Classification of lung carcinomas using gene expression analysis

FIELD OF THE INVENTION

[0003] In general, the invention relates to a gene expression based classification of lung cancer and a sub-classification of lung adenocarcinoma. This classification serves as a step towards a new molecular taxonomy of lung tumors and demonstrates the power of gene expression profiling in lung cancer diagnosis.

BACKGROUND

[0004] Carcinoma of the lung claims more than 150,000 lives every year in the United States, thus exceeding the combined mortality from breast, prostate and colorectal cancers. Current lung cancer classification is based on clinicopathological features. Lung carcinomas are usually classified as small cell lung carcinomas (SCLC) or non-small cell lung carcinomas (NSCLC). Neuroendocrine features, defined by microscopic morphology and immuno-histochemistry, are hallmarks of the high-grade SCLC and large cell neuroendocrine tumors and of intermediate/low-grade carcinoid tumors. NSCLC is histopathologically and clinically distinct from SCLC, and is further subcategorized as adenocarcinomas, squamous cell carcinomas, and large cell carcinomas, of which adenocarcinomas are the most common.

[0005] The histopathological sub-classification of lung adenocarcinoma is challenging. In one study, independent lung pathologists agreed on lung adenocarcinoma sub-classification in only 41% of cases. However, a favorable prognosis for bronchioloalveolar carcinoma (BAC), a histological sub-class of lung adenocarcinoma, argues for refining such distinctions. In addition, metastases of non-lung origin can be difficult to distinguish from lung adenocarcinomas.

[0006] Therefore, there is a need in the art for methods and compositions that are useful to distinguish cancer of lung origin from metastases of non-lung origin, and to distinguish different types of lung cancer.

SUMMARY

[0007] The development of microarray methods for large-scale analysis of gene expression makes it possible to search systematically for molecular markers of cancer classification and outcome prediction in a variety of tumor types. Currently, the only effective prognostic indicator for NSCLC in clinical use is surgical-pathological staging. However, according to the invention, the simultaneous analysis of a large number of independent clinical markers offers a powerful adjunct approach in surgical-pathological staging.

[0008] According to the invention, a comprehensive gene expression analysis of human lung tumors identified distinct lung adenocarcinoma sub-classes that were reproducibly generated across different cluster methods. Notably, the C2 adenocarcinoma subclass, defined by neuroendocrine gene expression, is associated with a less favorable outcome, while the C4 group appears to be associated with a more favorable outcome.

[0009] Hierarchical clustering methods offer a powerful approach for class discovery, but are less useful for determining confidence for the classes discovered. In one aspect of the invention, a bootstrap probabilistic clustering is combined with the hierarchical method to measure the strength of sample-sample association, thereby defining cluster membership with greater confidence.

[0010] Although adenocarcinomas with neuroendocrine features have been reported, unique markers that precisely define such tumors have not been described. In another aspect of the invention, putative neuroendocrine markers, for example, kallikrein 11, that discriminate the C2 tumors from all other lung tumors, are identified. In one embodiment, this marker, which is related to the vasodepressor renal kallikrein, is of clinical interest given the observation of orthostatic hypotension in some lung cancer patients.

[0011] In a further aspect of the invention, putative metastases of extra-pulmonary origin with non-lung expression signatures were discovered among presumed lung adenocarcinomas. According to the invention, gene expression analysis can serve as a diagnostic tool to confirm and identify metastases to the lung.

[0012] In one embodiment, the invention provides lung specific marker arrays. In another embodiment, the invention provides lung specific marker information in computer-accessible form. In other embodiments, methods and compositions of the invention are useful for drug selection, drug evaluation, patient prognosis, and patient monitoring.

[0013] Diagnostic methods and arrays of the invention can include all of the markers that are characteristic of one or more classes or subclasses of cancer described herein. Alternatively, single markers can be used. Preferably 1 to 20, 1 to 10, or about 5 genetic markers are used in an assay or on an assay to diagnose or detect a specific type of cancer. A single assay may be used to diagnose or detect one or more classes or subclasses of cancer disclosed herein. A useful assay includes one or more markers of one or more classes or subclasses of cancer. Preferred markers for different classes and subclasses of cancer are shown in Tables 1-9.

[0014] Drug screening methods of the invention involve assaying candidate compounds or drugs for their effect on one or more markers of one or more difference classes or subclasses of cancer described herein. Preferably 1 to 20, 1 to 10, or about 5 genetic markers are used in a screening assay to identify a drug that is effective to reduce the expression level of at least one of the markers. Preferred markers for different classes and subclasses of cancer are shown in Tables 1-9. Preferred drug candidates reduce the expression of markers associated with all classes of cancer. However, drug candidates that reduce the expression of markers associated with one or a subset of classes of cancer are also useful. Drug candidates identified in these assays are preferably subject to clinical testing to evaluate their effectiveness against different types of cancer, including different classes and subclasses of lung cancer.

