined to have SCLC-I.
  • 99. A method for treating a subject for SCLC, the method comprising administering a MRC2-binding protein to a subject determined to have SCLC-I.
  • 100. A method for treating a subject for SCLC, the method comprising administering a PIEZO1-binding protein to a subject determined to have SCLC-I.
Parent Case Info

This application claims benefit of priority of U.S. Provisional Patent Application No. 63/110,664 filed Nov. 6, 2020, which is hereby incorporated by reference in its entirety.

Government Interests

This invention was made with government support under grant number R01 CA207295 awarded by the National Institutes of Health. The government has certain rights in the invention.

PCT Information
Filing Document Filing Date Country Kind
PCT/US2021/058218 11/5/2021 WO
Provisional Applications (1)
Number Date Country
63110664 Nov 2020 US