Determining Cancer-Linked Genes and Therapeutic Targets Using Molecular Cytogenetic Methods

Information

  • Patent Application
  • 20080305493
  • Publication Number
    20080305493
  • Date Filed
    March 08, 2005
    19 years ago
  • Date Published
    December 11, 2008
    15 years ago
Abstract
Methods for identifying antineoplastic agents by using their ability to modify expression of specific genes or the biological activity of polypeptides encoded by such genes, wherein said genes are located in specific chromosomal regions, called amplicons, or regions of interest, and the presence of such amplified regions within a cancerous cell, are disclosed. Also described are methods for diagnosing cancerous, or potentially cancerous, conditions using these methods. Also encompassed are methods involving determining the modulated expression of the genes in these regions of interest (ROIs), or amplicons, as pharmacodynamic/pharmacogenetic/surrogate markers and/or for patient profiling prior to accrual for clinical trials/treatments based on the identification of these genes as validated gene/drug targets in various cancer tissue types.
Description
FIELD OF THE INVENTION

The present invention relates to Identification of amplifications/gains of genomic segments of DNA within human chromosomes in diseased states, such as cancer, that are demarcated and limited within specific chromosomal bands and defined herein as “amplicons” and whose disruption and/or change in expression is useful to distinguish cancerous from non-cancerous tissue and serve as potential therapeutic targets, pharmacodynamic/pharmacogenetic/surrogate and prognostic and diagnostic markers.


BACKGROUND OF THE INVENTION

Malignant tumors are a leading cause of death in the United States and one in four Americans is likely to die of cancer. This disease is often characterized by an increase in the number of abnormal, neoplastic cells that are ultimately derived from a normal tissue after which the cells proliferate to form a tumor, which can then metastasize (spreading into adjacent tissues or traveling elsewhere in the body via the bloodstream or lymphatic system).


The genomes of various well-studied tumors carry several different independently altered genes, including activated oncogenes and inactivated tumor suppressor genes. Chromosomal abnormalities have been identified in most cancer cells. Conventional chromosome banding techniques allow for the detection of specific chromosomal defects in tumor cells but interpretation of the banding pattern is sometimes difficult, particularly when complex chromosomal rearrangements or subtle abnormalities are present. In recent years, new techniques, such as CGH and SKY, based on fluorescent in situ hybridization (FISH) (Pinkel et al., Proc Nat Acad Sci USA 85:9138-42 (1988)) have been developed to overcome the limitations of conventional chromosome banding. CGH measures intensities of fluorescently labeled tumor DNA and normal DNA following hybridization to normal chromosomes (Kallioniemi et al., Science 258:818-21 (1992)). Gain or loss of copy number of a particular chromosome or chromosome region in the tumor DNA is determined by the relative intensity of a fluorescence ratio. SKY utilizes a cocktail of chromosome probes, fluorescently labeled to specify each chromosome, which is hybridized to tumor chromosomes in an effort to identify numerical and structural abnormalities in the tumor cell (Schröck et al., Science 273:494-7 (1996)). CGH and SKY have been used to identify chromosomal regions that harbor genes significant to the process of tumor initiation or progression.


The identification of amplifications of genomic DNA within well defined and demarcated limits on human chromosomes is done at a resolution of human chromosome banding limited to 400-550 bands by the technique of Comparative Genomic Hybridization (CGH). The present invention applies custom protocols to obtain human template chromosomes that are resolved to 850 to 1000 band resolution of human chromosomes (ISCN, 1985), to perform CGH on a large number of cell lines/tissue samples/tumor cells. This allows the identification of regions of genomic DNA amplifications ranging from 2-5 Mbp at the highest limits of resolution of human chromosomes, detected by fluorescent intensity evaluations performed at the microscope. Amplicons, or regions of interest, from 10-20 Mb and more are also defined by these methods. These amplicons contain a gene, or genes, that are amplified (meaning copy number gains), and/or differentially expressed in the tissue/cells of origin. Genes identified as being amplified and/or over-expressed provide targets for intervention with a small molecular therapeutic, antibodies, anti-sense or other therapeutic modalities. A gene or genes within these regions could also be used for diagnostic or prognostic molecular pathology characterization and useful as pharmacodynamic biomarkers for drug response profiling and patient sub-set selection and stratification.


BRIEF SUMMARY OF THE INVENTION

In one aspect the present invention relates to a set of genes that have been localized within human chromosomal regions of interest (ROI) that have been identified by molecular cytogenetic techniques. In particular, the present invention relates to chromosomal regions of interest, or amplicons, that are summarized in Table 1 and containing genes corresponding to cDNA sequences shown in the sequence listing described herein.


In another aspect, the present invention relates to a method for diagnosing the presence of a cancerous condition, or diagnosing a predisposition to developing a cancerous condition, in an animal, especially a human being, by determining the amplification and/or over-expression, of one or more genes corresponding to SEQ ID NO: 1-3049 in a cell, or tissue sample, obtained from an animal. The animal may be afflicted with, or at risk of developing, such a cancerous condition, or otherwise predisposed to develop such a condition.


In a further aspect, the present invention relates to a method for the treatment of a cancerous condition, especially one involving breast, colon, lung, cervix, kidney, pancreas and prostate tissues, utilizing selected chemical agents having anti-tumor activity as identified using one of the assays disclosed herein.


Thus, in one aspect the present invention relates to a method for identifying an antineoplastic agent, comprising:


(a) contacting a test compound with a cell that expresses at least one gene corresponding to a polynucleotide comprising a nucleotide sequence of SEQ ID NO: 1-3049 and under conditions promoting expression of said gene; and


(b) determining a change in expression of said gene as a result of said contacting


wherein a change in expression indicates gene modulation thereby identifying said test compound as a gene modulating agent. In a preferred embodiment thereof, the change in expression is a decrease in expression.


In a further aspect, the present invention relates to a method for identifying a compound as an anti-neoplastic agent, comprising:


(a) contacting a test compound with a polypeptide encoded by a gene selected from SEQ ID NO: 1-3049,


(b) determining a change in a biological activity of said polypeptide due to said contacting,


wherein a change in activity indicates anti-neoplastic activity and thereby identifies such test compound as an agent having antineoplastic activity.


Preferably, the change in biological activity is a decrease in biological activity. Also preferred is where the biological activity is an enzyme activity, most preferably involving an enzyme selected from kinase, protease, peptidase, phosphodiesterase, phosphatase, dehydrogenase, reductase, carboxylase, transferase, deacetylase and polymerase. Also preferred is a biological activity that is a membrane transport activity, an integrin, a Cytochrome P450 enzyme, a nuclear hormone receptor, or a receptor activity, such as a G-protein-coupled receptor. In other preferred embodiments, the polypeptide is contained in a cell.


The present invention also relates to a method for treating cancer comprising contacting a cancerous cell with an agent first identified as having gene modulating activity using any of the methods of the invention and in an amount effective to cause a reduction in cancerous activity of said cell. In a preferred embodiment, said cancerous cell is contacted in vivo, as where the agent is administered to a mammal, especially a human being, afflicted with cancer and in an amount sufficient to ameliorate the cancer.


The present invention further relates to a method for treating cancer comprising contacting a cancerous cell with an agent having affinity for an expression product of a gene corresponding to a polynucleotide comprising a nucleotide sequence of SEQ ID NO: 1-3049 and in an amount effective to cause a reduction in cancerous activity of said cell. Preferably, the expression product is a polypeptide and the agent is an antibody.


The present invention also relates to a method for monitoring the progress of cancer therapy in a patient comprising monitoring in a patient undergoing cancer therapy the expression of a gene corresponding to a polypeptide having a sequence selected from SEQ ID NO: 1-3049, preferably wherein the gene comprises a sequence of SEQ ID NO: 1-3049, such as where the cancer therapy is chemotherapy.


In a further embodiment, the present invention relates to a method for determining the likelihood of success of cancer therapy in a patient, comprising monitoring in a patient undergoing cancer therapy the expression of a gene corresponding to a polynucleotide having a sequence of one or SEQ ID NO: 1-3049 wherein a decrease in said expression prior to completion of said cancer therapy is indicative of a likelihood of success of said cancer therapy, preferably wherein the gene comprises a sequence of SEQ ID NO: 1-3049 and wherein the cancer therapy is chemotherapy.


The present invention still further relates to a method for determining the progress of a treatment for cancer in a patient afflicted therewith, following commencement of a cancer treatment on said patient, comprising:


(a) determining in said patient a change in expression of one or more genes corresponding to a polynucleotide comprising a nucleotide sequence of SEQ ID NO: 1-3049; and


(b) determining a change in expression of said gene compared to expression of said one or more determined genes prior to commencement of said cancer treatment;


wherein said change in expression indicates progress of said treatment thereby determining the progress of said treatment. Preferred embodiments include where the change in expression is a decrease in expression and said decrease indicates success of said treatment.


DEFINITIONS

As used herein, the following terms have the indicated definition unless expressly stated otherwise.


The term “amplicon” refers to regions of interest, i.e., genomic segments of DNA within human chromosomes in diseased states like cancer that are demarcated and limited within specific chromosomal bands. Since these amplicons contain sequences of a gene/or genes that are amplified (copy number gains), and/or differentially expressed in the tissue/cells of origin, a listing of these genes within the amplicons detected are listed in Table 3. Genes identified as being amplified and/or over-expressed within the amplicons provide a useful target for intervention with small/large molecule/protein/antibody therapeutics, anti-sense or other therapeutic modalities. A gene or genes within these regions is also useful for diagnostic or prognostic molecular pathology characterization/companion diagnostics, and useful as pharmacodynamic biomarkers for drug response profiling and patient sub-set selection and stratification.


The term “percent identity” or “percent identical,” when referring to a sequence, means that a sequence is compared to a claimed or described sequence after alignment of the sequence to be compared (the “Compared Sequence”) with the described or claimed sequence (the “Reference Sequence”). The Percent Identity is then determined according to the following formula:





Percent Identity=100 [1−(C/R)]


wherein C is the number of differences between the Reference Sequence and the Compared Sequence over the length of alignment between the Reference Sequence and the Compared Sequence wherein (i) each base or amino acid in the Reference Sequence that does not have a corresponding aligned base or amino acid in the Compared Sequence and (ii) each gap in the Reference Sequence and (iii) each aligned base or amino acid in the Reference Sequence that is different from an aligned base or amino acid in the Compared Sequence, constitutes a difference; and R is the number of bases or amino acids in the Reference Sequence over the length of the alignment with the Compared Sequence with any gap created in the Reference Sequence also being counted as a base or amino acid.


If an alignment exists between the Compared Sequence and the Reference Sequence for which the percent identity as calculated above is about equal to or greater than a specified minimum Percent Identity then the Compared Sequence has the specified minimum percent identity to the Reference Sequence even though alignments may exist in which the hereinabove calculated Percent Identity is less than the specified Percent Identity.


As used herein, the terms “portion,” “segment,” and “fragment,” when used in relation to polypeptides, refer to a continuous sequence of residues, such as amino acid residues, which sequence forms a subset of a larger sequence. For example, if a polypeptide were subjected to treatment with any of the common endopeptidases, such as trypsin or chymotrypsin, the oligopeptides resulting from such treatment would represent portions, segments or fragments of the starting polypeptide. When used in relation to a polynucleotide, such terms refer to the products produced by treatment of said polynucleotides with any of the common endonucleases, or any stretch of polynucleotides that could be synthetically synthesized.


As used herein, the term “DNA segment” or “DNA sequence” refers to a DNA polymer, in the form of a separate fragment or as a component of a larger DNA construct, which has been derived from DNA, and may include both single stranded and duplex sequences. Such segments are provided in the form of an open reading frame uninterrupted by internal non-translated sequences, or introns, which are typically present in eukaryotic genes.


The term “coding region” refers to that portion of a gene which either naturally or normally codes for the expression product of that gene in its natural genomic environment, i.e., the region coding in vivo for the native expression product of the gene.


The term “nucleotide sequence” refers to a heteropolymer of deoxyribonucleotides. Generally, DNA segments encoding the proteins provided by this invention are assembled from cDNA fragments and short oligonucleotide linkers, or from a series of oligonucleotides, to provide a synthetic gene which is capable of being expressed in a recombinant transcriptional unit comprising regulatory elements derived from a microbial or viral operon.


The term “expression product” means that polypeptide or protein that is the natural translation product of the gene and any nucleic acid sequence coding equivalents resulting from genetic code degeneracy and thus coding for the same amino acid(s).


The term “fragment,” when referring to a coding sequence, means a portion of DNA comprising less than the complete coding region whose expression product retains essentially the same biological function or activity as the expression product of the complete coding region.







DETAILED SUMMARY OF THE INVENTION

The present invention relates to a set of genes that are amplified and/or over-expressed genes in cancer cell lines and have been localized to various chromosomal regions of interest. These genes have been identified through a combination of CGH, SKY, expression analysis and Reverse Transcriptase-Polymerase Chain Reaction (RT-PCR). Such genes are both markers and potential therapeutic targets for cancer, in particular breast; colon, lung and prostate malignancies. In addition, the amplified nature of such genes provides a means of diagnosing a cancerous condition, or predisposition to a cancerous conditions, by determining the amplification of one or more of such genes in a patient afflicted with, or predisposed toward, or otherwise at risk of developing, cancer.


In one aspect the present invention relates to a set of genes that have been localized within human chromosomal regions of interest (ROI) that have been identified by molecular cytogenetic techniques. In particular, the present invention relates to chromosomal regions of interest, or amplicons, that are summarized in Table 1. Table 2 lists tissues where the amplicons are found, cell lines expressing them, the amplification ratios found in those tissues for cancer versus normal cells, amplicon size and the chromosomal locations of the amplicons. Table 3 lists the chromosomal locations and accession number identifications of these regions of interest and which serve to correlate amplicons with the cDNA sequences of SEQ ID NO: 1-3049.









TABLE 1







List of Amplicons











AMPLICON
CHR
BPSTART
BPEND
BPLENGTH














A1
8
122000000
127500000
5500000


A2
13
96500000
100000000
3500000


A3
5
175000000
181500000
6500000


A4
13
26500000
34000000
7500000


A5
7
101000000
106000000
5000000


A6
10
73500000
82500000
9000000


A7
7
71000000
77500000
6500000


A8
1
116500000
120000000
3500000


A9
6
36000000
41000000
5000000


 A10
18
70500000
76500000
6000000


 A11
9
9000000
18500000
9500000









For Table 1, CHR means chromosome number, BPLENGTH represents the number of nucleotides in the amplicon. BPSTART refers to “base pair start point” and BPEND refers to “base pair end point” along the chromosome based on the July 2003 human reference sequence UCSC version hg16 (NCBI Build 34).









TABLE 2







Amplicon Locations



















band

amplicon


cell line
Amp #
tissue
chrom
band start
stop
Ratio
size_MB

















HCC1954
A1
Breast
8
q24.13
q24.13
14
5.3


NCI_H446
A1
scLung
8
q24.13
q24.21
8
8.3


NCI_H827
A1
scLung
8
q24.13
q24.21
6
8.3


HCC202
A1
Breast
8
q24.13
q24.21
6
8.3


NCI_H82
A1
scLung
8
q24.13
q24.13
7
5.3


NCI_H23
A1
nscLung
8
q24.13
q24.13
7
5.3


MDA_MB436
A2
Breast
13
q32.2
q32.3
6
5.3


NCI_H1963
A2
scLung
13
q32.3
q32.3
6
3.3


EFM192A
A2
Breast
13
q32.3
q34
8
18.8


MDA_MB157
A2
Breast
13
q32.3
q34
5
18.8


HCC1937
A2
Breast
13
q32.3
q32.3
4
3.3


SKBR3
A2
Breast
13
q32.3
q32.3
4
18.8


NCI_H1963
A2
nscLung
13
q32.3
q32.3
6
3.3


HCC1954
A3
Breast
5
q35.3
q35.3
4
4.3


MDA_MB436
A3
Breast
5
q35.1
q35.3
7
14


BT20
A4
Breast
5
q35.1
q35.3
4
14


KPL1
A5
Breast
5
q35.1
q35.3
4
14


HCC3153
A6
Breast
5
q35.3
q35.3
3
4.3


HT29
A4
Colon
13
q12.3
q13.2
5
9


SW403
A4
Colon
13
q21.1
q21.2
15
6


BT20
A4
Breast
13
q12.3
q13.2
4
9


CPDR9
A4
Prostate
13
q12.2
q12.3
2
7.1


SW480
A5
Colon
7
q22.2
q22.2
9
1


X71
A5
Colon
7
q22.1
q22.2
5
7.2


X72
A5
Colon
7
q22.3
q22.3
6
3.3


Lovo
A6
Colon
7
q22.1
q22.2
5
7.2


X1819_1
A7
Colon
7
q22.1
q22.2
5
7.2


EFM19
A6
Breast
10
q22.1
q22.3
6
15.3


PC3
A6
Prostate
10
q22.2
q22.3
7
8.3


MDA_MB436
A6
Breast
10
q22.1
q22.2
3
10.7


SKBR3
A6
Breast
10
q22.2
q22.3
4
8.3


SW48
A6
Colon
10
q22.1
q22.3
4
15.3


X71
A6
Colon
10
q22.2
q22.3
2
8.3


SKBR3
A7
Breast
7
q11.23
q11.23
5
4


X72
A7
Colon
7
q11.23
q11.23
7
4


X71
A7
Colon
7
q11.23
q11.23
5
4


X1819_1
A7
Colon
7
q11.23
q11.23
4
4


NCI_H69
A7
scLung
7
q11.23
q11.23
4
4


BT20
A8
Breast
1
p12.2
p13.2
10
9


CAMA-1
A8
Breast
1
p12
p12
6
6.7


KPL-1
A8
Breast
1
p11.2
p13.3
11
14.7


Colo205
A9
Colon
6
p21.2
p21.2
8
3.4


MDA_MB231
A9
Breast
6
p21.1
p21.2
7
9.8


NCI——H522
A9
nscLung
6
p21.2
p21.31
6
9.1


PANC-1
A10
Pancreas
18
q23
q23
7
5.2


NCI_H1607
A11
scLung
9
p22.2
p23
10
14.5


NCI_H446
A11
scLung
9
p22.3
p22.3
8
2.9


HCC1954
A11
Breast
9
p22.2
p23
10
14.5









In addition, SEQ ID NO: 1-3049 represents the nucleotide sequences for cDNA sequences corresponding to genes located in these regions of interest. Such regions contain genes found to be amplified and over-expressed in cancerous tissues, especially of breast, colon, lung, cervix, kidney, pancreas and prostate.


Each amplicon may contain about 75 genes, at least one of which will be amplified in a cancerous condition. Genes that show amplification and/or over-expression can be indicative of the cancerous status of a given cell.


Briefly, the procedures used to identify the genes disclosed herein may be summarized as follows:


For CGH analysis, based on detailed molecular cytogenetic characterizations, the following data sets are generated, which may include regions reported in the public domain as well as unique regions not previously known.

    • 1. A map of chromosomal regions involved in consistent, recurrent and high level genomic gains (i.e., amplifications) for a representative cancer cell line or tumor type (e.g. colon, prostate, breast and lung) that can be recognized as a pattern/signature for a given tumor type.
    • 2. A map of chromosomal regions containing genomic losses (i.e., deletions) in each tumor type and individual cell line to be examined.
    • 3. Levels of intensities of gains and losses categorized for entry into a database.
    • 4. A comparison of the patterns of gains and losses between the clinical samples (e.g. colon xenografts) and cell lines (e.g., colon) of matched Stages and Grades.
    • 5. A comparison of the patterns of gains and losses between primary prostate tumor cell lines (e.g., CPDR lines) and metastatic prostate tumor cell lines (e.g., DU 145, PC3 and LNCaP).


In accordance with the present invention, for SKY analysis, data sets were generated according to the following steps:

    • 1. Identification and development of a database of novel chromosomal rearrangements in epithelial cancer cell lines.
    • 2. Identification of novel translocations involving specific chromosomes or chromosomal regions
    • 3. Reconciliation of SKY and CGH analysis on the same cell line as a verification of the combined findings.


Combining genomic DNA analysis of gains and losses in the tumor cell lines/clinical samples with cDNA expression analysis from matched tumor types displayed ordered on the assembled Human genome sequence:

    • 1. A pattern of gene expression on a Affymetrix chip set (U95 and U133) was used to generate differential gene expression profiles between samples sets containing normal and malignant tissues from colon, prostate, lung, breast and various cell lines.
    • 2. A Spoffire™ visualization tool was developed that allowed the generation of a list of all the genes that are present in the Human genome sequence within the defined regions of gains/losses for each cell type/tumor type to identify genes to include in the HITS platform and for identification of cancer associated genes
    • 3. The following algorithm was employed:
      • i) Match chromosomal regions of amplification/gains defined by CGH with the location of genes/ESTs on an Affymetrix chip as mapped to a Human genome template.
      • ii) Identify genes/ESTs over-expressed in tumor tissue compared to normal tissue in said chromosomal regions using.
      • iii) Compile data on cell lines of a particular tumor type and different tumor types showing clusters of genomic gains and losses at certain chromosomal regions.
      • iv) Pick BACs that span the chromosomal regions consistently gained and containing over-expressed genes in an effort to positionally clone novel cancer genes (oncogenes and genes in relevant pathways)
      • v) Validate the identified genes by
        • A) Picking STS markers that identify the gene sequence and quantify the relative copy number in genomic DNA and RNA across a panel of tumor cell lines.
        • B) Develop probes for FISH on chromosomes from tumor cell lines and primary tumor tissue micro-arrays.
    • 4. The expression data from tumor cell lines that have undergone SKY/CGH analysis was used to pick candidate genes to validate as individual targets in functional genomic assays and in-vivo assays and for use in the transcriptional assay platform.