[0015] According to the invention, markers shown to be overexpressed in different types of cancer (including different classes or subclasses of lung cancer) can be used as targets for drug development. Useful drugs include antisense nucleic acids that decrease the expression of one or more markets described herein. Useful drugs also include antibodies or other compounds that interfere with the gene product of one or more markers of the invention. For example, a protease inhibitor that inhibits the activity of kallikrein 11 may be therapeutically useful.

DESCRIPTION OF THE DRAWINGS

[0016]
FIG. 1. Survival analysis of neuroendocrine C2 adenocarcinomas is shown. Kaplan-Meier curves for C2 versus all other adenocarcinomas. A, All patients. C2 (n=9) and non-C2 (n=117). B, Patients with stage I tumors only. C2 (n=4) and non-C2 (n=72).

[0017]
FIG. 2. A computer system is shown. The Memory can be a RAM, ROM, CDROM, Tape, Disk, or other form of memory. The Removable data medium can be a magnetic disk, a CDROM, a tape, an optical disk, or other form of removable data medium.

[0018]
FIG. 3. A box plot of median array intensity across IVT batches is shown and examples of uncorrected and corrected non-linear responses on same specimens following linear and non-linear scaling methods are also shown.

[0019]
FIG. 4. Non-linear responses in reference RNA samples are shown following linear scaling (a, c and e) that is corrected after rank invariant scaling (b, d and f).

[0020]
FIG. 5. Pairwise agreement (R.sq values) of 12600 rank invariant scaled expression values of genes are shown between replicate arrays.

[0021]
FIG. 6. Clusters selected by AutoClass over several runs of the algorithm are shown. The left panel plots the distribution over 200 runs of the algorithm on the original data set (experiment 1), and on the bootstrapped data sets (experiment 2), both defined over 675 genes. The right panel plots the corresponding distributions with respect to the data sets defined over 1514 genes.

DETAILED DESCRIPTION OF THE INVENTION

[0022] The invention provides methods and compositions for classifying lung carcinomas based on gene expression information. In general, the invention relates to the analysis of gene expression information in normal and cancerous lung tissue and the identification of types or classes of lung cancer based on different patterns of gene expression in different lung carcinomas. In addition, the invention provides specific markers of the different types and classes of lung cancer. According to the invention, markers are useful to classify and evaluate new lung cancers, to provide a prognosis for a lung cancer patient, to identify drugs, and to monitor the progression of a lung cancer in a patient.

[0023] According to the invention, gene expression can be assayed by analyzing and/or quantifying the nucleic acid (including mRNA, rRNA, tRNA and other RNA products of gene transcription) or protein (including short peptide and other protein translation products) products of gene expression. Methods for measuring gene expression are known in the art, and examples are discussed herein. However, one of ordinary skill in the art will understand that methods of the invention relate to all assays of gene expression in normal or diseased lung samples.

[0024] In one embodiment, a gene expression analysis of 186 human carcinomas from the lung provides evidence for biologically distinct sub-classes of lung adenocarcinoma.

[0025] More fundamental knowledge of the molecular basis and classification of lung carcinomas is useful in the prediction of patient outcome, the informed selection of currently available therapies, and the identification of novel molecular targets for chemotherapy. The recent development of targeted therapy against the Abl tyrosine kinase for chronic myeloid leukemia illustrates the power of such biological knowledge.

Molecular Classification of Diverse Lung Tumors

[0026] The present invention provides methods for classifying diverse lung tumors based on gene expression profiles. In preferred embodiments, lung tumors are classified based on the expression of a set of marker genes characteristic of a type of lung cancer. In a more preferred embodiment, classification is based on the expression of between 1 and 50, preferably between 1 and 20, more preferably between 1 and 10, and more preferably between 5 and 10 marker genes, the expression of which is strongly correlated with a type of lung cancer.

[0027] First, hierarchical clustering (Eisen, M. B., Spellman, P. T., Brown, P. O. & Botstein, D. (1998) Proc Natl Acad Sci USA 95, 14863-8) was applied to classify all 203 samples using the 3312 most variably expressed transcripts. The resulting clusters recapitulated the distinctions between established histologic classes of lung tumors-pulmonary carcinoid tumors, SCLC, squamous cell lung carcinomas, and adenocarcinomasthus validating the experimental and analytic approach of the invention. Two-dimensional hierarchical clustering of 203 lung tumors and normal lung samples was performed with 3,312 transcript sequences. The expression index for each transcript was normalized. Adenocarcinomas resected from the lung and a subset of adenocarcinomas suspected as colon metastases were analyzed.

[0028] Normal lung samples form a distinct group, but are most similar to the adenocarcinomas. Marker genes that characterize normal lung samples include TGFβ receptor type II, tetranectin and ficolin 3. A cluster of genes with high relation expression in normal lung includes: TGF-β receptor II; epithelial membrane prot. 2; PECAM-1 (CD31 antigen); PECAM-1 (CD31 antigen); cadherin 5, type 2, VE-cadherin; AF070648; four and a half LIM domains 1; microfibrillar-associated prot. 4; amine oxidase, copper containing 3; A kinase anchor prot. 2; ficolin 3; receptor activity modifying prot. 2; tetranectin; adv. glycosylation end prod.-sp. receptor; TEK tyrosine kinase, endothelial; and slit homolog 2. Elevated TGFβ receptor type II levels have been previously reported for normal bronchial and alveolar epithelium compared to lung carcinomas.

[0029] SCLC and carcinoid tumors both show high-level expression of neuroendocrine genes including insulinoma-associated gene 1 (Ball, D. W., Azzoli, C. G., Baylin, S. B., Chi, D., Dou, S., DonisKeller, H., Cumaraswamy, A., Borges, M. & Nelkin, B. D. (1993) Proc Natl Acad Sci USA 90, 5648-52, Lan, M. S., Russell, E. K., Lu, J., Johnson, B. E. & Notkins, A. L. (1993) Cancer Res 53, 4169-71), achaete scute homolog 1 (Ball, D. W., Azzoli, C. G., Baylin, S. B., Chi, D., Dou, S., DonisKeller, H., Cumaraswamy, A., Borges, M. & Nelkin, B. D. (1993) Proc Natl Acad Sci USA 90, 5648-52, Lan, M. S., Russell, E. K., Lu, J., Johnson, B. E. & Notkins, A. L. (1993) Cancer Res 53, 4169-71), gastrin-releasing peptide and chromogranin A. Several previously undescribed markers for SCLC such as thymosin-β and the cell cycle inhibitor p18ink4C were also observed. A cluster of genes with high relative expression in neuroendocrine tumors (small cell lung cancer and pulmonary carcinonas) includes: tubulin, βpolypeptide; insulinoma-associated 1; extra spindle poles, yeast homolog; core-binding factor, (runt), α subunit 2; guanine nucleotide binding prot. 4; achaete-scute homolog-like 1; achaete-scute homolog-like 1; CDKN2C (p18); forkhead box GIB; thymosin p, neuroblastoma; ISL1 transcription factor; distal-less homeobon 6; transcription factor 12 (HTF4); PC4 and SFRS1 interacting prot. 2. In one embodiment of the invention, only a few markers are shared between SCLC and carcinoids, while a distinct group of genes defines carcinoid tumors. Two-dimensional hierarchical clustering of 203 lung tumor and normal samples (data set A) was performed with 3,312 genes as described herein. Different clusters of genes with high relative expressions were observed for normal lung; lung carcinoid; small cell lung carcinoma; squamous cell lung carcinoma; and colon metastasis. Clusters C1, C2, C3 and C4 were defined by clustering of data set B. This suggests that carcinoids are highly divergent from malignant lung tumors.

[0030] Squamous cell lung carcinomas, for which diagnostic criteria include evidence of squamous differentiation such as keratin formation form a discrete cluster with high-level expression of transcripts for multiple keratin types and the keratinocytespecific protein stratifin. A cluster of genes with high relative expression in squamous cell lung carcinomas with keratin markers includes: glypican 1; collagen, type VII, α 1; desmoglein 3; W27953; keratin 17; keratin 5; tumor prot. 63; keratin 6; ataxia-telangiectasia group D-assoc. prot.; serine proteinase inhibitor, clade B (5); bullous pemphigoid antigen 1; KIAA0699; CaN19/M87068; S100 calcium-binding prot. A2; and galectin 7. The squamous tumors also show over-expression of p63, a p53-related gene essential for the formation of squamous epithelia. Several adenocarcinomas that express high levels of squamous associated genes, also display histological evidence of squamous features.

[0031] Finally, expression of proliferative markers, such as PCNA, thymidylate synthase, MCM2 and MCM6, is highest in SCLC, which is known to be the most rapidly dividing lung tumor A cluster of genes with high relative expression associated with proliferation includes: MCM2; MCM6; Rad2; flap structure-specific endonuclease 1; PCNA; thymidylate synthetase; DEK oncogene; H2A histone family, member Z; high-mobility group prot. 2; and ZW10 interactor. However, unlike the other major lung tumor classes shown above, lung adenocarcinomas were not defined by a unique set of marker genes.

[0032] Class Discovery among Lung Adenocarcinomas.