In accordance with the present invention, over-expression of cellular genes is conveniently monitored in model cellular systems using cell lines (such as is used in the example below), primary cells, or tissue samples maintained in growth media. For different purposes, these may be treated with compounds at one or more different concentrations to assay for modulating agents. Thus, cellular RNAs are isolated from the cells or cultures as an indicator of selected gene expression. The cellular RNAs are then divided and subjected to analysis to determine the presence and/or quantity of specific RNA transcripts, which transcripts are then amplified for detection purposes using standard methodologies, such as reverse transcriptase polymerase chain reaction (RT-PCR). The levels of specific RNA transcripts, including their presence or absence, are determined. When used for identification of modulating agents, such as anti-neoplastic agents, a metric is derived for the type and degree of response of the treated sample compared to control samples.


In accordance with the foregoing, the amplicons identified as being amplified and/or over-expressed, which can include increased copy number thereof, in cancerous cells are localized in chromosomal regions of interest as identified in Tables 2 and 3.


The genes localized in these amplicons may be utilized to characterize, the cancerous, or non-cancerous, status of cells, or tissues. The methods of the invention may be used with a variety of cell lines or with primary samples from tumors maintained in vitro under suitable culture conditions for varying periods of time, or in situ in suitable animal models.


The amplicons disclosed herein are expressed at levels in cancer cells that are different from the expression levels in non-cancer cells. Expression in cancer versus non-cancer cells of the same tissue type is a key identifier.


In accordance with the forgoing, the present invention also relates to a method for identifying a gene modulating agent, such as an anti-neoplastic agent, comprising:


(a) contacting a test compound, a compound whose gene-modulating and/or anti-neoplastic activity is to be determined, with one or more cells expressing one or more genes mapped to the chromosomal region of interest, or amplicon, for genes as identified in Table 3, and


(b) determining a change in expression of said one or more genes compared to when said contacting has not occurred,


wherein a change in expression of said gene is indicative of gene modulating activity, thereby identifying said test compound as a gene modulating agent.


In accordance with the foregoing, the present invention relates to a method for identifying an antineoplastic agent, comprising:


(a) contacting a test compound with a cell that expresses one or more amplicons of Table 2 having an amplification ratio of at least 2.0; and


(b) determining a change in said amplification ratio due to said contacting;


wherein a change in said amplification ratio due to said contacting indicates that said test compound has gene modulating activity


thereby identifying said test compound as a gene modulating agent.


The present invention also contemplates a method for identifying an antineoplastic agent, comprising:


(a) contacting a test compound with a cell that expresses at least one gene corresponding to a polynucleotide comprising a nucleotide sequence of SEQ ID NO: 1-3049 and under conditions promoting expression of said gene; and


(b) determining a change in expression of said gene as a result of said contacting


wherein a change in expression indicates gene modulation thereby identifying said test compound as a gene modulating agent.


In preferred embodiments of these methods, the change in expression is a decrease in expression and/or the decrease in expression is a decrease in copy number of the gene and/or the gene comprises a nucleotide sequence of one of SEQ ID NO: 1-3049 and/or the cell was genetically engineered to express said gene.


Because the genes disclosed herein are over-expressed and relate to the cancerous condition of a cell, successful anti-neoplastic activity will commonly be exhibited by agents that reduce the expression of said genes In one embodiment thereof, the change in expression is a decrease in copy number of the gene or genes under study. In accordance therewith, said change in gene copy number is conveniently determined by detecting a change in expression of messenger RNA encoded by said gene sequence. In another preferred embodiment, expression is determined for more than one such gene, such as 2, 5, 10 or more of the genes.


Thus, the present invention also encompasses a method for detecting the cancerous status of a cell, comprising detecting elevated expression in said cell of at least one gene corresponding to a polynucleotide comprising a nucleotide sequence of SEQ ID NO: 1-3049 whereby such elevated expression is indicative of cancerous status of the cell. In preferred embodiments thereof, the elevated expression is an elevated copy number of the gene.


Other methods useful in measuring a change in expression of the genes disclosed herein include measuring a change in the amount or rate of synthesis of a polypeptide encoded by said gene, preferably a decrease in synthesis of said polypeptide. Most preferably, the polypeptide comprises an amino acid sequence highly homologous to a sequence encoded by a gene mapping to an amplicon disclosed herein and whose expression is elevated in cancer.


The methods of the invention can thus be utilized to identify anti-neoplastic agents useful in treatment of cancerous conditions. Such activity can be further modified by first identifying such an agent using an assay as already described and further contacting such agent with a cancerous cell, followed by monitoring of the status of said cell, or cells. A change in status indicative of successful anti-neoplastic activity may include a decrease in the rate of replication of the cancerous cell(s), a decrease in the total number of progeny cells that can be produced by said cancerous cell(s), or a decrease in the number of times said cancerous cell(s) can replicate, or the death of said cancerous cell(s).


Anti-neoplastic agents may also be identified using recombinant cells suitably engineered to contain and express the cancer-related genes disclosed herein. In one such embodiment, a recombinant cell is formed using standard technology and then utilized in the assays disclosed herein. Methods of forming such recombinant cells are well known in the literature. See, for example, Sambrook, et al., Molecular Cloning: A Laboratory Manual, Second Edition, Cold Spring Harbor, N.Y., (1989), Wu et al, Methods in Gene Biotechnology (CRC Press, New York, N.Y., 1997), and Recombinant Gene Expression Protocols, in Methods in Molecular Biology, Vol. 62, (Tuan, ed., Humana Press, Totowa, N.J., 1997), the disclosures of which are hereby incorporated by reference.


The present invention also relates to a method for detecting the cancerous status of a cell, comprising detecting elevated copy number and/or expression in said cell of at least one gene that maps to a chromosomal region of interest, or amplicon, as identified in Table 3. Such elevated expression may be readily monitored by comparison to that of otherwise normal cells having the same genes. Elevated expression of such genes is indicative of the cancerous state. Such elevated expression, including increased copy number, may be the expression of more than one such gene.


The present invention also relates to a method for detecting a cancer-linked gene comprising the steps of contacting a test compound, identified as having gene modulating activity for a gene mapping to one of the amplicons disclosed herein, with a cell expressing a test gene and detecting modulation, such as decreased activity, of such test gene relative to when said compound is not present thereby identifying said test gene as a cancer-related gene. In preferred embodiments, the gene determined by said method is an oncogene, or cancer facilitating gene.


In another embodiment, there is provided a method for treating cancer comprising contacting a cancerous cell with an agent first identified as having gene modulating activity using any of the assay methods disclosed according to the invention and in an amount effective to reduce the cancerous activity of said cell. In a preferred embodiment, the cancerous cell is contacted in vivo. In other preferred embodiments, said reduction in cancerous activity is a decrease in the rate of proliferation of said cancerous cell, or said reduction in cancerous activity is the death of said cancerous cell.


The present invention further relates to a method for treating cancer comprising contacting a cancerous cell with an agent having activity against an expression product encoded by a gene mapping to an amplicon as disclosed herein, preferably where the expression product is a polypeptide. In a preferred embodiment, said cancerous cell is contacted in vivo. In another preferred embodiment, the agent is an antibody.


Nucleotide sequences mapping to the amplicons disclosed herein may be genomic in nature and thus represent the sequence of an actual gene, such as a human gene, or may be a cDNA sequence derived from a messenger RNA (mRNA) and thus represent contiguous exonic sequences derived from a corresponding genomic sequence or they may be wholly synthetic in origin for purposes of testing. Such cDNA sequences, mapping to the amplicons disclosed herein are identified as SEQ ID NO: 1-3049.


As described in the Example below, the expression of cancer-related genes may be determined from the relative expression levels of the RNA complement of a cancerous cell relative to a normal (i.e., non-cancerous) cell. Because of the processing that may take place in transforming the initial RNA transcript into the final mRNA, the sequences disclosed herein may represent less than the full genomic sequence. They may also represent sequences derived from ribosomal and transfer RNAs. Consequently, the genes present in the cell (and representing the genomic sequences) and the sequences disclosed in SEQ ID NO: 1-3049, which are mostly cDNA sequences, may be identical or may be such that the cDNAs contain less than the full genomic sequence. Such genes and cDNA sequences are still considered corresponding sequences because they both encode similar RNA sequences. Thus, by way of non-limiting example only, a gene that encodes an RNA transcript, which is then processed into a shorter mRNA, is deemed to encode both such RNAs and therefore encodes an RNA complementary to (using the usual Watson-Crick complementarity rules), or that would otherwise be encoded by, a cDNA (for example, a sequence as disclosed herein). Thus, the sequences disclosed herein correspond to genes contained in the cancerous or normal cells used to determine relative levels of expression because they represent the same sequences or are complementary to RNAs encoded by these genes. Such genes also include different alleles and splice variants that may occur in the cells used in the methods of the invention.


In addition, sequences encoding the same proteins as any of these genes, regardless of the percent identity of such sequences, are also specifically contemplated by any of the methods of the present invention that rely on any or all of said sequences, regardless of how they are otherwise described or limited. Thus, any such sequences are available for use in carrying out any of the methods disclosed according to the invention. Such sequences also include any open reading frames, as defined herein, present within any genes mapping to the amplicons of the invention.


The present invention also finds use as a means of diagnosing the presence of cancer in a patient, as where a sample of cancerous tissue or cells, or tissues or cells suspected of being cancerous, are examined for elevated expression, such as at least 2 fold expression, of a gene in one of the amplicons disclosed herein, such as an increased expression of a cDNA sequence, or polypeptide encoded by said cDNA sequence, disclosed in Table 3 and being one of the sequences of SEQ ID NC): 1-3049.


For such purposes, and in accordance with the disclosure elsewhere herein, such diagnosis is based on the detection of elevated expression or amplification, such as elevated copy number, of one or more of the genes identified according to the invention. Such elevated expression can be determined by any of the means described herein.


In one such embodiment, the elevated expression, as compared to normal cells and/or tissues of the same organ, is determined by measuring the relative rates of transcription of RNA, such as by production of corresponding cDNAs and then analyzing the resulting DNA using probes developed from genes mapping to the amplicons of the invention. Thus, the levels of cDNA produced by use of reverse transcriptase with the full RNA complement of a cell suspected of being cancerous produces a corresponding amount of cDNA that can then be amplified using polymerase chain reaction, or some other means, such as rolling circle amplification, to determine the relative levels of resulting cDNA and, thereby, the relative levels of gene expression.


For RNA analysis, the latter may be isolated from samples in a variety of ways, including lysis and denaturation with a phenolic solution containing a chaotropic agent (e.g., triazol) followed by isopropanol precipitation, ethanol wash, and resuspension in aqueous solution; or lysis and denaturation followed by isolation on solid support, such as a Qiagen resin and reconstitution in aqueous solution; or lysis and denaturation in non-phenolic, aqueous solutions followed by enzymatic conversion of RNA to DNA template copies. Steady state RNA levels for a given type of cell or tissue may have to be ascertained prior to employment of the methods of the invention but such is well within the skill of those in the art and will not be further described in detail herein.


Alternatively, increased expression, such as increased copy number, may be determined for the genes present in a cancerous cell, or a cell suspected of being cancerous, by determining elevated expression within the regions of interest, or amplicons, disclosed herein. Thus, the DNA of such cells may be extracted and probed for increased gene expression within the area disclosed herein as amplified in different cancer types and tissues.


In employing the methods of the invention, it should be borne in mind that gene expression indicative of a cancerous state need not be characteristic of every cell found to be cancerous. Thus, the methods disclosed herein are useful for detecting the presence of a cancerous condition within a tissue where less than all cells exhibit the complete pattern of over-expression. For example, a set of selected genes, which are found within the regions of interest disclosed herein, may be found, using appropriate probes, either DNA or RNA, to be present in as little as 60% of cells derived from a sample of tumorous, or malignant, tissue while being absent from as much as 60% of cells derived from corresponding non-cancerous, or otherwise normal, tissue (and thus being present in as much as 40% of such normal tissue cells). In a preferred embodiment, such gene pattern is found to be present in at least 70% of cells drawn from a cancerous tissue and absent from at least 70% of a corresponding normal, non-cancerous, tissue sample. In an especially preferred embodiment, such gene pattern is found to be present in at least 80% of cells drawn from a cancerous tissue and absent from at least 80% of a corresponding normal, non-cancerous, tissue sample. In a most preferred embodiment, such gene pattern is found to be present in at least 90% of cells drawn from a cancerous tissue and absent from at least 90% of a corresponding normal, non-cancerous, tissue sample. In an additional embodiment, such gene pattern is found to be present in at least 100% of cells drawn from a cancerous tissue and absent from at least 100% of a corresponding normal, non-cancerous, tissue sample, although the latter embodiment may represent a rare occurrence.


Because changes in expression of these genes (up-regulation) are linked to the disease state (i.e. cancer), the change in expression may contribute to the initiation or progression of the disease. For example, if a gene that is up-regulated is an oncogene such a gene provides for a means of screening for small molecule therapeutics beyond screens based upon expression output alone. For example, genes that display up-regulation in cancer and whose elevated expression contributes to initiation or progression of disease represent targets in screens for small molecules that inhibit or block their function. Examples include, but are not be limited to, kinase inhibition, cellular proliferation, substrate analogs that block the active site of protein targets, etc.


It should be noted that there are a variety of different contexts in which genes have been evaluated as being involved in the cancerous process. Thus, some genes may be oncogenes and encode proteins that are directly involved in the cancerous process and thereby promote the occurrence of cancer in an animal. Other genes may simply be involved either directly or indirectly in the cancerous process or condition and may serve in an ancillary capacity with respect to the cancerous state. All such types of genes are deemed with those to be determined in accordance with the invention as disclosed herein. Thus, the gene determined by said method of the invention may be an oncogene, or the gene determined by said method may be a cancer facilitating gene, the latter including a gene that directly or indirectly affects the cancerous process, either in the promotion of a cancerous condition or in facilitating the progress of cancerous growth or otherwise modulating the growth of cancer cells, either in vivo or ex vivo. Such genes may work indirectly where their expression alters the activity of some other gene or gene expression product that is itself directly involved in initiating or facilitating the progress of a cancerous condition. For example, a gene that encodes a polypeptide, either wild or mutant in type, which polypeptide acts to suppress of tumor suppressor gene, or its expression product, will thereby act indirectly to promote tumor growth.


Many cancerous genes appear to have their effect by encoding an aberrant protein that functions in a cell in a manner different from that of normal cells, or else said protein is overproduced or underproduced as a result of some mutation in the coding sequence, or promoter or enhancer sequences, of a particular gene, such as one of Genes 1-3049 disclosed herein and expressed by the amplicons of the invention.


In accordance with the present invention, there are provided methods for measuring the activity, such as a biological activity, of such a polypeptide. Such biological activity may include any measurable activity, such as chemical reactivity, catalytic ability, binding to specific structures and receptors, acting as a receptor, or just being present in a membrane of a cell and therefore available as a target site for antibodies or other agents. Any such polypeptides may thus provide a target for a chemotherapeutic agent, especially an antineoplastic agent.


As is well known in the art, polypeptide activities can be measured in different ways so as to enable screening procedures for agents, such as test compounds, that inhibit the activity of the polypeptide and thereby work against the function of that polypeptide, such as where the polypeptide is some type of cancer-related protein, such as that produced by expression of an oncogene, or where the polypeptide is overproduced as part of the cancer initiating or facilitating process. As non-limiting examples, such screening methods for antineoplastic agents can include the measurement of compounds that bind to proteins (or that bind to a gene or a transcript of a gene), compounds that inhibit expression (including processing and/or maturation) of a protein, or the detection of downstream reaction product, most often with specific antibodies using enzyme-linked immunosorbent assay (ELISA) procedures well known in the art, or compounds that inhibit activity, such as enzyme activity or some other function, or compounds that interact with upstream or downstream proteins (such as with transcription factors or other binding proteins that may serve to regulate gene expression).


In accordance with the foregoing, the present invention relates to a method for identifying a compound as an anti-neoplastic agent, comprising:


(a) contacting a test compound with a polypeptide encoded by a gene selected from SEQ ID NO: 1-3049,


(b) determining a change in a biological activity of said polypeptide due to said contacting,


wherein a change in activity indicates anti-neoplastic activity and thereby identifies such test compound as an agent having antineoplastic activity.


In a preferred embodiment, the change in biological activity is a decrease in biological activity.


In another preferred embodiment, the biological activity is an enzyme activity, such as where the enzyme is one selected from the group kinase, protease, peptidase, phosphodiesterase, phosphatase, dehydrogenase, reductase, carboxylase, transferase, deacetylase and polymerase.


Assays for these enzymes are available, such as for phosphodiesterases (the most pharmacologically relevant phosphodiesterases are those that hydrolyze cyclic nucleotides (see, for example, cAMP and cGMP assays available from Perkin-Elmer, as well as Estrade et al., Eur. J. Pharmacol. 352:2-3, 157-163 (1998)).


Protein phosphatases remove phosphate residues from proteins. Most tests of their activity use the same assays as for protein kinases. A non-radioactive phosphatase assay system is available from Promega Biotech.


The therapeutically most relevant dehydrogenases oxidize or reduce small molecular weight metabolites, esp. steroid hormones, or that generally use or generate NAD or NADP (see: Haeseleer et al., J. Biol. Chem., 273:21790-21799 (1998)). A commercial assay is available from Cayman Chemical (at www.caymanchem.com).


Gamma-carboxylases are important enzymes in the blood coagulation process. The main assay protocols use synthetic peptides (see: Ulrich et al., J. Biol. Chem., 263:9697-9702 (1988); Begley et al., J. Biol. Chem., 275:36245-36249 (2000)).


In highly preferred embodiments, the kinase is one of a protein kinase, a serine or threonine kinase, or a receptor tyrosine protein kinase. Where the polypeptide encoded by a gene of the invention is a protein kinase, especially involving tyrosine kinase, various assays for activity are available. Protein kinases add phosphate groups to serine, threonine or tyrosine residues on proteins, most commonly measured with phospho-serine, threonine, or tyrosine-specific antibodies, or generation of radiolabeled substrate, or consumption of ATP, or phosphorylation of (synthetic) small peptides, or measuring downstream enzyme activity and gene transcription. Such assays are commercially available. (See, for example, the tyrosine kinase assay from Roche Molecular Biochemicals). Assays for serine/threonine kinases are also available at Chromagen.com, Upstate Biotechnology, Inc. (Lake Placid, N.Y., and at upstatebiotech.com) and from Applied BioSystems (Foster City, Calif. (home.appliedbiosystems.com)).


In other specific embodiments, the protease is a serine protease, cysteine protease or aspartic acid protease, or the transferase is a methyltransferase, preferably a cytosine methyltransferase or an adenine methyltransferase, or the deacetylase is a histone deacetylase, or the carboxylase is a γ-carboxylase, or the peptidase is a zinc peptidase, or the polymerase is a DNA polymerase or an RNA polymerase.


Proteases degrade proteins, un-specifically or at specific sites. Almost all pharmacologically relevant ones have very narrowly defined specific substrates, and their activity is most often measured by directly measuring cleavage product or generation of (fluorescent) light after cleavage of synthetic substrates. Assays are available for serine proteases (Calbiochem, Palo Alto, Calif., and see Berdichevsky et al., J. Virol. Methods, 107:245-255 (2003), for systeine proteases (See: Schulz et al., Mol. Pathol., 51:222-24 (1998) and Seizer et al., PNAS, 96:11015-11022 (1999)), for aspartic acid proteases (Geno Tech, Inc. at www.genotech.com) and for zinc peptidases (see Evans et al., J. Biol. Chem., 278:23180-23186 (2003)).


Both (regulatory) DNA-methylases and (biosynthetic) protein methylases that are drug targets. (See: Jonassen and Clarke, J. Biol. Chem., 275:12381-12387 (2000); Jackson et al., Nature, 416:556-560 (2002)).


Most HDAC (histone deacetylase) assays use colorimetric or fluorometric (synthetic) substrates. Standard assays are for binding, especially molecular size changes, blocking a specific site, and effects on transcription or downstream reactions (if DNA or RNA is the direct target of a drug). A commercial assay is available from Vinci Biochem (at www.vincibiochem.it).


In another specific embodiment, the biological activity is a membrane transport activity, preferably wherein the polypeptide is a cation channel protein, an anion channel protein, a gated-ion channel protein or an ABC transporter protein. Drug effects on the activity of transporter and channel proteins are screened by measuring increase or decrease of the ((radio-)labeled) transported entity inside or outside the cell, in cell-based assays, ATP consumption (in the case of ATPases), or changes in cell membrane potential. Assays employing such proteins are available, such as for ABC transporter (see: Marcil et al., Lancet, 354:1341-46 (1999) and for ion channels (from Evotec OAI, at www.evotecoai.com and from PharmaLinks, at www.pharmalinks.org/research/cellsignalling).


In one embodiment, the polypeptide is an integrin (the signal transduction pathways elicited by the integrins are slow and not very well characterized, hence most assays are either just binding assays or measure downstream biological phenomena (such as migration, invasion, etc.) (See: Ganta et al., Endocrinology, 138:3606-3612 (1997); Sim et al., J. Biomed. Mater. Research, 68A:352-359 (2004); and Weinreb et al., Anal. Biochem., 306:305-313 (2002)), or a Cytochrome P450 enzyme (almost all cytochrome assays require knowledge of what the substrate is and measure conversion of substrate (free or (radio-)labeled) or generation of product; useful C14-labeled substrates are available from Amersham Biosciences at www1.amershambiosciences.com), or a nuclear hormone receptor (Assays available from Discoverx, Fremont, Calif., such as an estrogen assay; also see Rosen et al., Curr. Opin. Drug. Discov. Devel., 6:224-30 (2003)).


In one preferred embodiment, the biological activity is a receptor activity, preferably where the receptor is a G-protein-coupled receptor (GPCR).


GPCRs are transmembrane proteins that wind 7 times back and forth through a cell's plasma membrane with a ligand binding site located on the outside of the membrane surface of the cell and the effector site being present inside the cell. These receptors bind GDP and GTP. In response to ligand binding, GPCRs activate signal transduction pathways which induce a number of assayable physiological changes, e.g., an increase in intracellular calcium levels, cyclic-AMP, inositol phosphate turnover, and downstream gene transcription (directly or via reporter-assays) along with other translocation assays available for measuring GPCR activation when the polypeptide encoded by a gene of the invention is a GPCR. Thus, such proteins work through a second messenger. The result is activation of CREB, a transcription factor that stimulates the production of gene products. One useful assay is the so-called BRET2/arrestin assay, useful in screening for compounds that interact with GPCRs. (See: Bertrand et al, J. Recept. Signal Transduct Res., 22:533-41 (February-November 2002)). In addition, numerous assays are commercially available, such as the Transfluor Assay, available from Norak Biosciences, Inc. (www.norakbio.com) or ArrayScan and KineticScan, both from Cellomics, or assays from CyBio (Jena, Germany).


Assays useful with the invention are usually set up to screen for agonists or antagonists after adding ligand, but effects on most of these parameters can be measured whether or not the ligand for the receptor is known. Such assays may involve radioligand-binding assays. Activation of the majority of GPCRs by agonists leads to the interaction of beta-arrestin (a protein that is involved in receptor desensitization and sequestration) with the receptor, which is measurable by fluorescence energy transfer


The disclosure of all journal articles, or other publications, referred to herein are hereby incorporated by reference in their entirety.


In one embodiment, the polypeptide is in a solution or suspension and contact with the test compound is by direct contact between the test compound and the protein molecule. Alternatively, the polypeptide may be in a cell and the test compound may have to diffuse into the cell in order to contact the polypeptide. In an alternative embodiment, the test compound may be contacted with a cell that contains or expresses the polypeptide but the test compound may have no direct contact with the polypeptide. In stead, the test compound may act to induce production and/or activity of a different compound, such as an intracellular second messenger that serves to contact the polypeptide and modulate or change the biological activity of this polypeptide.


In accordance with the foregoing, the method of the present invention includes cancer modulating agents that are themselves either polypeptides, or small chemical entities, that affect the cancerous process, including initiation, suppression or facilitation of tumor growth, either in vivo or ex vivo. Such agents may also be antibodies that react with one or more polypeptides encoded by genes present in the amplicons of the invention.


In keeping with the disclosure herein, the present invention also relates to a method for treating cancer comprising contacting a cancerous cell with an agent having activity against an expression product encoded by a gene mapping within regions of chromosomal interest.


The method of the present invention includes embodiments of the above-recited method wherein said cancer cell is contacted in vivo as well as ex vivo, preferably wherein said agent comprises a portion, or is part of an overall molecular structure, having affinity for said expression product. In one such embodiment, said portion having affinity for said expression product is an antibody.


In one embodiment of the present invention, a chemical agent, such as a protein or other polypeptide, is joined to an agent, such as an antibody, having affinity for an expression product of a cancerous cell, such as a polypeptide or protein encoded by a gene related to the cancerous process, especially a gene mapping to an amplicon as disclosed herein In a specific embodiment, said expression product acts as a therapeutic target for the affinity portion of said anticancer agent and where, after binding of the affinity portion of such agent to the expression product, the anti-cancer portion of said agent acts against said expression product so as to neutralize its effects in initiating, facilitating or promoting tumor formation and/or growth. In a separate embodiment of the present invention, binding of the agent to said expression product may, without more, have the effect of deterring cancer promotion, facilitation or growth, especially where the presence of said expression product is related, either intimately or only in an ancillary manner, to the development and growth of a tumor. Thus, where the presence of said expression product is essential to tumor initiation and/or growth, binding of said agent to said expression product will have the effect of negating said tumor promoting activity. In one such embodiment, said agent is an apoptosis-inducing agent that induces cell suicide, thereby killing the cancer cell and halting tumor growth.


Many cancers contain chromosomal rearrangements, which typically represent translocations, amplifications, or deletions of specific regions of genomic DNA. A recurrent chromosomal rearrangement that is associated with a specific stage and type of cancer always affects a gene (or possibly genes) that play a direct and critical role in the initiation or progression of the disease. Many of the known oncogenes or tumor suppressor genes that play direct roles in cancer have either been initially identified based upon their positional cloning from a recurrent chromosomal rearrangement or have been demonstrated to fall within a rearrangement subsequent to their cloning by other methods. In all cases, such genes display amplification at both the level of DNA copy number and at the level of transcriptional expression at the mRNA level.


In accordance with the present invention, said functionally related genes are genes modulating the same metabolic pathway or said genes are genes encoding functionally related polypeptides. In one such embodiment, said genes are genes whose expression is modulated by the same transcriptional activator or enhancer sequence, especially where said transcriptional activator or enhancer increases, or otherwise modulates, the activity of a gene mapping to one of the amplicons of the invention.


The present invention also relates to a process that comprises a method for producing a product, such as test data, comprising identifying an agent according to one of the disclosed methods for identifying such an agent (i.e., the therapeutic agents identified according to the assay procedures disclosed herein) wherein said product is the data collected with respect to said agent as a result of said identification process, or assay, and wherein said data is sufficient to convey the chemical character and/or structure and/or properties of said agent. For example, the present invention specifically contemplates a situation whereby a user of an assay of the invention may use the assay to screen for compounds having the desired enzyme modulating activity and, having identified the compound, then conveys that information (i.e., information as to structure, dosage, etc) to another user who then utilizes the information to reproduce the agent and administer it for therapeutic or research purposes according to the invention. For example, the user of the assay (user 1) may screen a number of test compounds without knowing the structure or identity of the compounds (such as where a number of code numbers are used the first user is simply given samples labeled with said code numbers) and, after performing the screening process, using one or more assay processes of the present invention, then imparts to a second user (user 2), verbally or in writing or some equivalent fashion, sufficient information to identify the compounds having a particular modulating activity (for example, the code number with the corresponding results). This transmission of information from user 1 to user 2 is specifically contemplated by the present invention.


In accordance with the foregoing, the present invention relates to a method for producing test data with respect to the anti-neoplastic activity of a compound, such as a test compound as defined herein, comprising:


(a) identifying a test compound as having anti-neoplastic activity using a method of the invention, such as measuring the biological activity of a polypeptide encoded by a gene of Table 3 (SEQ ID NO: 1-3049), and


(b) producing test data with respect to the anti-neoplastic activity of said test compound sufficient to identify the chemical structure of said test compound.


In another embodiment, the present invention provides a method for monitoring the progress of a cancer treatment, such as where the methods of the invention permit a determination that a given course of cancer therapy is or is not proving effective because of an increased or decreased expression of a gene, or genes, mapping to an amplicon as disclosed herein. For example, where there is an increased copy number of one or more of said genes monitoring of such genes can predict success or failure of a course of therapy, such as chemotherapy, or predict the likelihood of a relapse based on elevated activity or expression of one or more of these genes following such course of therapy.


In accordance with the foregoing, the present invention contemplates a method for determining the progress of a treatment for cancer in a patient afflicted with cancer, following commencement of a cancer treatment on said patient, comprising determining in said patient a change in expression of one or more genes, preferably more than one, corresponding to a gene of Table 3 or encoding a polypeptide or transcript of such a gene, or genes compared to expression of said one or more determined genes prior to commencement of said cancer treatment, wherein a change in expression, especially a decrease in expression, indicates positive effects of such treatment, thereby determining the progress of said treatment.


In a preferred embodiment, the detected change in expression is a decrease in expression. In another preferred embodiment, the cancer treatment is treatment with a chemotherapeutic agent, especially an agent that modulates, preferably decreases, expression of a gene identified herein, such as where said agent was first identified as having anti-neoplastic activity using a method of the invention. Thus, in accordance with this aspect of the present invention, a patient, or even a research animal, such as a mouse, rat, rabbit or primate, afflicted with cancer, including a cancer induced for research purposes, is introduced to a cancer treatment regimen, such as administration of an anti-cancer agent, including one first identified as having anti-neoplastic activity by one or more of the screening methods disclosed herein. The progress and success or failure of such treatment is subsequently ascertained by determining the subsequent expression of one or more, preferably at least 3, or 5, or 10, of genes mapping to one or more of the amplicons disclosed herein, preferably to the same amplicon, or that encodes a transcript or polypeptide of such a gene following said treatment. In a preferred embodiment, a treatment that reduces said expression is deemed advantageous and may then be the basis for continuing said treatment. The methods of the invention thereby provide a means of continually monitoring the success of the treatment and evaluating both the need, and desirability, of continuing said treatment. In addition, more than one said treatment may be administered simultaneously without diminishing the value of the methods of the invention in determining the overall success of such combined treatment. Thus, more than one said anti-neoplastic agent may be administered to the same patient and overall effectiveness ascertained by the recited methods.


In accordance with the foregoing, the present invention also contemplates a method for determining the likelihood of survival of a patient afflicted with cancer, following commencement of a cancer treatment on said patient, comprising determining in said patient a change in expression of one or more genes, preferably more than one, corresponding to a gene of Table 3 or encoding a polypeptide or transcript of such a gene, or genes, compared to expression of said one or more determined genes prior to commencement of said cancer treatment, wherein a change in expression, especially a decrease in expression, indicates positive and life-extending effects of such treatment, thereby determining the likelihood of survival of said treatment.


In a preferred embodiment, the detected change in expression is a decrease in expression and said determined gene, or genes, may include 2, 3, 5, 10 or more of the genes described herein. Thus, the methods of the invention may be utilized as a means for compiling cancer survival statistics following one or more, possibly combined, treatments for cancer as in keeping with the other methods disclosed herein.


The genes of the amplicons, or regions of interest, identified herein also offer themselves as pharmacodynamic markers (or as pharmacogenetic and/or surrogate markers), such as for patient profiling prior to clinical trials and/or targeted therapies, including combination treatments, resulting from the identification of these genes as valid gene targets for chemotherapy based on the screening procedures of the invention. In one embodiment thereof, the likelihood of success of a cancer treatment with a selected chemotherapeutic agent may be based on the fact that such agent has been determined to have expression modulating activity with one or more genes identified herein, especially where said genes have been identified as showing elevated expression levels in samples from a prospective patient afflicted with cancer. Methods described elsewhere herein for determining cancerous status of a cell may find ready use in such evaluations.


It should be cautioned that, in carrying out the procedures of the present invention as disclosed herein, any reference to particular buffers, media, reagents, cells, culture conditions and the like are not intended to be limiting, but are to be read so as to include all related materials that one of ordinary skill in the art would recognize as being of interest or value in the particular context in which that discussion is presented. For example, it is often possible to substitute one buffer system or culture medium for another and still achieve similar, if not identical, results. Those of skill in the art will have sufficient knowledge of such systems and methodologies so as to be able, without undue experimentation, to make such substitutions as will optimally serve their purposes in using the methods and procedures disclosed herein.


The present invention will now be further described by way of the following non-limiting example. In applying the disclosure of the example, it should be kept clearly in mind that other and different embodiments of the methods disclosed according to the present invention will no doubt suggest themselves to those of skill in the relevant art.


EXAMPLE

Cancerous cells that over-express one or more genes mapping to the amplicons disclosed herein, are grown to a density of 105 cells/cm2 in Leibovitz's L-15 medium supplemented with 2 mM L-glutamine (90%) and 10% fetal bovine serum. The cells are collected after treatment with 0.25% trypsin, 0.02% EDTA at 37° C. for 2 to 5 minutes. The trypsinized cells are then diluted with 30 ml growth medium and plated at a density of 50,000 cells per well in a 96 well plate (200 μl/well). The following day, cells are treated with either compound buffer alone, or compound buffer containing a chemical agent to be tested, for 24 hours. The media is then removed, the cells lysed and the RNA recovered using the RNAeasy reagents and protocol obtained from Qiagen. RNA is quantitated and 10 ng of sample in 1 μl are added to 24 μl of Taqman reaction mix containing 1×PCR buffer, RNAsin, reverse transcriptase, nucleoside triphosphates, amplitaq gold, tween 20, glycerol, bovine serum albumin (BSA) and specific PCR primers and probes for a reference gene (18S RNA) and a test gene (Gene X). Reverse transcription is then carried out at 48° C. for 30 minutes. The sample is then applied to a Perlin Elmer 7700 sequence detector and heat denatured for 10 minutes at 95° C. Amplification is performed through 40 cycles using 15 seconds annealing at 60° C. followed by a 60 second extension at 72° C. and 30 second denaturation at 95° C. Data files are then captured and the data analyzed with the appropriate baseline windows and thresholds.


The quantitative difference between the target and reference genes is then calculated and a relative expression value determined for all of the samples used. This procedure is then repeated for each of the target genes in a given signature, or characteristic, set and the relative expression ratios for each pair of genes is determined (i.e., a ratio of expression is determined for each target gene versus each of the other genes for which expression is measured, where each gene's absolute expression is determined relative to the reference gene for each compound, or chemical agent, to be screened). The samples are then scored and ranked according to the degree of alteration of the expression profile in the treated samples relative to the control. The overall expression of the set of genes relative to the controls, as modulated by one chemical agent relative to another, is also ascertained. Chemical agents having the most effect on a given gene, or set of genes, are considered the most anti-neoplastic.


Sequence Listing on CD-ROM Only

The sequences disclosed herein as SEQ ID NO: 1-3049 in the sequence listing are contained on compact disc (CD-ROM) only (denoted as Filename: Avalon 237 (5,279 kB), 4 copies of which appear on discs denoted Copy 1, Copy 2, Copy 3 and CRF, and which discs were generated on 7 Mar. 2005), which accompanies this application and the contents of said CD-ROMs are hereby incorporated by reference in their entirety. These sequence numbers correspond to cDNA sequences derived from the genes identified in Table 3.









TABLE 3







Amplicon Identification















Chro-




Amplicon
Transcript Id
Name
mosome
bpstart
bpend















A1
ENST00000303924
HAS2
8
122582937
122598168


A1
ENSESTT00000046662
t
8
122585931
122609941


A1
ENSESTT00000046660

8
122608522
122610061


A1
ENSESTT00000046661

8
122640599
122653390


A1
ENST00000328524

8
123738119
123738958


A1
ENSESTT00000047108

8
123750171
123920219


A1
ENST00000314393
NM_014943
8
123750577
123943336


A1
ENSESTT00000047109

8
123789727
123790358


A1
ENSESTT00000047110

8
123921884
123943336


A1
ENSESTT00000047116

8
123983935
123988137


A1
ENSESTT00000047111

8
123983935
124011208


A1
ENSESTT00000047112

8
123983935
124011208


A1
ENST00000259512
NM_024295
8
123984034
124011088


A1
ENSESTT00000047115

8
123984041
123990329


A1
ENSESTT00000047114

8
123987689
123999547


A1
ENSESTT00000047113

8
123991511
124011208


A1
ENSESTT00000065616

8
124041564
124062478


A1
ENST00000287380
NM_145647
8
124041598
124120767


A1
ENSESTT00000065617

8
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A1
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A1
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A1
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A1
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A1
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A1
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A1
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A1
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A1
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A1
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A1
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A1
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A1
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A1
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A1
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A1
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A1
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A1
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A1
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A1
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A1
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A1
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A1
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A1
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A1
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A1
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A1
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A1
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A1
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A1
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A1
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A1
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A1
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A1
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A1
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A1
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A1
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A1
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A1
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A1
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A1
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A1
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A1
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A1
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A1
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A1
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A1
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A1
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A1
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A1
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A1
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A1
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A1
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A1
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A1
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A1
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A1
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A1
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A1
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A1
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A1
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A1
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A1
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A1
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A1
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A1
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A1
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A1
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A1
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A1
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A1
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A1
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A1
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A1
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A1
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A1
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A1
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A2
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A2
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A2
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A2
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A2
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A2
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A2
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A2
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A2
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A2
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A2
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A2
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A2
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A2
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A2
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A2
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A2
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A2
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A2
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A2
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A2
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A2
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A2
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A2
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A2
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A2
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A2
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A2
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A2
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A2
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A2
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A2
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A2
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A2
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A2
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A2
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A2
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A2
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A2
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A2
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A2
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A2
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A2
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A2
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A2
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A2
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A2
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13
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A2
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A2
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A2
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A2
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A2
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A2
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A2
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A2
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A2
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A2
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A2
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A2
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A2
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A2
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A2
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13
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A2
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A2
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A2
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A2
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A2
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A2
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A2
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A2
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A2
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A2
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A2
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A2
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A2
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A2
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A2
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A2
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A2
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A2
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A2
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A2
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A2
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A2
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A2
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A2
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A2
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A2
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A2
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A2
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A2
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A2
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A2
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A2
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A2
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A2
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A2
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A2
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A2
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A2
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A2
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A2
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A2
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A2
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A2
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A2
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A2
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A2
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A2
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A2
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A2
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A2
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A2
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A2
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A2
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A2
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A2
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A2
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A2
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A2
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A2
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A2
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A2
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A2
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A2
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A2
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A2
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13
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A2
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A2
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A2
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13
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A2
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A2
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A2
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A2
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13
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A2
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13
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A2
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13
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A2
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13
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A2
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13
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A2
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13
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A2
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A2
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97932961
97933435


A2
ENSESTT00000040478

13
97956924
98215198


A2
ENSESTT00000040477

13
97956924
98221218


A2
OTTHUMT00013002980
CLYBL-001
13
97956924
98242825


A2
ENST00000323941
CLYBL
13
97956937
98242824


A2
OTTHUMT00013002981
CLYBL-002
13
97956945
98241868


A2
OTTHUMT00013002982
CLYBL-003
13
97956951
98242819


A2
OTTHUMT00013002974
bA279D17.1-001
13
98040336
98041226


A2
OTTHUMT00013002976
bA279D17.2-001
13
98076502
98077746


A2
ENSESTT00000040339

13
98076717
98079197


A2
ENSESTT00000040309

13
98123162
98215493


A2
OTTHUMT00013002978
bA134O15.2-001
13
98124280
98125544


A2
OTTHUMT00013002983
CLYBL-004
13
98209116
98215493


A2
OTTHUMT00013002984
CLYBL-005
13
98209116
98215493


A2
ENSESTT00000040310

13
98213298
98242825


A2
ENSESTT00000040311

13
98215060
98242825


A2
ENSESTT00000040312

13
98215103
98242825


A2
OTTHUMT00013002986
CLYBL-007
13
98216572
98243149


A2
ENSESTT00000040313

13
98216572
98243149


A2
OTTHUMT00013002985
CLYBL-006
13
98221273
98241868


A2
ENSESTT00000040314

13
98235260
98241868


A2
OTTHUMT00013003004
bA12G12.1-001
13
98315452
98322164


A2
ENST00000267294
ZIC5
13
98315452
98322179


A2
OTTHUMT00013002994
ZIC2-001
13
98332294
98337019


A2
ENST00000245295
ZIC2
13
98332320
98337019


A2
ENSESTT00000040315

13
98332599
98335720


A2
OTTHUMT00013002995
ZIC2-002
13
98334544
98335747


A2
ENSESTT00000040316

13
98334544
98335747


A2
OTTHUMT00013002997
ZIC2-004
13
98334944
98335747


A2
ENSESTT00000040317

13
98334944
98335747


A2
OTTHUMT00013002998
ZIC2-005
13
98335044
98335729


A2
ENSESTT00000040318

13
98335044
98335729


A2
ENSESTT00000040319

13
98335196
98335747


A2
OTTHUMT00013002996
ZIC2-003
13
98335749
98336159


A2
ENSESTT00000040320

13
98335749
98336160


A2
OTTHUMT00013003006
bA12G12.3-001
13
98378024
98378429


A2
OTTHUMT00013003008
bA12G12.4-001
13
98412551
98413856


A2
ENSESTT00000040321

13
98439330
98660115


A2
OTTHUMT00013003012
PCCA-001
13
98439338
98880687


A2
ENSESTT00000040322

13
98439361
98660115


A2
ENSESTT00000040323

13
98439372
98660115


A2
ENSESTT00000040324

13
98439395
98660115


A2
ENST00000310787
PCCA
13
98453138
98880421


A2
OTTHUMT00013003017
PCCA-006
13
98499456
98511880


A2
OTTHUMT00013003010
bA340C20.2-001
13
98500772
98501347


A2
ENSESTT00000040325

13
98585858
98660115


A2
OTTHUMT00013003014
PCCA-003
13
98643479
98775986


A2
ENSESTT00000040326

13
98643479
98881032


A2
ENSESTT00000040327

13
98643479
98881032


A2
ENSESTT00000040328

13
98643479
98881032


A2
OTTHUMT00013003013
PCCA-002
13
98656031
98690514


A2
ENSESTT00000040329

13
98660116
98881032


A2
OTTHUMT00013003015
PCCA-004
13
98718727
98880687


A2
OTTHUMT00013003016
PCCA-005
13
98718754
98842072


A2
OTTHUMT00013003028
bA151A6.5-001
13
98814695
98830540


A2
OTTHUMT00013003030
bA151A6.5-003
13
98829802
98831270


A2
OTTHUMT00013003029
bA151A6.5-002
13
98829814
98831412


A2
ENSESTT00000040330

13
98865680
98881032


A2
OTTHUMT00013003018
PCCA-007
13
98865682
98880687


A2
OTTHUMT00013003052
bA151A6.2-001
13
98881802
98934252


A2
ENST00000257302
Q9BT41
13
98881812
98883998


A2
ENSESTT00000040335

13
98882280
98934255


A2
ENSESTT00000040336

13
98882742
98934255


A2
ENSESTT00000040338

13
98882742
98939783


A2
OTTHUMT00013003055
bA151A6.2-004
13
98882750
98883924


A2
OTTHUMT00013003054
bA151A6.2-003
13
98882750
98939783


A2
ENSESTT00000040337

13
98882766
98883908


A2
OTTHUMT00013003056
bA151A6.2-005
13
98882769
98883908


A2
OTTHUMT00013003053
bA151A6.2-002
13
98882769
98938986


A2
OTTHUMT00013003034
bA151A6.4-001
13
98887578
98930372


A2
OTTHUMT00013003026
bA151A6.3-001
13
98890071
98890529


A2
ENST00000245316

13
98890156
98890503


A2
OTTHUMT00013003036
bA113J24.1-001
13
98954189
99025171


A2
OTTHUMT00013003037
bA113J24.1-002
13
98954189
99025171


A2
ENST00000245302
NM_032813
13
98955249
98989063


A2
ENSESTT00000040332

13
98975664
98987865


A2
ENSESTT00000040334

13
98975708
98986863


A2
OTTHUMT00013003038
bA113J24.1-003
13
98975708
98992566


A2
OTTHUMT00013003042
bA113J24.1-007
13
98975790
98986863


A2
ENSESTT00000040333

13
98976035
98987865


A2
OTTHUMT00013003041
bA113J24.1-006
13
98985320
98986887


A2
OTTHUMT00013003039
bA113J24.1-004
13
98992475
99025134


A2
ENSESTT00000040331

13
98992500
99014571


A2
ENSESTT00000040306

13
99006632
99025080


A2
ENSESTT00000040307

13
99013216
99025060


A2
ENSESTT00000040308

13
99018487
99020990


A2
ENSESTT00000040305

13
99018833
99025134


A2
OTTHUMT00013003043
bA113J24.1-008
13
99018834
99025134


A2
OTTHUMT00013003040
bA113J24.1-005
13
99018996
99020990


A2
OTTHUMT00013003066
bA430M15.1-001
13
99058580
99409639


A2
OTTHUMT00013003062
bA190K16.2-001
13
99106806
99107314


A2
ENST00000310576

13
99106812
99107311


A2
ENST00000310558
Q9BXE6
13
99111961
99112335


A2
OTTHUMT00013003064
bA118F16.1-001
13
99291117
99294619


A3
ENSESTT00000026233

5
175066018
175091447


A3
ENST00000231683
HRH2
5
175091160
175092239


A3
ENST00000274620
CPLX2
5
175204533
175288154


A3
ENST00000274615
Q96NN7
5
175288871
175289290


A3
ENST00000334259
Q8N9L3
5
175289858
175290319


A3
ENST00000265097
THOC3
5
175367459
175376203


A3
ENST00000333723

5
175414077
175415294


A3
ENST00000331171

5
175414077
175415309


A3
ENST00000330220

5
175414083
175415294


A3
ENST00000253490
Q8TBX6
5
175492772
175517499


A3
ENSESTT00000026234

5
175492798
175504815


A3
ENSESTT00000026235

5
175514024
175528803


A3
ENSESTT00000026236

5
175531948
175533047


A3
ENSESTT00000026237

5
175532319
175534252


A3
ENSESTT00000026238

5
175646358
175697849


A3
ENSESTT00000026239

5
175646582
175697880


A3
ENST00000303137
Q8NDZ2
5
175671357
175753911


A3
ENSESTT00000026240

5
175702967
175753921


A3
ENST00000330147

5
175714285
175714659


A3
ENST00000332772
Q8IZ15
5
175721351
175753371


A3
ENST00000298569
NM_020444
5
175753991
175769668


A3
ENSESTT00000026241

5
175755867
175762014


A3
ENSESTT00000026242

5
175758565
175763625


A3
ENST00000310389
NM_173664
5
175773428
175781426


A3
ENSESTT00000026243

5
175773498
175776896


A3
ENST00000327101
CGB7_HUMAN
5
175791865
175796511


A3
ENSESTT00000026244

5
175795923
175797685


A3
ENST00000274787
NM_138820
5
175796696
175797683


A3
ENSESTT00000026253

5
175800471
175824467


A3
ENST00000310407
CLTB
5
175800698
175824287


A3
ENST00000310418
NM_001834
5
175800698
175824287


A3
ENSESTT00000026254

5
175800716
175824462


A3
ENSESTT00000026246

5
175856279
175904920


A3
ENSESTT00000026245

5
175856279
175915561


A3
ENST00000261942
NM_014613
5
175856301
175917997


A3
ENSESTT00000026247

5
175856353
175861483


A3
ENSESTT00000026248

5
175907924
175914952


A3
ENST00000274811
RNF44
5
175934638
175940396


A3
ENSESTT00000026249

5
175957282
175983069


A3
ENST00000261944
NM_017675
5
175957315
176003596


A3
ENSESTT00000026250

5
175986469
175992466


A3
ENSESTT00000026251

5
175994575
176000693


A3
ENSESTT00000026252

5
175994607
176000693


A3
ENST00000303991
NM_052899
5
176003728
176018054


A3
ENST00000335532
Q96PZ4
5
176004664
176007764


A3
ENST00000310112
SNCB
5
176028134
176037898


A3
ENST00000318682

5
176051522
176053904


A3
ENSESTT00000025931

5
176052504
176054064


A3
ENST00000310032
Q96S98
5
176055391
176066978


A3
ENSESTT00000025934

5
176055433
176064052


A3
ENSESTT00000025933

5
176055433
176065755


A3
ENSESTT00000025932

5
176055433
176065798


A3
ENST00000274797
FBXO23
5
176055504
176060711


A3
ENSESTT00000025937

5
176055510
176064052


A3
ENSESTT00000025936

5
176055510
176065755


A3
ENSESTT00000025935

5
176055510
176065798


A3
ENST00000298564
Q96FV3
5
176055540
176064848


A3
ENSESTT00000025938

5
176059752
176065560


A3
ENST00000318314
Q9H7Q1
5
176062303
176065622


A3
ENST00000329542

5
176270544
176282324


A3
ENSESTT00000025945

5
176276066
176278347


A3
ENST00000261961
Q96GP4
5
176281909
176287810


A3
ENSESTT00000025946

5
176281927
176285515


A3
ENST00000292432
HK3
5
176288997
176304083


A3
ENST00000323774
Q9BZR1
5
176313206
176377614


A3
ENST00000274827
NM_016290
5
176313206
176390539


A3
ENSESTT00000025947

5
176323181
176337765


A3
ENST00000261948
NM_012279
5
176430663
176472523


A3
ENSESTT00000025948

5
176430665
176472752


A3
ENSESTT00000025949

5
176452251
176458816


A3
ENSESTT00000025951

5
176494862
176499035


A3
ENSESTT00000025950

5
176494862
176500300


A3
ENSESTT00000025952

5
176494947
176500300


A3
ENST00000292408
FGFR4
5
176497522
176505600


A3
ENST00000292410
NM_022963
5
176497527
176505600


A3
ENSESTT00000025956

5
176500568
176504578


A3
ENSESTT00000025957

5
176501099
176504578


A3
ENSESTT00000025958

5
176505115
176506050


A3
ENSESTT00000025959

5
176505286
176507234


A3
ENSESTT00000025960

5
176541049
176612169


A3
ENST00000298507
NSD1
5
176543028
176703698


A3
ENSESTT00000025961

5
176543093
176545330


A3
ENSESTT00000025963

5
176612187
176617686


A3
ENSESTT00000025966

5
176619693
176654715


A3
ENST00000312855

5
176673510
176674522


A3
ENSESTT00000025977

5
176699894
176702992


A3
ENSESTT00000025979

5
176709391
176710012


A3
ENST00000303270
RAB24
5
176709392
176711227


A3
ENSESTT00000025981

5
176711722
176714120


A3
ENSESTT00000025980

5
176711722
176714888


A3
ENST00000303204
PX19_HUMAN
5
176711736
176714888


A3
ENST00000303182
Q96ME3
5
176715058
176719769


A3
ENST00000303165
MXD3
5
176715151
176719769


A3
ENST00000303127
LMAN2
5
176739703
176759624


A3
ENSESTT00000025989

5
176765891
176779165


A3
ENST00000303066
RGS14
5
176765973
176780117


A3
ENSESTT00000025990

5
176775288
176776866


A3
ENSESTT00000025991

5
176779454
176780554


A3
ENSESTT00000025992

5
176792400
176794461


A3
ENST00000324417
SLC34A1
5
176792400
176806801


A3
ENSESTT00000025994

5
176804912
176806144


A3
ENST00000319628

5
176808126
176808530


A3
ENST00000253496
F12
5
176810246
176817481


A3
ENSESTT00000025997

5
176834655
176841379


A3
ENSESTT00000026002

5
176834669
176842058


A3
ENSESTT00000026001

5
176834669
176844638


A3
ENSESTT00000025999

5
176834669
176849007


A3
ENSESTT00000026000

5
176834669
176849007


A3
ENSESTT00000025998

5
176834669
176850575


A3
ENST00000230673
GPRK6
5
176834797
176849743


A3
ENSESTT00000026007

5
176841092
176842058


A3
ENSESTT00000026006

5
176841092
176844638


A3
ENSESTT00000026004

5
176841092
176849007


A3
ENSESTT00000026005

5
176841092
176849007


A3
ENSESTT00000026003

5
176841092
176850575


A3
ENSESTT00000025996

5
176842854
176844638


A3
ENSESTT00000025995

5
176842854
176849007


A3
ENSESTT00000026008

5
176842854
176850575


A3
ENST00000323249
NM_030567
5
176854746
176864135


A3
ENSESTT00000026009

5
176854894
176864139


A3
ENST00000309007
DBN1
5
176864466
176881467


A3
ENST00000292385
NM_080881
5
176865288
176880013


A3
ENST00000327525
NM_005451
5
176891199
176905416


A3
ENST00000328562
Q14250
5
176891449
176904318


A3
ENST00000330043
Q9BXB9
5
176891449
176904318


A3
ENSESTT00000026018

5
176891939
177031673


A3
ENSESTT00000026017

5
176897221
177038162


A3
ENSESTT00000026016

5
176897716
177038203


A3
ENST00000330641
Q96C91
5
176898295
176904318


A3
ENST00000331981
Q9BXB8
5
176898906
176904318


A3
ENST00000312943
Q9BQB3
5
176909731
176916090


A3
ENST00000274826
NM_024872
5
176911807
176917676


A3
ENST00000330503
DDX41
5
176919402
176924661


A3
ENSESTT00000026010

5
176926890
176943796


A3
ENST00000329540
NM_019057
5
176926890
176961637


A3
ENSESTT00000026015

5
176945068
177094067


A3
ENSESTT00000026011

5
176999291
177002623


A3
ENSESTT00000026013

5
176999295
177133284


A3
ENSESTT00000026012

5
176999295
177136090


A3
ENST00000328179
NM_017510
5
176999300
177003200


A3
ENSESTT00000026014

5
176999308
177136081


A3
ENSESTT00000035756

5
177000737
177003218


A3
ENSESTT00000035757

5
177000783
177136346


A3
ENSESTT00000035758

5
177001245
177136718


A3
ENSESTT00000035760

5
177007252
177150698


A3
ENST00000333469
NM_005451
5
177023996
177038192


A3
ENSESTT00000035801

5
177024173
177038191


A3
ENST00000292374
Q14250
5
177024246
177037114


A3
ENST00000331561
Q9BXB9
5
177024246
177037114


A3
ENST00000331867
Q96C91
5
177031099
177037114


A3
ENSESTT00000035800

5
177031469
177038195


A3
ENSESTT00000035802

5
177031684
177037209


A3
ENST00000332347
Q9BXB8
5
177031702
177037114


A3
ENST00000331704

5
177042509
177048868


A3
ENST00000333364
NM_024872
5
177044585
177050454


A3
ENSESTT00000035798

5
177045241
177050448


A3
ENSESTT00000035797

5
177045345
177050987


A3
ENSESTT00000035799

5
177045385
177050435


A3
ENST00000330228
DDX41
5
177052393
177057440


A3
ENSESTT00000035796

5
177060391
177064902


A3
ENSESTT00000035761

5
177060392
177077299


A3
ENST00000274788
NM_019057
5
177060394
177072665


A3
ENSESTT00000035795

5
177065352
177077000


A3
ENSESTT00000035794

5
177078577
177094163


A3
ENSESTT00000035759

5
177132801
177136335


A3
ENST00000332598
NM_017510
5
177132810
177136711


A3
ENST00000029410
B4GALT7
5
177140813
177150931


A3
ENSESTT00000035762

5
177151883
177159317


A3
ENST00000302857
Q9HAI8
5
177159504
177159962


A3
ENST00000318185

5
177166961
177173303


A3
ENST00000303108
NM_173663
5
177263967
177321278


A3
ENST00000324610

5
177269572
177285570


A3
ENSESTT00000035793

5
177281869
177293899


A3
ENST00000329355
Q8TE30
5
177314834
177318658


A3
ENST00000331417

5
177377030
177378248


A3
ENST00000328082

5
177377030
177378266


A3
ENST00000303154
THOC3
5
177416128
177424868


A3
ENSESTT00000035763

5
177416183
177424870


A3
ENST00000332215
Q9H7L9
5
177511798
177512883


A3
ENST00000308304
PROP1
5
177532838
177536844


A3
ENSESTT00000035764

5
177582334
177589578


A3
ENSESTT00000035765

5
177589720
177594471


A3
ENSESTT00000035766

5
177593021
177594534


A3
ENST00000332649

5
177596176
177596784


A3
ENST00000274605
Y341_HUMAN
5
177654157
177663002


A3
ENSESTT00000035767

5
177660981
177662330


A3
ENST00000313376
YE01_HUMAN
5
177671613
177689151


A3
ENSESTT00000035769

5
177671744
177688239


A3
ENSESTT00000035768

5
177671744
177689170


A3
ENSESTT00000035770

5
177684377
177689170


A3
ENSESTT00000035792

5
177690065
177694571


A3
ENST00000274606
NOLA2
5
177690069
177694497


A3
ENST00000327842
NM_022471
5
177726321
177727901


A3
ENST00000261953
HNRPAB
5
177745109
177751782


A3
ENSESTT00000035781

5
177745132
177746614


A3
ENSESTT00000035779

5
177745132
177751397


A3
ENSESTT00000035780

5
177745132
177751397


A3
ENSESTT00000035777

5
177745132
177751563


A3
ENSESTT00000035778

5
177745132
177751563


A3
ENSESTT00000035771

5
177745132
177751762


A3
ENSESTT00000035772

5
177745132
177751762


A3
ENSESTT00000035773

5
177745132
177751762


A3
ENSESTT00000035774

5
177745132
177751762


A3
ENSESTT00000035775

5
177745132
177751762


A3
ENSESTT00000035776

5
177745132
177751762


A3
ENST00000307328
NM_004499
5
177745440
177751225


A3
ENSESTT00000035782

5
177746443
177751762


A3
ENSESTT00000035783

5
177747326
177751762


A3
ENSESTT00000035790

5
177749103
177770674


A3
ENSESTT00000035787

5
177749103
177772179


A3
ENST00000308158
NM_032921
5
177749186
177773152


A3
ENSESTT00000035791

5
177749189
177763185


A3
ENSESTT00000035788

5
177749189
177772179


A3
ENSESTT00000035789

5
177749225
177772179


A3
ENSESTT00000035784

5
177750732
177751762


A3
ENSESTT00000035786

5
177779162
177788865


A3
ENSESTT00000035785

5
177891469
177892852


A3
ENSESTT00000025813

5
178143370
178154143


A3
ENST00000316308
CLK4
5
178144219
178171217


A3
ENSESTT00000025820

5
178153016
178159432


A3
ENSESTT00000025818

5
178153016
178167610


A3
ENSESTT00000025819

5
178157479
178160721


A3
ENSESTT00000025816

5
178157835
178167668


A3
ENSESTT00000025814

5
178158920
178171217


A3
ENSESTT00000025815

5
178159118
178167738


A3
ENSESTT00000025817

5
178160838
178167632


A3
ENST00000306591
ZNF354A
5
178252662
178269624


A3
ENSESTT00000025812

5
178267657
178269949


A3
ENSESTT00000025811

5
178307485
178309124


A3
ENST00000331699

5
178307800
178322947


A3
ENSESTT00000025799

5
178400555
178423360


A3
ENST00000322434
ZNF354B
5
178400555
178425630


A3
ENSESTT00000025800

5
178401325
178406916


A3
ENST00000320451
ZNF271
5
178472120
178473301


A3
ENST00000320129
ZNF454
5
178481825
178507035


A3
ENSESTT00000025801

5
178483299
178505397


A3
ENST00000319065
Q8NHA9
5
178505697
178533033


A3
ENSESTT00000025802

5
178509517
178530722


A3
ENST00000231188
GRM6
5
178522259
178535546


A3
ENSESTT00000025810

5
178535880
178536808


A3
ENSESTT00000025803

5
178564407
178573529


A3
ENST00000315475
ZNF354C
5
178601202
178621290


A3
ENSESTT00000025809

5
178623365
178624025


A3
ENSESTT00000025808

5
178653824
178654193


A3
ENSESTT00000025806

5
178654498
178665387


A3
ENSESTT00000025807

5
178661813
178663369


A3
ENST00000251582
ADAMTS2
5
178662264
178699481


A3
ENST00000274609
ADAMTS2
5
178691731
178885702


A3
ENSESTT00000025805

5
178692740
178699439


A3
ENSESTT00000025804

5
178917905
178919135


A3
ENSESTT00000035851

5
179043326
179055582


A3
ENSESTT00000035852

5
179090766
179129747


A3
ENSESTT00000035853

5
179099890
179129747


A3
ENSESTT00000035854

5
179099924
179129747


A3
ENST00000319449

5
179100164
179146212


A3
ENSESTT00000035855

5
179100278
179107690


A3
ENSESTT00000035856

5
179107577
179131807


A3
ENSESTT00000035857

5
179133252
179146705


A3
ENST00000319571
NM_030970
5
179140510
179140581


A3
ENST00000258707

5
179148300
179148368


A3
ENSESTT00000035915

5
179150871
179154755


A3
ENSESTT00000035916

5
179150871
179154755


A3
ENSESTT00000035908

5
179150871
179160390


A3
ENSESTT00000035909

5
179150871
179160390


A3
ENST00000326748
HNRPH1
5
179150872
179160359


A3
ENSESTT00000035918

5
179151147
179154344


A3
ENSESTT00000035910

5
179151147
179160390


A3
ENSESTT00000035917

5
179151282
179154755


A3
ENSESTT00000035911

5
179151282
179160390


A3
ENST00000329433

5
179152814
179157705


A3
ENSESTT00000035914

5
179154867
179159858


A3
ENSESTT00000035912

5
179154867
179160364


A3
ENSESTT00000035913

5
179157887
179160362


A3
ENST00000331874
Q8NA96
5
179176906
179177448


A3
ENSESTT00000035858

5
179184188
179186866


A3
ENST00000328856
Q86VE1
5
179184188
179187649


A3
ENSESTT00000035859

5
179215326
179231463


A3
ENSESTT00000035907

5
179215692
179217634


A3
ENST00000329156

5
179230857
179231354


A3
ENSESTT00000035861

5
179235589
179245048


A3
ENSESTT00000035860

5
179235589
179267552


A3
ENST00000247461
CANX
5
179235655
179267584


A3
ENSESTT00000035865

5
179240421
179242025


A3
ENSESTT00000035862

5
179243792
179267552


A3
ENSESTT00000035863

5
179246533
179256391


A3
ENSESTT00000035864

5
179263334
179267552


A3
ENST00000292599
MAML1
5
179269772
179313948


A3
ENSESTT00000035866

5
179303154
179307853


A3
ENST00000298607
NM_024978
5
179314421
179314996


A3
ENST00000292596
LTC4S
5
179330648
179333175


A3
ENSESTT00000035868

5
179330696
179333148


A3
ENSESTT00000035869

5
179330774
179333175


A3
ENSESTT00000035870

5
179332229
179332994


A3
ENSESTT00000035867

5
179332243
179333174


A3
ENST00000292591
MGAT4B
5
179334262
179343246


A3
ENSESTT00000035906

5
179334633
179337617


A3
ENSESTT00000035901

5
179334633
179338133


A3
ENSESTT00000035902

5
179334633
179338133


A3
ENSESTT00000035895

5
179334633
179343595


A3
ENSESTT00000035903

5
179334876
179338133


A3
ENSESTT00000035904

5
179334883
179338133


A3
ENSESTT00000035900

5
179334883
179342992


A3
ENSESTT00000035896

5
179334883
179343595


A3
ENSESTT00000035897

5
179334883
179343595


A3
ENSESTT00000035905

5
179335007
179333133


A3
ENSESTT00000035898

5
179335007
179343595


A3
ENSESTT00000035899

5
179337988
179343595


A3
ENSESTT00000035871

5
179357567
179374487


A3
ENST00000292588
SQSTM1
5
179357599
179373255


A3
ENSESTT00000035894

5
179370411
179373916


A3
ENST00000292586
NM_016175
5
179373936
179378682


A3
ENSESTT00000035893

5
179373938
179395443


A3
ENST00000328625
NM_016175
5
179374053
179395458


A3
ENST00000261956O75163

5
179398735
179444516


A3
ENST00000312107
NM_015043
5
179400110
179407115


A3
ENSESTT00000035892

5
179400203
179402065


A3
ENSESTT00000035891

5
179400212
179402552


A3
ENSESTT00000035890

5
179400359
179404512


A3
ENSESTT00000035889

5
179409551
179415194


A3
ENSESTT00000035887

5
179415747
179444521


A3
ENSESTT00000035888

5
179416330
179444521


A3
ENSESTT00000035886

5
179492143
179507146


A3
ENSESTT00000035885

5
179492144
179514948


A3
ENSESTT00000035884

5
179492144
179549976


A3
ENSESTT00000035881

5
179492144
179608429


A3
ENST00000261947
RNF130
5
179492168
179608763


A3
ENSESTT00000035882

5
179514859
179608429


A3
ENSESTT00000035883

5
179516790
179608429


A3
ENST00000332144

5
179622379
179623665


A3
ENST00000274820
NM_175062
5
179638729
179745830


A3
ENST00000316131

5
179763049
179763664


A3
ENSESTT00000035880

5
179772812
179779418


A3
ENSESTT00000035877

5
179772812
179817172


A3
ENST00000057533
NM_139069
5
179773046
179817223


A3
ENST00000316123
MAPK9
5
179773046
179817223


A3
ENSESTT00000035879

5
179783749
179798444


A3
ENSESTT00000035878

5
179790169
179801503


A3
ENST00000328081

5
179794621
179796637


A3
ENSESTT00000035876

5
179816486
179828537


A3
ENST00000253778
GFPT2
5
179837361
179875263


A3
ENSESTT00000035874

5
179837891
179868310


A3
ENSESTT00000035875

5
179861517
179867483


A3
ENSESTT00000035873

5
179868152
179889985


A3
ENSESTT00000035872

5
179872531
179889987


A3
ENST00000261951
NM_015455
5
180065924
180110862


A3
ENSESTT00000035640

5
180065968
180087268


A3
ENSESTT00000035639

5
180065968
180101184


A3
ENST00000332929
Q8TAJ0
5
180112873
180113151


A3
ENSESTT00000035680

5
180126767
180128147


A3
ENST00000292641
SCGB3A1
5
180126768
180128145


A3
ENSESTT00000035679

5
180139821
180148082


A3
ENST00000261937
FLT4
5
180145626
180186207


A3
ENSESTT00000035678

5
180162667
180166645


A3
ENSESTT00000035677

5
180166890
180186286


A3
ENST00000315712
Q8NHB0
5
180229572
180230422


A3
ENST00000307832
Q8NGV0
5
180275785
180276720


A3
ENSESTT00000035676

5
180327203
180328628


A3
ENSESTT00000035675

5
180327203
180328768


A3
ENST00000333055
MGAT1
5
180327210
180352203


A3
ENSESTT00000035663

5
180327543
180339485


A3
ENST00000307826
Q8NBL8
5
180328296
180329633


A3
ENSESTT00000035662

5
180329112
180339503


A3
ENSESTT00000035659

5
180329155
180345445


A3
ENSESTT00000035661

5
180329332
180340541


A3
ENSESTT00000035665

5
180332068
180352229


A3
ENSESTT00000035664

5
180332092
180339429


A3
ENSESTT00000035660

5
180332309
180345357


A3
ENSESTT00000035658

5
180344545
180346738


A3
ENSESTT00000035666

5
180345508
180352200


A3
ENSESTT00000035657

5
180345511
180346792


A3
ENSESTT00000035673

5
180384273
180397228


A3
ENSESTT00000035672

5
180384335
180397947


A3
ENST00000330037
NM_152283
5
180385559
180387766


A3
ENST00000302108

5
180386417
180388132


A3
ENSESTT00000035674

5
180387577
180397213


A3
ENST00000231229
NM_024850
5
180435821
180487566


A3
ENSESTT00000035641

5
180435955
180448194


A3
ENSESTT00000035642

5
180448211
180487568


A3
ENST00000301996
BTNL3
5
180525529
180543025


A3
ENST00000298708
NM_152547
5
180582152
180590225


A3
ENSESTT00000035643

5
180589782
180591964


A3
ENST00000327705
Q8N324
5
180590141
180598180


A3
ENSESTT00000035644

5
180592305
180595974


A3
ENST00000328095

5
180635802
180637319


A3
ENST00000328767

5
180650805
180651920


A3
ENST00000329365

5
180661176
180661966


A3
ENST00000328275
Q8NGV1
5
180691605
180692552


A3
ENSESTT00000035645

5
180728586
180731091


A3
ENST00000274773
Q96J89
5
180731275
180736815


A3
ENSESTT00000035646

5
180734864
180739766


A3
ENSESTT00000035671

5
180739916
180741785


A3
ENST00000334421
TRIM7
5
180740159
180741772


A3
ENST00000312487
Q96Q10
5
180760899
180772041


A3
ENST00000315073
TRIM41
5
180760917
180772467


A3
ENSESTT00000035647

5
180769651
180772470


A3
ENSESTT00000035648

5
180770071
180772470


A3
ENST00000274821
GNB2L1
5
180773587
180780586


A3
ENSESTT00000035670

5
180773591
180776245


A3
ENSESTT00000035649

5
180783187
180783850


A3
ENSESTT00000035669

5
180791085
180796857


A3
ENST00000327725
NM_022907
5
180792443
180792880


A3
ENSESTT00000035668

5
180793051
180796920


A3
ENSESTT00000035667

5
180793672
180796987


A3
ENST00000327767
TRIM52
5
180794077
180797476


A3
ENSESTT00000035652

5
180797875
180800890


A3
ENSESTT00000035651

5
180797875
180800918


A3
ENSESTT00000035650

5
180797875
180800920


A3
ENSESTT00000035653

5
180854088
180864732


A3
ENSESTT00000035654

5
180866068
180886905


A3
ENST00000333864
O4F3_HUMAN
5
180903950
180904888


A3
ENSESTT00000035655

5
180988607
180991662


A3
ENSESTT00000035656

5
180990904
180991624


A3
ENST00000332522

5
181008629
181009085


A4
OTTHUMT00013000706
FLT1-001
13
26672489
26867232


A4
ENST00000282397
FLT1
13
26675304
26867254


A4
ENSESTT00000037419

13
26740528
26762136


A4
ENSESTT00000037420

13
26749569
26762136


A4
ENSESTT00000037421

13
26756741
26762136


A4
ENSESTT00000037417

13
26769173
26810483


A4
ENSESTT00000037415

13
26769173
26839090


A4
ENSESTT00000037418

13
26772654
26810483


A4
ENSESTT00000037416

13
26772654
26839090


A4
ENSESTT00000037414

13
26839038
26867241


A4
OTTHUMT00013000708
bA57H24.1-001
13
26970970
26972189


A4
ENST00000255315
C13orf12
13
27031241
27051059


A4
OTTHUMT00013000710
bA97E23.1-001
13
27031241
27051062


A4
OTTHUMT00013000711
bA97E23.1-002
13
27031241
27051062


A4
ENSESTT00000037329

13
27031251
27051047


A4
ENSESTT00000037330

13
27031270
27034993


A4
ENSESTT00000037328

13
27032876
27050475


A4
ENSESTT00000037342

13
27044487
27050337


A4
OTTHUMT00013000715
bA97E23.2-002
13
27072201
27076694


A4
ENST00000266943
NM_181785
13
27072854
27090734


A4
OTTHUMT00013000714
bA97E23.2-001
13
27072854
27091107


A4
ENSESTT00000037341

13
27073385
27082982


A4
ENSESTT00000037340

13
27073407
27085276


A4
ENSESTT00000037339

13
27085474
27091111


A4
OTTHUMT00013000718
bA97E23.3-001
13
27094523
27096158


A4
ENSESTT00000037338

13
27094840
27095270


A4
OTTHUMT00013000720
bA161P17.1-001
13
27150695
27151074


A4
ENST00000255289
Q8N5E2
13
27397451
27875542


A4
OTTHUMT00013000739
bA274A8.1-002
13
27397451
27875892


A4
OTTHUMT00013000726
bA351N4.3-003
13
27611516
27622691


A4
OTTHUMT00013000725
bA351N4.3-002
13
27611760
27622691


A4
OTTHUMT00013000724
bA351N4.3-001
13
27611924
27622691


A4
ENSESTT00000037331

13
27653849
27673230


A4
OTTHUMT00013000722
bA351N4.2-001
13
27678843
27680052


A4
OTTHUMT00013000738
bA274A8.1-001
13
27800764
27875873


A4
ENSESTT00000037332

13
27800922
27869445


A4
ENST00000323380
Q8N642
13
27848687
27859887


A4
OTTHUMT00013000730
bA274A8.2-001
13
27849033
27859887


A4
ENSESTT00000037337

13
27849033
27859887


A4
OTTHUMT00013000732
SLC7A1-001
13
27881547
27967721


A4
ENST00000266949
SLC7A1
13
27886617
27908325


A4
OTTHUMT00013000733
SLC7A1-002
13
27889004
27891647


A4
ENSESTT00000037336

13
27889008
27894543


A4
ENSESTT00000037335

13
27894554
27902860


A4
ENSESTT00000037333

13
27907953
27967721


A4
ENSESTT00000037334

13
27907955
27958929


A4
OTTHUMT00013000734
SLC7A1-003
13
27907961
27958929


A4
ENST00000330321
Q8NI69
13
27964863
27965033


A4
ENST00000255303
Q8TE30
13
28014062
28017889


A4
ENST00000310635
Q9P1E1
13
28017953
28018969


A4
OTTHUMT00013000746
UBL3-001
13
28136508
28222821


A4
ENST00000241470

13
28136546
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A4
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A4
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A4
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A4
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A4
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A4
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A4
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A4
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13
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13
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A4
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A4
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13
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A4
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A4
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A4
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A4
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A4
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A4
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A4
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A4
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A4
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A4
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A4
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A4
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A4
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A4
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A4
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A4
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A4
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A4
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A4
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A4
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A4
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A4
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A4
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A4
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A4
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A4
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A4
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A4
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A4
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A4
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A4
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A4
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A4
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A4
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A4
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A4
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A4
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A4
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A4
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A4
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A4
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A4
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A4
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A4
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A4
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A4
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A4
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A4
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A4
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A4
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A4
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A4
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A4
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A4
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A4
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A4
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A4
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A4
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A4
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A4
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A4
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A4
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A4
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A4
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A4
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A4
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A4
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A4
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A4
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A4
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13
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13
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13
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A4
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13
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A4
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13
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A4
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13
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13
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A4
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NBEA
13
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A5
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7
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A5
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A5
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A5
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A5
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A5
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7
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A5
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A5
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A5
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A5
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A5
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A5
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A5
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A5
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A5
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A5
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A5
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A5
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A5
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A5
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A5
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A5
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A5
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A5
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A5
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A5
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A5
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A5
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7
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A5
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A5
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7
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A5
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7
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A5
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A5
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7
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A5
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7
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A5
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A5
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7
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A5
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7
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A5
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Hs_7_c1623
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A5
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7
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A5
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7
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7
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A5
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7
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A5
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Q86WG0
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A5
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SRPK2
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A5
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SRPK2
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A5
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7
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A5
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7
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A5
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7
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A5
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7
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A5
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A5
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A5
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A5
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A5
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7
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A5
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Hs_7_c1625
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A5
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Hs_7_c1626
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A5
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Hs_7_c1627
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A5
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A5
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Hs_7_c1629
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A5
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7
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A5
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A5
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A5
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7
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A5
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A5
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A5
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7
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A5
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7
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A5
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A5
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A5
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7
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A5
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A5
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7
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A5
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A5
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A5
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A5
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A5
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A5
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7
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A5
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7
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A5
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7
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A5
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7
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A5
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Hs_7_c1634
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A5
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A5
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7
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A5
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A5
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Q9BTQ8
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A5
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A5
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A5
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A5
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7
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A5
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7
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A5
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A5
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A5
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Hs_7_c1637
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A5
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7
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A5
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7
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A5
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Hs_7_c1638
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A5
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mbhmh_h_103713457_104613456_m_26103716_2
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A5
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A5
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7
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A5
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A5
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A5
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7
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A5
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A5
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7
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A5
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A5
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SYPL
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A5
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7
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A5
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A5
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A5
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7
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A5
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7
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A5
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Hs_7_c1643
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A5
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PBEF
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A5
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7
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A5
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A5
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A5
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A5
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A5
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7
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A5
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7
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A5
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A5
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7
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A5
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7
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A5
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7
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A5
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7
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A5
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7
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A5
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Hs_7_c1646
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A5
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Hs_7_c1647
7
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A5
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Hs_7_c3104
7
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A5
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7
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A5
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7
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A5
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Hs_7_c1648
7
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A6
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10
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A6
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CBARA1
10
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A6
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10
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A6
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10
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A6
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10
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A6
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10
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A6
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NM_138357
10
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A6
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Q96FL3
10
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A6
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10
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A6
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10
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A6
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10
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A6
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10
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A6
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NM_152635
10
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A6
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Q8WWZ8
10
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A6
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10
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A6
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10
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A6
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10
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A6
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PLA2G13
10
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A6
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10
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A6
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P4HA1
10
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A6
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P4HA1
10
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A6
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10
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A6
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10
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A6
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10
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A6
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NUDT13
10
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A6
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10
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A6
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Q9Y3X2
10
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A6
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NUDT13
10
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A6
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SGT1_HUMAN
10
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74272420


A6
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10
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A6
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10
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A6
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10
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A6
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10
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A6
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Q9Y2I0
10
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A6
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10
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A6
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10
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A6
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10
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A6
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10
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A6
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10
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A6
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DNAJC9
10
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A6
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MRPS16
10
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A6
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10
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A6
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10
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A6
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10
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A6
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10
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A6
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NM_145170
10
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A6
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Q8N7D5
10
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74397767


A6
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ANXA7
10
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A6
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ANXA7
10
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A6
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10
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A6
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10
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A6
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10
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A6
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10
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A6
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10
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A6
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10
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A6
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10
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A6
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10
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A6
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10
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A6
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10
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A6
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10
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A6
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10
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A6
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10
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A6
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10
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A6
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10
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A6
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10
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A6
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ZMYND17
10
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A6
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PPP3CB
10
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A6
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10
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A6
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10
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A6
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10
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A6
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10
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A6
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Q8N3W4
10
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A6
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10
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A6
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10
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A6
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10
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A6
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NM_152586
10
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A6
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10
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A6
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MYOZ1
10
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A6
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10
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A6
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NM_024875
10
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A6
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10
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A6
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10
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A6
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10
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A6
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10
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A6
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10
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A6
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10
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A6
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10
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A6
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10
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A6
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SEC24C
10
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A6
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10
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A6
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10
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A6
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10
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74874530


A6
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NM_173540
10
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A6
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Q96CJ6
10
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A6
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10
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A6
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10
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A6
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10
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A6
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Q96BP2
10
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A6
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10
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A6
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Q8NB34
10
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A6
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10
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A6
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10
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A6
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10
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A6
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O94987
10
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A6
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10
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A6
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10
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A6
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Q9H8F3
10
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A6
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10
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A6
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10
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74903751


A6
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10
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A6
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Q8N420
10
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A6
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10
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74906153


A6
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NDST2
10
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A6
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Q8WV68
10
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74916144


A6
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10
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74916304


A6
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CAMK2G
10
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74978941


A6
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Q8NIA4
10
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74977443


A6
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NM_172169
10
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A6
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NM_001222
10
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A6
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10
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74978883


A6
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10
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A6
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10
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A6
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10
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A6
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10
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A6
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10
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A6
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10
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A6
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10
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A6
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10
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A6
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10
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A6
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10
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A6
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Q8NAK4
10
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A6
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10
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A6
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10
75015493
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A6
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10
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A6
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PLAU
10
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75020926


A6
ENSESTT00000021176

10
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75019765


A6
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10
75016395
75021858


A6
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10
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75019765


A6
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10
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75021858


A6
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10
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A6
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10
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75177160


A6
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10
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75168197


A6
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NM_003373
10
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75222530


A6
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VCL
10
75102569
75224513


A6
ENSESTT00000021187

10
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75177116


A6
ENSESTT00000021189

10
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75219023


A6
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10
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75223339


A6
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10
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A6
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10
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75219023


A6
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10
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75223339


A6
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10
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75223339


A6
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10
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75222883


A6
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10
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75224394


A6
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AP3M1
10
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75255181


A6
ENSESTT00000021206

10
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75255426


A6
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NM_030970
10
75229527
75229598


A6
ENSESTT00000021207

10
75233235
75234365


A6
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10
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A6
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10
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A6
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10
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75328956


A6
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ADK
10
75255640
75812806


A6
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10
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A6
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10
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10
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10
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A6
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10
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A6
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10
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A6
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10
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A6
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A6
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A6
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10
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A6
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A6
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10
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10
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A6
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A6
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10
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A6
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A6
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A6
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10
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A6
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10
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A6
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10
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A6
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A6
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10
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A6
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A6
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A6
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10
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A6
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A6
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A6
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10
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A6
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PPIF
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A6
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10
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A6
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A6
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10
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A6
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10
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A6
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10
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A6
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A6
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10
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A6
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10
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A6
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10
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A6
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10
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A6
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A6
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10
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A6
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10
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A6
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10
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A6
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10
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10
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10
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10
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A6
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10
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A6
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10
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A6
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10
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A6
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10
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A6
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A6
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10
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A6
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10
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A6
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10
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A6
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10
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A6
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SFTPA1
10
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A6
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10
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A6
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10
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A6
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10
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A6
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10
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A6
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10
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A6
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10
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A6
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10
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A6
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10
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A6
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10
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A6
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10
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A6
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10
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A6
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10
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A6
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10
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A6
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10
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A6
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10
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A6
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10
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A6
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Q96LH7
10
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A6
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10
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A6
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10
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A6
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10
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A6
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10
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A6
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10
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A6
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10
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A6
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SFTPD
10
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A6
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10
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A6
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10
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A6
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10
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A6
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NM_025125
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A6
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10
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A6
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10
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A6
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10
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A6
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10
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A6
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10
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A6
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10
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A6
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10
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A6
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10
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A6
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10
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A6
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10
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A6
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10
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A6
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10
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A6
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10
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A6
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ANXA11
10
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A6
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10
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A6
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10
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A6
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10
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A6
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10
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A6
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MAT1A
10
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A6
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10
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A6
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10
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A6
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10
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A6
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10
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A6
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10
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A6
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10
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A6
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NM_138812
10
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A6
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10
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A6
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10
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A6
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NM_032372
10
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A6
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10
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A6
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10
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A6
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10
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A6
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10
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A6
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10
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A6
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NM_032333
10
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A6
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Q9BU34
10
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A6
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Q8N2P5
10
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A6
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NM_030927
10
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A6
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10
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A6
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10
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A6
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10
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A6
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10
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A6
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10
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A6
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10
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A6
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Q8NB58
10
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A6
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10
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A7
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Hs_7_c5082
7
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A7
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7
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A7
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Hs_7_c1064
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A7
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7
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A7
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Hs_7_c1066
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A7
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7
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A7
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A7
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A7
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A7
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7
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A7
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LOC155370
7
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A7
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7
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A7
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Hs_7_c1068
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A7
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7
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A7
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Hs_7_c1069
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A7
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7
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A7
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A7
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A7
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A7
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A7
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A7
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7
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A7
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POM121
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A7
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O95746
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A7
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7
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A7
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POM121
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A7
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A7
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A7
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A7
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A7
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A7
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A7
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A7
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A7
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A7
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A7
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A7
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A7
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A7
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7
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A7
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7
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A7
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WBSCR20A.1
7
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71837376


A7
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NM_148936
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71832800


A7
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NM_149379
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71834307


A7
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7
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A7
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7
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A7
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7
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A7
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Q86UV6
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71852114


A7
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7
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71849602


A7
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mfhmh_h_70400969_71300968_m_133605736_13
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A7
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7
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A7
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7
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A7
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Q8N4N6
7
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71852366


A7
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Hs_7_c1076
7
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71854375


A7
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DKFZP434A0131.3
7
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71882155


A7
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NM_018991
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71882155


A7
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7
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A7
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7
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A7
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7
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A7
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7
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A7
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7
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A7
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7
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A7
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7
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A7
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7
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A7
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7
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A7
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7
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A7
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7
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A7
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7
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A7
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7
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A7
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7
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A7
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7
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A7
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7
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A7
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7
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A7
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7
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A7
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7
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A7
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7
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71888584


A7
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7
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71888584


A7
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7
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71888562


A7
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Hs_7_c1079
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A7
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A7
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A7
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7
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A7
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7
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A7
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7
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A7
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7
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A7
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Q86WY7
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A7
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7
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A7
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7
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A7
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7
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A7
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A7
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A7
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7
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A7
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PMS2L5
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A7
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Q86WY7
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71936531


A7
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7
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71933081


A7
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mfhmh_H_NH0396K03_F218045.fgenesh2.5
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A7
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7
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71937429


A7
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7
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A7
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Hs_7_c1083
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A7
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7
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A7
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7
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A7
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7
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A7
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7
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A7
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7
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A7
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7
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A7
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A7
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7
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A7
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7
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A7
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7
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A7
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7
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A7
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7
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A7
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7
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A7
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7
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A7
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7
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A7
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7
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A7
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7
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A7
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7
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A7
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7
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A7
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7
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A7
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7
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A7
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7
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A7
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A7
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7
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A7
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7
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A7
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7
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A7
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7
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A7
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7
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A7
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7
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A7
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Hs_7_c5085
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A7
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mbhmh_h_71200968_72100967_m_133605736_13
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A7
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7
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A7
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A7
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WBSCR20A
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A7
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7
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A7
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7
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A7
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7
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A7
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NM_178125
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A7
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Hs_7_c1089
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A7
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7
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A7
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7
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A7
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7
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A7
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Hs_7_c1090
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A7
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FKBP6
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A7
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A7
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7
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A7
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7
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A7
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7
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A7
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FZD9
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A7
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A7
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BAZ1B
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A7
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A7
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A7
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A7
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7
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A7
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7
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A7
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A7
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BCL7B
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A7
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7
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A7
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7
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A7
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7
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A7
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7
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A7
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7
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A7
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7
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A7
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7
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A7
ENSESTT00000041262

7
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A7
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A7
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A7
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7
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A7
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7
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A7
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A7
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A7
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WBSCR14
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A7
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7
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A7
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WBSCR14
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A7
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7
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A7
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7
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A7
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A7
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WBSCR24
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A7
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7
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A7
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WBSCR18
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A7
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WBSCR18
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A7
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7
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A7
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WBSCR22
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A7
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WBSCR22
7
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A7
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7
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A7
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7
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A7
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7
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A7
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7
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A7
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7
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A7
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7
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A7
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STX1A
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A7
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STX1A
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A7
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7
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A7
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7
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A7
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A7
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7
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A7
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7
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A7
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WBSCR21
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A7
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NM_148914
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A7
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WBSCR21
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A7
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CLDN3
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A7
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CLDN3
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72596476


A7
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nh_nm_gi18182840
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A7
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CLDN4
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A7
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7
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A7
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NM_152559
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A7
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A7
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7
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A7
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NM_182504
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A7
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A7
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7
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A7
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ELN
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A7
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Q14235
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A7
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Q8NBI4
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A7
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ELN
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A7
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Q8N2G0
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A7
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A7
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A7
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7
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A7
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7
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A7
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LIMK1
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A7
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LIMK1
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A7
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7
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A7
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7
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A7
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7
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A7
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7
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A7
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7
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A7
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7
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A7
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7
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A7
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7
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A7
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WBSCR1
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A7
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WBSCR1
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A7
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WBSCR1
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A7
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7
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A7
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7
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A7
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WBSCR5
7
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A7
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WBSCR5
7
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A7
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7
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A7
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7
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A7
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7
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A7
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7
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A7
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7
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A7
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7
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A7
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7
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A7
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WBSCR5
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A7
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7
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A7
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RFC2
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A7
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RFC2
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A7
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7
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A7
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7
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A7
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7
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A7
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7
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A7
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7
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A7
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RFC2
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A7
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7
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A7
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CYLN2
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A7
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CYLN2
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A7
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CYLN2
7
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A7
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7
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A7
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7
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A7
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7
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A7
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7
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A7
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7
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A7
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GTF2IRD1
7
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73429013


A7
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GTF2IRD1
7
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73428857


A7
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7
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73381903


A7
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7
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73364601


A7
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WBSCR23
7
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73361335


A7
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Hs_7_c1118
7
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A7
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7
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73429028


A7
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7
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73429022


A7
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7
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A7
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GTF2I
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A7
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7
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A7
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7
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A7
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7
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A7
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7
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A7
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7
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73566495


A7
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NM_033000
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A7
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GTF2I
7
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73585257


A7
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GTF2I
7
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73587109


A7
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7
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73555329


A7
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7
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A7
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7
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A7
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7
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A7
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7
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A7
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7
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A7
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7
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73586401


A7
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7
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73575881


A7
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7
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A7
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7
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73585643


A7
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7
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73586353


A7
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7
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73586387


A7
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7
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73586401


A7
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7
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A7
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7
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73585643


A7
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7
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73586353


A7
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7
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73586387


A7
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7
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73586401


A7
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7
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A7
ENSESTT00000036076

7
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73585027


A7
ENSESTT00000036077

7
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73586387


A7
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NCF1.2
7
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A7
ENSESTT00000036086

7
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A7
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NCF1
7
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A7
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7
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A7
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7
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73615748


A7
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7
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73615753


A7
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NM_032203
7
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73679914


A7
OTTHUMT00007006446
mbhmh_H_NH0813J07_F171046.fgenesh2.2
7
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73663589


A7
ENSESTT00000036101

7
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73679927


A7
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DKFZP434A0131.1
7
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73718764


A7
ENST00000308103
NM_018991
7
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73713295


A7
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Hs_7_c5086
7
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73713351


A7
OTTHUMT00007007303
Hs_7_c1127
7
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73733865


A7
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PMS2L5
7
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73733868


A7
ENSESTT00000036090

7
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73726032


A7
ENSESTT00000036091

7
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73733949


A7
ENST00000318568
Q16673
7
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73729180


A7
ENSESTT00000036092

7
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73728321


A7
ENST00000333385
Q86WY7
7
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73739325


A7
OTTHUMT00007006291
mfhmh_chr7.73.013.a
7
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73770943


A7
ENST00000328350

7
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73740340


A7
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7
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A7
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7
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73850892


A7
ENSESTT00000036097

7
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73883752


A7
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WBSCR16
7
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73901788


A7
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7
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A7
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7
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A7
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7
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A7
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Q86WX4
7
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73954376


A7
ENSESTT00000036093

7
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73940594


A7
ENST00000312575
NM_032203
7
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73977192


A7
ENSESTT00000036094

7
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73969279


A7
ENST00000297905

7
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A7
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7
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A7
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7
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A7
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7
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A7
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7
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A7
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7
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A7
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7
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74027990


A7
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7
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A7
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7
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A7
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7
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74027990


A7
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7
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74029114


A7
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7
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74030393


A7
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7
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74027990


A7
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7
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74029114


A7
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7
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74030393


A7
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7
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74025862


A7
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7
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74027990


A7
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7
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74029114


A7
ENSESTT00000037880

7
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74030393


A7
ENSESTT00000037864

7
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74065179


A7
ENST00000335657
Q86WY7
7
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74114021


A7
ENSESTT00000037828

7
74114121
74528229


A7
ENSESTT00000037860

7
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74600365


A7
ENST00000329909
PMS2L5
7
74115017
74124654


A7
ENST00000311576

7
74115017
74126741


A7
ENSESTT00000037831

7
74378046
74402224


A7
ENSESTT00000037829

7
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74402224


A7
ENSESTT00000037830

7
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74402224


A7
ENSESTT00000037832

7
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74413761


A7
ENSESTT00000037833

7
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74417728


A7
ENST00000317042
Q9P1E6
7
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74416214


A7
OTTHUMT00007006787
mbhmh_h_72800966_73394042_m_132005738_13
7
74418388
74470222


A7
ENST00000311251

7
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74479430


A7
OTTHUMT00007007356
Hs_7_c1145
7
74523575
74584324


A7
ENST00000333996
Q86WY7
7
74524542
74556308


A7
ENST00000335396
Q86WY7
7
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74528285


A7
ENST00000302439
PMS2L6
7
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74541042


A7
ENSESTT00000037834

7
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74556252


A7
ENSESTT00000037862

7
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74566962


A7
ENST00000311139
PMS2L5
7
74529281
74538934


A7
ENST00000314850

7
74529281
74541015


A7
OTTHUMT00007008169
Hs_7_c5090
7
74529284
74600754


A7
ENSESTT00000037861

7
74538952
74567012


A7
ENST00000251624
PMS2L6
7
74554875
74569067


A7
ENSESTT00000037835

7
74556408
74584271


A7
ENST00000305928

7
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74569040


A7
ENST00000335010
Q86WY7
7
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74584327


A7
ENSESTT00000037836

7
74584427
74743294


A7
ENSESTT00000037863

7
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74594942


A7
ENST00000310939

7
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74600345


A7
ENSESTT00000037837

7
74600539
74603386


A7
ENSESTT00000037838

7
74600635
74607984


A7
OTTHUMT00007008170
Hs_7_c5091
7
74605989
74608444


A7
ENST00000325462
NM_018991
7
74606045
74609003


A7
OTTHUMT00007007218
DKFZP434A0131.2
7
74606957
74631908


A7
ENSESTT00000037840

7
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74637304


A7
ENSESTT00000037839

7
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74640405


A7
ENSESTT00000037841

7
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74612259


A7
ENST00000275590
Q8WW08
7
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74636644


A7
ENSESTT00000037859

7
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74636774


A7
OTTHUMT00007006277
mbhmh_h_73557902_74457901_m_133948896_13
7
74634728
74636644


A7
ENST00000323819
Q86UV7
7
74636992
74646977


A7
OTTHUMT00007006661
mfhmh_h_73557902_74457901_m_133948896_13
7
74640307
74649026


A7
ENSESTT00000037842

7
74640495
74645112


A7
ENSESTT00000037843

7
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74653100


A7
OTTHUMT00007007377
Hs_7_c1152
7
74651740
74657781


A7
ENSESTT00000037844

7
74651742
74656591


A7
ENSESTT00000037845

7
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74657514


A7
ENST00000323788
NM_145645
7
74654800
74657968


A7
ENSESTT00000037846

7
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74657893


A7
ENSESTT00000037847

7
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74658035


A7
ENSESTT00000037848

7
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74657787


A7
ENST00000257665
POM121
7
74658837
74684082


A7
ENSESTT00000037858

7
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74663188


A7
OTTHUMT00007006280
mbhmh_h_73557902_74457901_m_133948896_13
7
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74684082


A7
ENSESTT00000037857

7
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74666568


A7
ENSESTT00000037856

7
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74679035


A7
ENSESTT00000037855

7
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74716115


A7
ENSESTT00000037854

7
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74769374


A7
ENST00000301990

7
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74745533


A7
OTTHUMT00007007168
mbhmh_ts.74.012.a
7
74738139
74744350


A7
OTTHUMT00007007383
Hs_7_c1157
7
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74752527


A7
ENST00000248606
PMS2L3
7
74749246
74756200


A7
ENST00000301956
PMS2L9
7
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74769228


A7
OTTHUMT00007007380
Hs_7_c1154
7
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74769228


A7
ENSESTT00000037853

7
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74769401


A7
OTTHUMT00007006447
HIP1
7
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74840649


A7
ENSESTT00000037852

7
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74786565


A7
ENST00000320938
HIP1
7
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74980306


A7
ENSESTT00000037851

7
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74797481


A7
ENSESTT00000037850

7
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74804723


A7
ENSESTT00000037849

7
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74980379


A7
OTTHUMT00007007406
Hs_7_c1160
7
74980208
74980327


A7
ENST00000005180
CCL26
7
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75013663


A7
ENSESTT00000040258

7
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A7
OTTHUMT00007006539
SCYA26
7
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75013583


A7
ENST00000222902
CCL24
7
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75055122


A7
OTTHUMT00007006535
SCYA24
7
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75055122


A7
OTTHUMT00007007412
Hs_7_c1163
7
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75077548


A7
ENST00000006777
NM_020684
7
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75130328


A7
OTTHUMT00007007126
NPD007
7
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75134177


A7
ENSESTT00000040185

7
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A7
ENSESTT00000040186

7
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A7
ENSESTT00000040257

7
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A7
ENST00000318622
Q9UDT1
7
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A7
ENSESTT00000040187

7
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A7
ENSESTT00000040195

7
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75222052


A7
ENSESTT00000040194

7
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A7
ENSESTT00000040192

7
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A7
ENSESTT00000040193

7
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75225268


A7
ENSESTT00000040188

7
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A7
ENSESTT00000040189

7
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A7
ENSESTT00000040190

7
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A7
ENSESTT00000040191

7
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75226369


A7
ENSESTT00000040202

7
75156536
75226773


A7
ENSESTT00000040203

7
75156536
75226773


A7
OTTHUMT00007007414
Hs_7_c1165
7
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75164746


A7
OTTHUMT00007006487
mbhmh_h_73557902_74457901_m_133948896_13
7
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75227888


A7
ENSESTT00000040200

7
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A7
ENSESTT00000040199

7
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75225268


A7
ENSESTT00000040197

7
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A7
ENSESTT00000040198

7
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75226369


A7
ENSESTT00000040196

7
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75226773


A7
ENST00000265302
POR
7
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A7
ENSESTT00000040201

7
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75226773


A7
OTTHUMT00007007077
TMPIT
7
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A7
ENSESTT00000040252

7
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A7
ENSESTT00000040253

7
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A7
ENSESTT00000040254

7
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A7
ENSESTT00000040255

7
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75236046


A7
ENSESTT00000040256

7
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75236046


A7
ENSESTT00000040248

7
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A7
ENSESTT00000040244

7
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A7
ENSESTT00000040245

7
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A7
ENSESTT00000040238

7
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A7
ENSESTT00000040239

7
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A7
ENSESTT00000040240

7
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A7
ENSESTT00000040236

7
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A7
ENSESTT00000040251

7
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A7
ENSESTT00000040250

7
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A7
ENSESTT00000040249

7
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A7
ENSESTT00000040247

7
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A7
ENSESTT00000040246

7
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A7
ENSESTT00000040241

7
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A7
ENSESTT00000040242

7
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75289395


A7
OTTHUMT00007006727
MK-STYX
7
75237749
75289410


A7
ENSESTT00000040237

7
75237749
75295682


A7
ENST00000248600
MSTY_HUMAN
7
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A7
ENSESTT00000040243

7
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75289370


A7
ENST00000315790

7
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A7
ENSESTT00000040204

7
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75308009


A7
ENST00000315758
MDH2
7
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75308017


A7
OTTHUMT00007007151
MDH2
7
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75308020


A7
ENSESTT00000040205

7
75289536
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A7
ENSESTT00000040206

7
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75308009


A7
OTTHUMT00007007750
Hs_7_c3073
7
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75313204


A7
OTTHUMT00007007439
Hs_7_c1171
7
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75316216


A7
OTTHUMT00007008045
Hs_7_c5123
7
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75342813


A7
OTTHUMT00007007443
Hs_7_c1174
7
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75373549


A7
ENST00000332057

7
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75354842


A7
OTTHUMT00007007445
Hs_7_c1175
7
75354317
75354842


A7
OTTHUMT00007007446
Hs_7_c1176
7
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75390964


A7
OTTHUMT00007007447
Hs_7_c1177
7
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75418535


A7
ENSESTT00000040208

7
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A7
ENSESTT00000040207

7
75443300
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A7
ENSESTT00000040209

7
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A7
ENSESTT00000040210

7
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A7
ENST00000326382

7
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A7
OTTHUMT00007006504
mbhmh_h_73557902_74457901_m_133948896_13
7
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A7
ENSESTT00000040211

7
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75522893


A7
ENSESTT00000040212

7
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75527181


A7
ENST00000326284
NM_153043
7
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75528692


A7
ENSESTT00000040213

7
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75545679


A7
OTTHUMT00007006552
HSPB1
7
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75545701


A7
ENST00000248553
HSPB1
7
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75545702


A7
OTTHUMT00007006186
YWHAG
7
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75600405


A7
ENST00000307630
YWHAG
7
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75600214


A7
ENSESTT00000040235

7
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A7
ENST00000325070

7
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75603507


A7
ENST00000275560
SRCRB4D
7
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75651095


A7
OTTHUMT00007006188
SRCRB4D
7
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75651101


A7
ENSESTT00000040234

7
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A7
ENST00000297799
Q96BF5
7
75631465
75635032


A7
OTTHUMT00007006555
ZP3A
7
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75683471


A7
ENST00000257652
ZP3
7
75666371
75683468


A7
ENSESTT00000040214

7
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75683476


A7
ENSESTT00000040215

7
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75683368


A7
ENSESTT00000040216

7
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75724019


A7
ENSESTT00000040217

7
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75724170


A7
ENSESTT00000040218

7
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75722103


A7
ENSESTT00000040219

7
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75724122


A7
ENSESTT00000040220

7
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75724190


A7
OTTHUMT00007006196
DTX2
7
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75747397


A7
ENST00000324432
DTX2
7
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75747007


A7
ENSESTT00000040221

7
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75721985


A7
OTTHUMT00007007472
Hs_7_c1183
7
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75712557


A7
ENST00000329896

7
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75712530


A7
ENSESTT00000040222

7
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75747401


A7
ENSESTT00000040223

7
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A7
ENSESTT00000040224

7
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75755467


A7
ENSESTT00000040225

7
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A7
ENST00000334348
UPK3B
7
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75756610


A7
ENST00000257632
UPK3B
7
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75756657


A7
ENSESTT00000040226

7
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A7
ENSESTT00000040227

7
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75756621


A7
ENST00000333674

7
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75774103


A7
OTTHUMT00007007476
Hs_7_c1187
7
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75774100


A7
ENST00000332397

7
75772915
75781708


A7
OTTHUMT00007007156
mbhmh_H_DJ1158B01_F218045.fgenesh2.2
7
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75782865


A7
ENSESTT00000040233

7
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75781751


A7
ENST00000328339

7
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75780226


A7
OTTHUMT00007007474
Hs_7_c1186
7
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75792928


A7
ENSESTT00000040229

7
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75867091


A7
ENSESTT00000040228

7
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75867499


A7
ENSESTT00000040232

7
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75867499


A7
OTTHUMT00007006838
POMZP3
7
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75868655


A7
ENST00000310842
POMZP3
7
75851570
75868652


A7
ENSESTT00000040230

7
75852858
75867011


A7
ENSESTT00000040231

7
75859587
75868162


A7
OTTHUMT00007007515
Hs_7_c1194
7
75891805
75892303


A7
OTTHUMT00007007518
Hs_7_c1196
7
76201256
76245716


A7
OTTHUMT00007007520
Hs_7_c1197
7
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76210656


A7
ENST00000331556

7
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76210629


A7
ENSESTT00000037296

7
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76218367


A7
ENST00000307569

7
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76231777


A7
ENST00000162863
PMS2L11
7
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76257202


A7
ENSESTT00000037258

7
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76245780


A7
ENSESTT00000037261

7
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76265170


A7
ENSESTT00000037259

7
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76440006


A7
OTTHUMT00007007328
Hs_7_c1202
7
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76295598


A7
ENST00000285792
Q86WY7
7
76263908
76269847


A7
ENSESTT00000037292

7
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76266386


A7
OTTHUMT00007006602
mfhmh_gw11359887.75188365.75365376.7.9e−
7
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A7
ENSESTT00000037291

7
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76294084


A7
ENSESTT00000037295

7
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76270744


A7
ENSESTT00000037294

7
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A7
ENSESTT00000037293

7
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76281262


A7
ENSESTT00000037290

7
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76300803


A7
ENST00000330572

7
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76299277


A7
OTTHUMT00007007330
Hs_7_c1203
7
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76313732


A7
ENSESTT00000037289

7
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76363754


A7
OTTHUMT00007006666
mbhmh_h_75248517_76148516_m_19731738_198
7
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76352916


A7
ENSESTT00000037288

7
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76363761


A7
ENST00000327285

7
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76357619


A7
OTTHUMT00007007332
Hs_7_c1204
7
76356814
76357592


A7
ENSESTT00000037260

7
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76409308


A7
OTTHUMT00007006412
mbax_nh_gi17389564
7
76437484
76441197


A7
ENST00000248598
FGL2
7
76437495
76441207


A7
ENSESTT00000037287

7
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76441213


A7
OTTHUMT00007006667
mbhmh_h_75248517_76148516_m_19731738_198
7
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76536234


A7
ENST00000285871
Q96MS1
7
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76520191


A7
ENST00000257657
Q9P223
7
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76536578


A7
ENSESTT00000037262

7
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76523986


A7
ENSESTT00000037264

7
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76536589


A7
ENSESTT00000037263

7
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76571386


A7
ENSESTT00000037284

7
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76571745


A7
ENST00000257626
Q9Y4L9
7
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76568852


A7
OTTHUMT00007007104
mbhmh_nh_h_75248517_76148516_m_18931739
7
76552726
76605693


A7
ENSESTT00000037285

7
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76571745


A7
ENSESTT00000037286

7
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76567945


A7
ENST00000334003
Q8ND73
7
76571601
76647477


A7
ENSESTT00000037283

7
76571643
76596756


A7
OTTHUMT00007007105
mbhmh_nh_h_75248517_76148516_m_18931739
7
76611431
76653274


A7
ENSESTT00000037282

7
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76657235


A7
ENST00000310324
Q9BXE6
7
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76751767


A7
ENSESTT00000037265

7
76778862
76839272


A7
OTTHUMT00007006825
PTPN12
7
76778886
76881437


A7
ENSESTT00000037266

7
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76842330


A7
ENST00000248594
PTPN12
7
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76880648


A7
ENSESTT00000037267

7
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76842330


A7
ENSESTT00000037269

7
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76881437


A7
ENSESTT00000037270

7
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76881437


A7
ENSESTT00000037271

7
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76881437


A7
ENSESTT00000037268

7
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76895005


A7
ENSESTT00000037272

7
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A7
ENSESTT00000037281

7
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A7
ENSESTT00000037273

7
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76881437


A7
ENSESTT00000037274

7
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76880309


A7
ENSESTT00000037278

7
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76937634


A7
ENSESTT00000037275

7
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76912750


A7
ENSESTT00000037279

7
76925217
76937634


A7
ENSESTT00000037280

7
76925311
76937620


A7
ENST00000334955
Q86X48
7
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76977836


A7
OTTHUMT00007006307
mbhmh_h_75248517_76148516_m_18931739_198
7
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77020536


A7
ENSESTT00000037277

7
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A7
ENSESTT00000037276

7
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A7
ENSESTT00000031431

7
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77021059


A7
OTTHUMT00007006265
DC32
7
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77039701


A7
ENST00000257663
C7orf35
7
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77039798


A7
ENSESTT00000031444

7
77035096
77039946


A7
ENSESTT00000031445

7
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77039797


A7
OTTHUMT00007006310
mbhmh_h_75248517_76148516_m_18931739_198
7
77081624
77196246


A7
ENST00000248550
Q8TBW4
7
77096101
77195265


A8
ENST00000256653
MAN1A2
1
117256452
117415542


A8
ENSESTT00000003501

1
117256479
117412324


A8
ENSESTT00000003500

1
117256479
117414355


A8
ENSESTT00000003502

1
117331232
117385841


A8
ENSESTT00000003523

1
117485833
117494713


A8
ENSESTT00000003503

1
117494976
117512577


A8
ENST00000328500
NM_017709
1
117495052
117517367


A8
ENST00000313132

1
117529727
117530632


A8
ENST00000334351
PNRC2
1
117667090
117667509


A8
ENSESTT00000003522

1
117667118
117667900


A8
ENSESTT00000003520

1
117759186
117818631


A8
ENSESTT00000003521

1
117759281
117818631


A8
ENST00000263166
GDAP2
1
117759572
117818591


A8
ENSESTT00000003504

1
117818779
117823687


A8
ENST00000309112
Q9H141
1
117822324
117848451


A8
ENST00000183319
WDR3
1
117822324
117849059


A8
ENSESTT00000003505

1
117831482
117849104


A8
ENSESTT00000003518

1
117842855
117853814


A8
ENSESTT00000003515

1
117842859
117859122


A8
ENSESTT00000003519

1
117842865
117852907


A8
ENSESTT00000003517

1
117842865
117855703


A8
ENST00000286203
Q8NAZ1
1
117842866
118074161


A8
ENSESTT00000003516

1
117842868
117855764


A8
ENSESTT00000003513

1
117861020
117880531


A8
ENSESTT00000003514

1
117862486
117876996


A8
ENSESTT00000003512

1
117885713
117905184


A8
ENSESTT00000003510

1
117917336
117943048


A8
ENSESTT00000003511

1
117920750
117928350


A8
ENSESTT00000003509

1
117943055
117962920


A8
ENSESTT00000003507

1
117943058
117970490


A8
ENSESTT00000003508

1
117962945
117970300


A8
ENSESTT00000003506

1
117974982
117976166


A8
ENSESTT00000003436

1
118039391
118074185


A8
ENST00000334368
Q9UN81
1
118742261
118743277


A8
ENST00000207157
TBX15
1
118772051
118820834


A8
ENSESTT00000003435

1
118889344
118890396


A8
ENSESTT00000003434

1
118889622
118890409


A8
ENST00000235521
WARS2
1
118920227
119029659


A8
ENSESTT00000003433

1
118921825
118934670


A8
ENSESTT00000003432

1
118922024
119029623


A8
ENST00000333224

1
119015816
119016295


A8
ENSESTT00000003526

1
119035413
119036037


A8
ENST00000330630

1
119108318
119108923


A8
ENSESTT00000003527

1
119217196
119219818


A8
ENSESTT00000003528

1
119217256
119245186


A8
ENSESTT00000003529

1
119257783
119275698


A8
ENSESTT00000003531

1
119257783
119281249


A8
ENSESTT00000003530

1
119269568
119281249


A8
ENST00000325945
HAO2
1
119270090
119282844


A8
ENST00000331050
Q8TDP9
1
119304149
119403649


A8
ENSESTT00000003533

1
119304154
119311277


A8
ENSESTT00000003532

1
119304154
119311779


A8
ENSESTT00000003534

1
119304167
119308609


A8
ENST00000303184
HSD3B2
1
119304424
119311624


A8
ENST00000333709
Q8TDP9
1
119304427
119403649


A8
ENST00000332017
Q8TDP9
1
119304427
119404056


A8
ENST00000256586
Q9H1N0
1
119328005
119334823


A8
ENST00000286193
Q9H1M9
1
119356225
119362218


A8
ENST00000331024

1
119385611
119385839


A8
ENSESTT00000003535

1
119396243
119404058


A8
ENSESTT00000003536

1
119396244
119397374


A8
ENSESTT00000003537

1
119396322
119404058


A8
ENST00000235547
HSD3B1
1
119396481
119403649


A8
ENST00000335580
Q9UDK8
1
119456897
119461071


A8
ENST00000331009

1
119485270
119485838


A8
ENST00000335229
Q9UD07
1
119494238
119494381


A8
ENST00000271263
Q96IT2
1
119511709
119512401


A8
ENSESTT00000003538

1
119600896
119633222


A8
ENSESTT00000003539

1
119600896
119633222


A8
ENST00000263167
PHGDH
1
119601027
119633206


A8
ENSESTT00000003540

1
119615847
119633222


A8
ENSESTT00000003541

1
119615847
119633222


A8
ENSESTT00000003542

1
119616052
119619075


A8
ENSESTT00000003543

1
119626114
119633222


A8
ENST00000256633
HMGCS2
1
119637386
119657898


A8
ENSESTT00000003552

1
119637543
119657890


A8
ENSESTT00000003553

1
119648894
119657887


A8
ENSESTT00000003544

1
119653323
119657877


A8
ENST00000324032
Q8NER6
1
119683168
119700499


A8
ENSESTT00000003551

1
119683421
119700465


A8
ENSESTT00000003550

1
119683593
119692170


A8
ENST00000256585
REG4
1
119683622
119697773


A8
ENSESTT00000003549

1
119687553
119697870


A9
OTTHUMT00006006260
SLC26A8-001
6
35958152
36039212


A9
ENST00000229784
SLC26A8
6
35958327
36034339


A9
ENST00000310888
SLC26A8
6
35958532
36034339


A9
ENSESTT00000033005

6
36012429
36039125


A9
ENSESTT00000032935

6
36042425
36067456


A9
OTTHUMT00006006277
MAPK14-002
6
36042428
36123079


A9
OTTHUMT00006006276
MAPK14-001
6
36042428
36125390


A9
ENST00000229794
NM_139014
6
36042790
36122248


A9
ENST00000229795
MAPK14
6
36042790
36123079


A9
ENST00000310795
MAPK14
6
36042790
36123079


A9
ENSESTT00000032936

6
36090530
36124509


A9
OTTHUMT00006006258
dJ179N16.3-001
6
36106623
36107278


A9
OTTHUMT00006006270
MAPK13-005
6
36142441
36150464


A9
ENSESTT00000032938

6
36142441
36154698


A9
ENSESTT00000032937

6
36142441
36155902


A9
OTTHUMT00006006268
MAPK13-003
6
36144953
36154312


A9
OTTHUMT00006006266
MAPK13-001
6
36144953
36154697


A9
ENST00000211287
MAPK13
6
36145117
36154697


A9
ENSESTT00000032940

6
36145142
36154698


A9
ENSESTT00000032939

6
36145142
36155902


A9
ENSESTT00000032941

6
36145145
36151536


A9
ENSESTT00000032943

6
36145202
36154698


A9
ENSESTT00000032942

6
36145202
36155902


A9
ENSESTT00000032944

6
36145273
36146034


A9
OTTHUMT00006006269
MAPK13-004
6
36145295
36153839


A9
OTTHUMT00006006267
MAPK13-002
6
36145501
36151147


A9
OTTHUMT00006006280
BRPF3-001
6
36211405
36247418


A9
ENST00000322766
BRPF3
6
36211405
36247421


A9
ENSESTT00000032945

6
36212028
36215240


A9
ENSESTT00000032946

6
36215902
36224498


A9
OTTHUMT00006006281
BRPF3-002
6
36225130
36247418


A9
ENST00000211291
Q9NWM1
6
36225982
36245352


A9
ENSESTT00000032947

6
36228665
36232584


A9
ENSESTT00000032948

6
36239919
36246148


A9
OTTHUMT00006006284
dJ50J22.1-001
6
36285116
36310051


A9
ENST00000312917
PNPLA1
6
36306032
36323227


A9
OTTHUMT00006006294
dJ50J22.5-001
6
36317034
36327443


A9
OTTHUMT00006006290
dJ50J22.3-001
6
36331805
36334066


A9
OTTHUMT00006006286
dJ50J22.2-001
6
36380826
36402415


A9
OTTHUMT00006006287
dJ50J22.2-002
6
36380826
36402415


A9
ENST00000229480
ETV7
6
36380827
36402349


A9
ENSESTT00000033001

6
36390551
36402400


A9
OTTHUMT00006006292
dJ50J22.4-001
6
36401463
36406626


A9
ENST00000316266
NM_152990
6
36405183
36415166


A9
OTTHUMT00006006296
dJ347L7.1-001
6
36415095
36457521


A9
ENSESTT00000032949

6
36457399
36458352


A9
ENST00000265344
C6orf69
6
36457399
36505168


A9
OTTHUMT00006006298
dJ108K11.3-001
6
36457619
36505775


A9
ENSESTT00000032950

6
36484759
36499460


A9
ENSESTT00000032952

6
36499410
36503191


A9
ENSESTT00000032951

6
36499410
36505772


A9
ENSESTT00000032953

6
36501514
36505772


A9
OTTHUMT00006006300
STK38-001
6
36508524
36562102


A9
ENST00000229812
STK38
6
36508531
36562102


A9
ENSESTT00000032999

6
36510468
36522221


A9
ENSESTT00000032996

6
36530077
36562102


A9
ENSESTT00000032955

6
36608994
36616435


A9
ENSESTT00000032954

6
36608994
36617545


A9
OTTHUMT00006006302
SFRS3-001
6
36609000
36618064


A9
OTTHUMT00006006303
SFRS3-002
6
36609023
36616672


A9
ENST00000244437
SFRS3
6
36611395
36617408


A9
ENST00000317631

6
36688401
36689903


A9
OTTHUMT00006006306
dJ193M11.1-001
6
36688449
36689902


A9
OTTHUMT00006012688
CDKN1A-005
6
36691160
36699143


A9
ENSESTT00000032956

6
36692420
36701950


A9
OTTHUMT00006012684
CDKN1A-001
6
36693290
36701971


A9
ENST00000244741
CDKN1A
6
36693342
36701963


A9
OTTHUMT00006012685
CDKN1A-002
6
36693353
36700556


A9
ENSESTT00000032957

6
36693354
36701950


A9
OTTHUMT00006012687
CDKN1A-004
6
36693358
36699130


A9
OTTHUMT00006012686
CDKN1A-003
6
36693403
36695312


A9
ENSESTT00000032958

6
36693403
36695312


A9
OTTHUMT00006011804
dJ431A14.3-001
6
36737227
36743433


A9
ENST00000229824

6
36737257
36745385


A9
ENST00000310390
Q8TDV1
6
36751637
36752338


A9
OTTHUMT00006006308
dJ431A14.4-001
6
36751682
36752618


A9
OTTHUMT00006006311
dJ431A14.5-002
6
36755407
36772013


A9
ENST00000244751
CPNE5
6
36755410
36854008


A9
OTTHUMT00006006310
dJ431A14.5-001
6
36755410
36854633


A9
ENSESTT00000032989

6
36758313
36772015


A9
OTTHUMT00006006312
dJ431A14.5-003
6
36760019
36772013


A9
ENSESTT00000032990

6
36760019
36772013


A9
ENSESTT00000032987

6
36760019
36780337


A9
ENSESTT00000032988

6
36760024
36772025


A9
OTTHUMT00006006351
PPIL1-002
6
36869458
36873266


A9
OTTHUMT00006006350
PPIL1-001
6
36869458
36889655


A9
ENST00000244367
PPIL1
6
36869463
36889629


A9
ENSESTT00000032983

6
36870099
36889655


A9
ENSESTT00000032984

6
36870254
36886506


A9
OTTHUMT00006006316
dJ90K10.2-001
6
36886501
36939186


A9
OTTHUMT00006006319
dJ90K10.2-004
6
36900485
36931139


A9
OTTHUMT00006006317
dJ90K10.2-002
6
36900495
36938153


A9
OTTHUMT00006006318
dJ90K10.2-003
6
36900495
36938153


A9
ENST00000314503
C6orf89
6
36900495
36941175


A9
ENSESTT00000032959

6
36900540
36938610


A9
OTTHUMT00006006320
dJ90K10.2-005
6
36900544
36938203


A9
ENSESTT00000032960

6
36900558
36929229


A9
ENSESTT00000032961

6
36909132
36938610


A9
OTTHUMT00006006326
dJ90K10.3-001
6
36943210
36943499


A9
OTTHUMT00006006328
dJ90K10.4-001
6
36954718
36959306


A9
ENST00000297048
PI16
6
36969064
36979463


A9
OTTHUMT00006006330
dJ90K10.5-001
6
36969064
36979468


A9
ENSESTT00000032962

6
36969360
36974006


A9
ENSESTT00000032963

6
36969368
36978833


A9
ENSESTT00000032964

6
36969383
36978833


A9
OTTHUMT00006006331
dJ90K10.5-002
6
36977621
36979298


A9
OTTHUMT00006006335
dJ90K10.6-002
6
36982772
36991863


A9
OTTHUMT00006006341
dJ90K10.6-008
6
36982772
37000929


A9
OTTHUMT00006006334
dJ90K10.6-001
6
36982772
37000929


A9
ENSESTT00000032969

6
36983213
36992788


A9
ENSESTT00000032965

6
36983213
37000795


A9
ENSESTT00000032966

6
36983310
37000795


A9
ENSESTT00000032967

6
36983310
37000795


A9
OTTHUMT00006006340
dJ90K10.6-007
6
36983368
37000612


A9
ENST00000259958
MTCH1
6
36983368
37000747


A9
OTTHUMT00006006337
dJ90K10.6-004
6
36983391
36985547


A9
OTTHUMT00006006336
dJ90K10.6-003
6
36983543
36992304


A9
OTTHUMT00006006338
dJ90K10.6-005
6
36984097
36987385


A9
ENSESTT00000032968

6
36984669
37000795


A9
OTTHUMT00006006339
dJ90K10.6-006
6
36984687
36987307


A9
OTTHUMT00006006356
FGD2-001
6
37020277
37042929


A9
ENSESTT00000035539

6
37020289
37026654


A9
ENSESTT00000035540

6
37020301
37028317


A9
ENST00000274963
FGD2
6
37020330
37043169


A9
ENSESTT00000035541

6
37040439
37042882


A9
OTTHUMT00006006354
dJ405J24.2-001
6
37059462
37060032


A9
ENST00000297147
O95101
6
37059560
37059820


A9
OTTHUMT00006006358
dJ441G21.1-001
6
37105853
37106493


A9
ENST00000310055

6
37105943
37106437


A9
ENSESTT00000035542

6
37184786
37185779


A9
ENSESTT00000035543

6
37184786
37185779


A9
OTTHUMT00006012708
PIM1-003
6
37184834
37190057


A9
ENST00000259722
PIM1
6
37184841
37190057


A9
ENSESTT00000035544

6
37185789
37190059


A9
OTTHUMT00006012709
PIM1-004
6
37187099
37188878


A9
ENSESTT00000035545

6
37187103
37190059


A9
OTTHUMT00006012706
PIM1-001
6
37187125
37188943


A9
ENSESTT00000035546

6
37187125
37190059


A9
OTTHUMT00006012707
PIM1-002
6
37187627
37190057


A9
OTTHUMT00006006360
dJ355M6.2-001
6
37226811
37272786


A9
ENST00000316899
Q8TC54
6
37226812
37233661


A9
OTTHUMT00006006361
dJ355M6.2-002
6
37227067
37272267


A9
ENST00000316909
NM_145316
6
37229829
37233661


A9
ENSESTT00000035577

6
37233261
37272786


A9
OTTHUMT00006006364
dJ744I24.2-001
6
37272403
37347601


A9
ENSESTT00000035547

6
37272498
37294209


A9
ENST00000229492
C6orf197
6
37298967
37347600


A9
ENSESTT00000035548

6
37331324
37347601


A9
ENSESTT00000035549

6
37331816
37339289


A9
OTTHUMT00006006366
RNF8-001
6
37368684
37409364


A9
ENSESTT00000035550

6
37368716
37386205


A9
ENST00000229866
RNF8
6
37368796
37395990


A9
ENSESTT00000035551

6
37383509
37405872


A9
OTTHUMT00006006367
RNF8-002
6
37383520
37391647


A9
ENSESTT00000035554

6
37383557
37405862


A9
ENSESTT00000035552

6
37383557
37405872


A9
ENSESTT00000035553

6
37383557
37405872


A9
ENSESTT00000035555

6
37391555
37405872


A9
ENSESTT00000035556

6
37447848
37474233


A9
OTTHUMT00006006384
dJ153P14.1-009
6
37447850
37458714


A9
ENSESTT00000035557

6
37447850
37474233


A9
OTTHUMT00006006377
dJ153P14.1-002
6
37447851
37476692


A9
OTTHUMT00006006376
dJ153P14.1-001
6
37447851
37496137


A9
ENST00000259729
NM_015050
6
37450261
37496137


A9
OTTHUMT00006006383
dJ153P14.1-008
6
37467109
37473320


A9
ENSESTT00000035558

6
37474283
37488203


A9
OTTHUMT00006006378
dJ153P14.1-003
6
37474290
37476703


A9
ENSESTT00000035559

6
37474290
37476703


A9
OTTHUMT00006006380
dJ153P14.1-005
6
37477502
37495903


A9
OTTHUMT00006006379
dJ153P14.1-004
6
37488199
37493826


A9
ENSESTT00000035560

6
37489154
37496138


A9
ENSESTT00000035561

6
37489159
37493872


A9
OTTHUMT00006006382
dJ153P14.1-007
6
37489950
37497458


A9
ENSESTT00000035562

6
37489950
37497460


A9
OTTHUMT00006006381
dJ153P14.1-006
6
37489976
37495777


A9
OTTHUMT00006006394
dJ153P14.2-001
6
37497551
37514553


A9
ENSESTT00000035575

6
37497563
37514525


A9
ENST00000259975
Q9P0B6
6
37497563
37514553


A9
ENSESTT00000035576

6
37497569
37499495


A9
ENSESTT00000035574

6
37497716
37514544


A9
OTTHUMT00006006395
dJ153P14.2-002
6
37497716
37514553


A9
OTTHUMT00006006370
dJ153P14.3-001
6
37558184
37561386


A9
ENSESTT00000035573

6
37558184
37561393


A9
OTTHUMT00006006372
dJ153P14.4-001
6
37561183
37562345


A9
ENSESTT00000035563

6
37564634
37565497


A9
OTTHUMT00006006374
dJ153P14.5-001
6
37564635
37565491


A9
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6
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A9
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dJ402N21.2-001
6
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A9
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MDGA1
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A9
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Q8NBE3
6
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A9
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6
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A9
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6
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A9
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6
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A9
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6
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A9
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6
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A9
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6
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A9
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dJ441A12.1-001
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A9
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6
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A9
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6
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A9
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TEX27-001
6
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A9
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6
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38166902


A9
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TEX27
6
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38167020


A9
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TEX27-002
6
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A9
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6
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A9
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bA420A21.1-001
6
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A9
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TEX27-003
6
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A9
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6
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38168417


A9
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TEX27-004
6
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A9
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dJ295F6.2-001
6
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A9
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6
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38654445


A9
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6
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A9
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6
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A9
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6
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A9
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Q8NAH5
6
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A9
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6
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A9
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6
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38497741


A9
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bA430C17.1-001
6
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A9
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dJ322I12.1-001
6
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A9
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dJ319M7.2-001
6
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A9
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BTBD9
6
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A9
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dJ322I12.1-003
6
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38654542


A9
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GLO1-002
6
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A9
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GLO1-001
6
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A9
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GLO1
6
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A9
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6
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A9
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6
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A9
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6
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A9
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6
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A9
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6
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A9
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6
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A9
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6
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A9
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6
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A9
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dJ503A6.2-001
6
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A9
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6
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38729848


A9
ENST00000327475
Q8IU65
6
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38749145


A9
OTTHUMT00006012038
DNAH8-003
6
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38986711


A9
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DNAH8-002
6
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39045150


A9
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DNAH8-001
6
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39045156


A9
ENST00000244699
DNAH8
6
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39045422


A9
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dJ217P22.2-001
6
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38779325


A9
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6
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38878623


A9
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DNAH8-004
6
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38885121


A9
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6
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38888176


A9
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dJ207H1.3-001
6
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A9
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dJ207H1.3-002
6
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A9
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6
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A9
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6
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A9
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6
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A9
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dJ207H1.3-003
6
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A9
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6
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A9
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6
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A9
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6
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A9
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6
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A9
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6
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A9
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dJ202I21.3-001
6
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39054616


A9
OTTHUMT00006006444
GLP1R-001
6
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39102374


A9
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GLP1R
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A9
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6
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A9
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6
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A9
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6
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39124203


A9
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dJ202I21.1-003
6
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39129820


A9
ENST00000229903
C6orf64
6
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39129720


A9
OTTHUMT00006006454
dJ202I21.5-001
6
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39127583


A9
OTTHUMT00006006447
dJ202I21.1-002
6
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A9
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6
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39129702


A9
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KCNK5-001
6
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39244081


A9
ENST00000297169
KCNK5
6
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39243742


A9
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6
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39243759


A9
ENSESTT00000028295

6
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39243759


A9
OTTHUMT00006006464
KCNK17-001
6
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39329053


A9
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6
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39315137


A9
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6
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39319209


A9
ENST00000244759
KCNK17
6
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39328951


A9
OTTHUMT00006006462
KCNK16-001
6
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39337171


A9
ENSESTT00000028290

6
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39337599


A9
ENST00000211196
KCNK16
6
39329633
39337171


A9
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6
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39337185


A9
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6
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39358362


A9
OTTHUMT00006006460
dJ137F1.4-001
6
39350785
39400304


A9
ENST00000297170
C6orf102
6
39358338
39445790


A9
ENST00000229913
Q86T87
6
39358338
39554716


A9
OTTHUMT00006006458
dJ137F1.3-001
6
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39368803


A9
OTTHUMT00006006466
dJ188D3.1-001
6
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A9
OTTHUMT00006006470
dJ1043E3.1-001
6
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A9
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6
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39599605


A9
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6
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39601027


A9
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dJ1043E3.1-003
6
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39592907


A9
ENST00000287152

6
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39739941


A9
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6
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39592907


A9
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6
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39600971


A9
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dJ1043E3.2-001
6
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39569574


A9
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6
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39599586


A9
OTTHUMT00006006471
dJ1043E3.1-002
6
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39610891


A9
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6
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39689117


A9
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dJ1043E3.1-004
6
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A9
ENSESTT00000028282

6
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39739928


A9
ENSESTT00000028269

6
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39879702


A9
ENST00000274867
DAAM2
6
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39919503


A9
ENSESTT00000028270

6
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39879669


A9
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6
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39875800


A9
OTTHUMT00006006489
dJ278E11.1-006
6
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39876106


A9
OTTHUMT00006006485
dJ278E11.1-002
6
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39882152


A9
OTTHUMT00006006484
dJ278E11.1-001
6
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39919499


A9
OTTHUMT00006006486
dJ278E11.1-003
6
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39919496


A9
ENSESTT00000028272

6
39884968
39893094


A9
OTTHUMT00006006487
dJ278E11.1-004
6
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39893404


A9
OTTHUMT00006006488
dJ278E11.1-005
6
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A9
OTTHUMT00006006480
bA61I13.3-001
6
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A9
OTTHUMT00006006481
bA61I13.3-002
6
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A9
ENSESTT00000028281

6
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A9
ENSESTT00000028273

6
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A9
ENSESTT00000028274

6
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39919761


A9
OTTHUMT00006006478
bA61I13.2-001
6
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39914702


A9
ENSESTT00000028279

6
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39919496


A9
ENSESTT00000028280

6
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39918030


A9
OTTHUMT00006006504
MOCS1-005
6
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39926973


A9
OTTHUMT00006006505
MOCS1-006
6
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39927603


A9
OTTHUMT00006006506
MOCS1-007
6
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39927603


A9
OTTHUMT00006006502
MOCS1-003
6
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39941994


A9
OTTHUMT00006006500
MOCS1-001
6
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39942310


A9
OTTHUMT00006006501
MOCS1-002
6
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39949091


A9
OTTHUMT00006006507
MOCS1-008
6
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39949106


A9
ENSESTT00000028275

6
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39926919


A9
ENST00000274884
MOCS1
6
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39949011


A9
ENST00000308559
MOCS1
6
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39942172


A9
ENSESTT00000028278

6
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39928029


A9
ENSESTT00000028276

6
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39949106


A9
OTTHUMT00006006503
MOCS1-004
6
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39947026


A9
ENSESTT00000028277

6
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39949056


A9
ENST00000320371

6
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39973427


A9
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dJ278E11.3-001
6
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39973427


A9
OTTHUMT00006006498
dJ278E11.5-001
6
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40014827


A9
ENST00000333628

6
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40014863


A9
OTTHUMT00006006516
bA552E20.1-001
6
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40290831


A9
OTTHUMT00006006524
bA535K1.1-003
6
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40394479


A9
OTTHUMT00006006525
bA535K1.1-004
6
40355059
40394479


A9
ENSESTT00000026515

6
40358936
40360627


A9
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bA552E20.3-001
6
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40360745


A9
OTTHUMT00006006520
bA552E20.4-001
6
40373338
40384068


A9
OTTHUMT00006006522
bA535K1.1-001
6
40392931
40394479


A9
OTTHUMT00006006523
bA535K1.1-002
6
40392931
40394479


A9
ENSESTT00000026510

6
40392944
40394492


A9
ENSESTT00000026509

6
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40394492


A9
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bA535K1.2-001
6
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40602059


A9
ENST00000287126
Q9ULH4
6
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40601981


A9
ENSESTT00000026512

6
40447652
40601916


A9
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bA121P10.1-001
6
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40516987


A9
ENSESTT00000026514

6
40516225
40516987


A9
OTTHUMT00006006534
dJ462C17.1-001
6
40530930
40538527


A9
ENSESTT00000026513

6
40530930
40538527


A9
OTTHUMT00006006536
bA570K4.1-001
6
40728005
40729957


A9
ENSESTT00000026511

6
40728005
40729957


A10
ENSESTT00000052482

18
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71313353


A10
ENSESTT00000052481

18
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71551301


A10
ENSESTT00000052480

18
71962357
71963077


A10
ENSESTT00000056790

18
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72054756


A10
ENSESTT00000056791

18
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72099051


A10
ENST00000217537
Y222_HUMAN
18
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72334123


A10
ENSESTT00000056807

18
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72217929


A10
ENSESTT00000056806

18
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72218100


A10
ENSESTT00000056792

18
72276438
72279133


A10
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18
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72326639


A10
ENSESTT00000056794

18
72367851
72401147


A10
ENSESTT00000056795

18
72688458
72707773


A10
ENST00000253159
ZNF236
18
72688458
72774998


A10
ENST00000320610
ZNF236
18
72688458
72807272


A10
ENSESTT00000056797

18
72717002
72734201


A10
ENSESTT00000056796

18
72717002
72734313


A10
ENSESTT00000056798

18
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72747435


A10
ENSESTT00000056799

18
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72819321


A10
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MBP
18
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72855988


A10
ENSESTT00000056804

18
72819098
72855989


A10
ENSESTT00000056803

18
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72856028


A10
ENSESTT00000056805

18
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72855988


A10
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18
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72828993


A10
ENSESTT00000056800

18
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72823085


A10
ENSESTT00000056801

18
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72823085


A10
ENSESTT00000056802

18
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72905291


A10
ENST00000309607

18
72867119
72867493


A10
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GALR1
18
73088710
73109070


A10
ENSESTT00000052501

18
73089280
73095131


A10
ENSESTT00000052502

18
73092673
73095150


A10
ENSESTT00000052503

18
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73463448


A10
ENSESTT00000052478

18
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74657295


A10
ENSESTT00000052477

18
74836231
74837820


A10
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SALL3
18
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74857165


A10
ENSESTT00000052474

18
74853768
74856489


A10
ENSESTT00000052475

18
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74861654


A10
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ATP9B
18
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75236360


A10
ENSESTT00000052476

18
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74972951


A10
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18
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75191977


A10
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18
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A10
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18
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A10
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18
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75204817


A10
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18
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75237133


A10
ENST00000253506
NFATC1
18
75254749
75345913


A10
ENSESTT00000065971

18
75255250
75270171


A10
ENST00000329101
NM_172387
18
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75345913


A10
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18
75270434
75311108


A10
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18
75270434
75327154


A10
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18
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75327154


A10
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18
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75345394


A10
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18
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A10
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18
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75310062


A10
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18
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75327154


A10
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18
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75314808


A10
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18
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75810501


A10
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18
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75550986


A10
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18
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75387291


A10
ENSESTT00000066012

18
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75388300


A10
ENSESTT00000066011

18
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75404501


A10
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18
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75415865


A10
ENST00000317008
NM_182570
18
75500963
75538593


A10
ENST00000299543
CTDP1
18
75538778
75613484


A10
ENST00000075430
NM_048368
18
75538925
75595497


A10
ENSESTT00000066010

18
75561698
75562628


A10
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18
75563836
75573932


A10
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18
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75613484


A10
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18
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75613484


A10
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18
75594535
75613484


A10
ENST00000316249
KCNG2
18
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75758793


A10
ENSESTT00000066009

18
75761442
75762272


A10
ENSESTT00000066008

18
75761446
75762510


A10
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NM_025078
18
75761465
75810007


A10
ENSESTT00000066004

18
75762569
75809829


A10
ENSESTT00000066005

18
75762569
75809829


A10
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18
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75809842


A10
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18
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A10
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18
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75809843


A10
ENSESTT00000066006

18
75762650
75809829


A10
ENSESTT00000066001

18
75762650
75809843


A10
ENST00000262199
Q9H6D0
18
75762953
75802393


A10
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18
75763093
75809836


A10
ENSESTT00000066007

18
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75775293


A10
ENSESTT00000065984

18
75823637
75826139


A10
ENSESTT00000065998

18
75825557
75831889


A10
ENST00000269601
DIM1_HUMAN
18
75831846
75847511


A10
ENSESTT00000065996

18
75832383
75836894


A10
ENSESTT00000065991

18
75832383
75847550


A10
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18
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75847452


A10
ENSESTT00000065995

18
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75847330


A10
ENSESTT00000065994

18
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75847391


A10
ENSESTT00000065997

18
75832541
75835766


A10
ENSESTT00000065992

18
75832715
75847514


A10
ENST00000306735
NM_024805
18
75893335
75905364


A10
ENSESTT00000065986

18
75893389
75901198


A10
ENSESTT00000065985

18
75893389
75905374


A10
ENSESTT00000065990

18
75893434
75905357


A10
ENST00000262197
Q8WZ65
18
75893473
75904914


A10
ENSESTT00000065987

18
75896424
75905374


A10
ENSESTT00000065988

18
75926233
75938117


A10
ENST00000262198
NM_014913
18
75966162
75997201


A10
ENSESTT00000065989

18
75989961
75992868


A10
ENSESTT00000052575

18
76004909
76006133


A10
ENST00000314741
PARD6G
18
76016631
76104208


A10
ENSESTT00000052576

18
76016997
76104406


A10
ENSESTT00000052577

18
76039710
76059638


A11
ENST00000319217.1
MPDZ
9
13096497
13240357


A11
ENST00000319198.3
MPDZ
9
13096497
13240357


A11
ENST00000276902.1
NFIB
9
14077605
14297550


A11
ENST00000331870.1

9
14194247
14194570


A11
ENST00000324876.2
NM_178566
9
14607036
14683474


A11
ENST00000276911.1
CER1
9
14710088
14712670


A11
ENST00000297595.3
NM_144966
9
14727207
14900993


A11
ENST00000324457.3
NM_144966
9
14727207
14900993


A11
ENST00000297593.1
NM_144966
9
14727207
14900993


A11
ENST00000297615.2
NM_152574
9
15161561
15297250


A11
ENST00000336042.1
NM_152574
9
15161561
15297250


A11
ENST00000297627.1
SNAPC3
9
15412732
15455830


A11
ENST00000336277.1
SNAPC3
9
15412732
15455830


A11
ENST00000297635.1
PSIP2
9
15454067
15500982


A11
ENST00000285482.4

9
15542895
15613411


A11
ENST00000297641.1
NM_173550
9
15734586
15961895


A11
ENST00000318677.2
NM_173550
9
15734586
15961895


A11
ENST00000309604.2
NM_017637
9
16408579
16427061


A11
ENST00000317612.2
NM_017637
9
16408579
16427061


A11
ENST00000316584.1
NM_152576
9
16517183
16517287


A11
ENST00000297642.1
NM_017738
9
17125064
17485003


A11
ENST00000262360.2
NM_017738
9
17125064
17485003








Claims
  • 1. A method for identifying an antineoplastic agent, comprising: (a) contacting a test compound with a cell that expresses one or more amplicons of Table 2 having an amplification ratio of at least 2.0; and(b) determining a change in said amplification ratio due to said contacting;wherein a change in said amplification ratio due to said contacting indicates that said test compound has gene modulating activitythereby identifying said test compound as a gene modulating agent.
  • 2. The method of claim 1 wherein said change in expression is a decrease in expression.
  • 3. The method of claim 2 wherein said decrease in expression is a decrease in copy number of the gene.
  • 4. The method of claim 1 wherein said cell was genetically engineered to express said amplicon.
  • 5. A method for identifying an antineoplastic agent, comprising: (a) contacting a test compound with a cell that expresses at least one gene corresponding to a polynucleotide comprising a nucleotide sequence of SEQ ID NO: 1-3049 and under conditions promoting expression of said gene; and(b) determining a change in expression of said gene as a result of said contactingwherein a change in expression indicates gene modulation thereby identifying said test compound as a gene modulating agent.
  • 6. The method of claim 5 wherein said change in expression is a decrease in expression.
  • 7. The method of claim 5 wherein said decrease in expression is a decrease in copy number of the gene.
  • 8. The method of claim 5 wherein said gene comprises a nucleotide sequence of one of SEQ ID NO: 1-3049.
  • 9. The method of claim 5 wherein said cell was genetically engineered to express said gene.
  • 10. A method for detecting the cancerous status of a cell, comprising detecting elevated expression in said cell of at least one gene corresponding to a polynucleotide comprising a nucleotide sequence of SEQ ID NO: 1-3049 whereby such elevated expression is indicative of cancerous status of the cell.
  • 11. The method of claim 10 wherein said elevated expression is an elevated copy number of the gene.
  • 12. A method for identifying a compound as an anti-neoplastic agent, comprising: (a) contacting a test compound with a polypeptide encoded by a gene selected from SEQ ID NO: 1-3049,(b) determining a change in a biological activity of said polypeptide due to said contacting,wherein a change in activity indicates anti-neoplastic activity and thereby identifies such test compound as an agent having antineoplastic activity.
  • 13. The method of claim 12 wherein said change in biological activity is a decrease in biological activity.
  • 14. The method of claim 12 wherein said biological activity is an enzyme activity.
  • 15. The method of claim 14 wherein said enzyme is selected from kinase, protease, peptidase, phosphodiesterase, phosphatase, dehydrogenase, reductase, carboxylase, transferase, deacetylase and polymerase.
  • 16. The method of claim 15 wherein said kinase is a protein kinase.
  • 17. The method of claim 15 wherein said kinase is a serine or threonine kinase.
  • 18. The method of claim 15 wherein said kinase is a receptor tyrosine protein kinase.
  • 19. The method of claim 15 wherein said protease is a serine protease, cysteine protease or aspartic acid protease.
  • 20. The method of claim 15 wherein said transferase is a methyltransferase.
  • 21. The method of claim 20 wherein said methyl transferase is a cytidine methyltransferase or an adenine methyltransferase.
  • 22. The method of claim 15 wherein said deacetylase is a histone deacetylase.
  • 23. The method of claim 11 wherein said carboxylase is a γ-carboxylase.
  • 24. The method of claim 15 wherein said peptidase is a zinc peptidase.
  • 25. The method of claim 15 wherein said polymerase is a DNA polymerase.
  • 26. The method of claim 15 wherein said polymerase is a RNA polymerase.
  • 27. The method of claim 12 wherein said biological activity is a membrane transport activity.
  • 28. The method of claim 12 wherein said polypeptide is a cation channel protein, an anion channel protein, a gated-ion channel protein or an ABC transporter protein.
  • 29. The method of claim 12 wherein said polypeptide is an integrin.
  • 30. The method of claim 12 wherein said polypeptide is a Cytochrome P450 enzyme.
  • 31. The method of claim 12 wherein said polypeptide is a nuclear hormone receptor.
  • 32. The method of claim 12 wherein said biological activity is a receptor activity.
  • 33. The method of claim 12 wherein said receptor is a G-protein-coupled receptor.
  • 34. The method of claim 12 wherein said polypeptide is contained in a cell.
  • 35. A method for identifying an anti-neoplastic agent comprising contacting a cancerous cell with a compound found to have anti-neoplastic activity in the method of claim 12 under conditions promoting the growth of said cell and detecting a change in the activity of said cancerous cell.
  • 36. The method of claim 35 wherein said change in activity is a decrease in the rate of replication of said cancerous cell.
  • 37. The method of claim 35 wherein said change in activity is a decrease in the total number of progeny cells that can be produced by said cancerous cell.
  • 38. The method of claim 35 wherein said change in activity is a decrease in the number of times said cancerous cell can replicate.
  • 39. The method of claim 35 wherein said change in activity is the death of said cancerous cell.
  • 40. A method for treating cancer comprising contacting a cancerous cell with an agent first identified as having gene modulating activity using the method of claim 1, 5, or 12 and in an amount effective to cause a reduction in cancerous activity of said cell.
  • 41. The method of claim 40 wherein said cancerous cell is contacted in vivo.
  • 42. The method of claim 40 wherein said reduction in cancerous activity is a decrease in the rate of proliferation of said cancerous cell.
  • 43. The method of claim 40 wherein said reduction in cancerous activity is the death of said cancerous cell.
  • 44. The method of claim 40 wherein said cancer is a cancer of breast, colon, lung or prostate tissues.
  • 45. A method for treating cancer comprising contacting a cancerous cell with an agent having affinity for an expression product of a gene corresponding to a polynucleotide comprising a nucleotide sequence of SEQ ID NO: 1-3049 and in an amount effective to cause a reduction in cancerous activity of said cell.
  • 46. The method of claim 45 wherein said expression product is a polypeptide.
  • 47. The method of claim 45 wherein said agent is an antibody.
  • 48. A method for monitoring the progress of cancer therapy in a patient comprising monitoring in a patient undergoing cancer therapy the expression of a gene corresponding to a polypeptide having a sequence selected from SEQ ID NO: 1-3049.
  • 49. The method of claim 48 wherein said gene comprises a sequence of SEQ ID NO: 1-3049.
  • 50. The method of claim 48 wherein said cancer therapy is chemotherapy.
  • 51. The method of claim 48 wherein said cancer is a cancer of breast, colon, lung or prostate tissues.
  • 52. A method for determining the likelihood of success of cancer therapy in a patient, comprising monitoring in a patient undergoing cancer therapy the expression of a gene corresponding to a polynucleotide having a sequence of one of SEQ ID NO: 1-3049 wherein a decrease in said expression prior to completion of said cancer therapy is indicative of a likelihood of success of said cancer therapy.
  • 53. The method of claim 52 wherein said gene comprises a sequence of SEQ ID NO: 1-3049.
  • 54. The method of claim 52 wherein said cancer therapy is chemotherapy.
  • 55. The method of claim 52 wherein said cancer is a cancer of breast, colon, lung or prostate tissues.
  • 56. A method for producing test data with respect to the anti-neoplastic activity of a compound comprising: (a) identifying a test compound as having anti-neoplastic activity using a method of claim 12;(b) producing test data with respect to the anti-neoplastic activity of said test compound sufficient to identify the chemical structure of said test compound.
  • 57. A method for determining the progress of a treatment for cancer in a patient afflicted therewith, following commencement of a cancer treatment on said patient, comprising: (a) determining in said patient a change in expression of one or more genes corresponding to a polynucleotide comprising a nucleotide sequence of SEQ ID NO: 1-3049; and(b) determining a change in expression of said gene compared to expression of said one or more determined genes prior to commencement of said cancer treatment;wherein said change in expression indicates progress of said treatmentthereby determining the progress of said treatment.
  • 58. The method of claim 57 wherein said change in expression is a decrease in expression and said decrease indicates success of said treatment.
  • 59. A method for determining the progress of a treatment for cancer in a patient afflicted therewith, following commencement of a cancer treatment on said patient, comprising: (a) determining in said patient a change in expression of one or more genes corresponding to a polynucleotide comprising a nucleotide sequence of SEQ ID NO: 1-3049; and(b) determining a change in expression of said gene compared to expression of said one or more determined genes prior to commencement of said cancer treatment;wherein said change in expression indicates progress of said treatmentthereby determining the progress of said treatment.
  • 60. The method of claim 59 wherein said change in expression is a decrease in expression and said decrease indicates success of said treatment.
Parent Case Info

This application claims priority of U.S. Provisional Application Ser. No. 60/550,304, filed 8 Mar. 2004, the disclosure of which is hereby incorporated by reference in its entirety.

PCT Information
Filing Document Filing Date Country Kind 371c Date
PCT/US2005/007748 3/8/2005 WO 00 5/5/2008
Provisional Applications (1)
Number Date Country
60550304 Mar 2004 US