[0033] Strong signatures in other lung tumors may obscure the successful subclassification of lung adenocarcinoma in the above analysis. Therefore, a hierarchical clustering was used to sub-classify a data set restricted to adenocarcinomas. Classifications derived by hierarchical clustering and probabilistic clustering algorithms were compared. A two-dimensional colored matrix was generated as a visual representation of a corresponding numerical matrix whose entries record a normalized measure of association strength between samples. Strong association approaches a value of 1 and poor association is close to 0. Associations were obtained for colon metastasis; normal lung; C1 through C4 (adenocarcinoma clusters); additional groups with weaker association were also observed (groups I, II, and III). Genes expressed at high levels in specific subsets of adenocarcinomas can be clustered as a function of histologic differentiation within lung adenoma sub-classes. To avoid spurious variations contributing to the clustering process, 675 transcript sequences were selected with expression levels that were most highly reproducible in duplicate adenocarcinoma samples, yet whose expression varied widely across the chosen sample set (Dataset B); as discussed in the Examples. Normal lung specimens were included in this dataset, as normal epithelium is a component of the grossly dissected adenocarcinoma samples.

[0034] To reduce potential classification-bias due to choice of clustering method, and to clarify adenocarcinoma sub-class boundaries, a model-based probabilistic clustering method (Kang, Y., Prentice, M. A., Mariano, J. M., Davarya, S., Linnoila, R. I., Moody, T. W., Wakefield, L. M. & Jakowlew, S. B. (2000) Exp Lung Res 26, 685-707) was also used. To assess the overall strength of each pair-wise association, the frequency with which two samples appeared together was measured in a cluster in 200 clustering iterations over bootstrap data sets. A stable cluster was defined as a set of at least 10 samples with a high degree of association (a threshold of 0.45 was used, corresponding to shared cluster membership in at least 45% of the bootstrap datasets in which both samples were included). According to this definition, several clusters suggested by the hierarchical tree are stable. These associations can be shown, as a color matrix overlaid on a tree structure obtained from hierarchical clustering. The blocks of associated samples show that both clustering methods recognized subclasses corresponding to normal lung and putative colon metastases (CM). Four subclasses of primary lung adenocarcinoma (C 1 to C4) were also observed by both probabilistic and hierarchical clustering. Several smaller and/or less robust groups were also observed (Groups I, II, and III).

[0035] Probabilistic clustering also revealed correlations between samples that do not directly cluster together. For example, although cluster C4 falls in the right branch of the hierarchical dendrogram with normal lung, it shows significant association with some subclasses in the left dendrogram (groups I and III and cluster C3) but not with other subclasses (clusters CM, C1, and C2).

[0036] Clusters C2, C3, and C4 were also seen as coherent adenocarcinoma groups within the hierarchical clustering of the larger set of lung tumors using the 3,312 transcript sequence set (Dataset A). The reproducible generation of these adenocarcinoma subclasses, across both clustering methods and both gene sets analyzed, supports the validity of the adenocarcinoma clusters and their boundaries.

[0037] In order to identify genes that best defined the proposed clusters, a supervised approach was used to extract marker genes from the entire set of 12,600 transcript sequences. For each cluster, selected genes were the most preferentially expressed in the cluster relative to all other samples, using the signal-to-noise metric described previously (Golub, T. R., Slonim, D. K., Tamayo, P., Huard, C., Gaasenbeek, M., Mesirov, J. P., Coller, H., Loh, M. L., Downing, J. R., Caligiuri, M. A., et al. (1999) Science 286, 5317). The genes whose expression correlated best with each class are useful as markers for class prediction of unknown lung cancer samples.

[0038] Identification of Adenocarcinomas Metastatic to the Lung.

[0039] The present invention provides methods for identifying metastatic tumors of non-lung origin. A key issue in lung tumor diagnosis is the discrimination of a primary lung adenocarcinoma from a distant metastasis to the lung. One distinct hierarchical cluster of 12 samples was identified that most likely represent metastatic adenocarcinomas from the colon. These tumors express high levels of galectin-4, CEACAMI and liverintestinal cadherin 17, as well as c-myc, which is commonly overexpressed in colon carcinoma. Genes expressed at high levels in colon metastases include: c-myc; ETS-2; expressed in thyroid; cadherin 17, (liver-intestine); galectin-4; transmem. 4 superfam. mem. 3; integrin, α 6; trypsin 4, brain; diacylglycerol O-acyltransferase; E74-like factor 3; claudin 4; claudin 3; KIAA0792 gene product; CEA CAM-1; and immediate early response 3. Of the 10 samples in this group for which clinical history and/or histopathologic information was available, only 7 samples had been previously diagnosed as metastases of colonic origin. Other adenocarcinomas that showed nonlung signatures included AD 163, which expressed several breast-associated markers including estrogen receptor and mammaglobin, and was associated with a clinical history and histopathology consistent with breast metastasis. Also, AD368, which was not identified as a metastasis, expressed high levels of albumin, transferrin, and other markers associated with the liver. Thus, clustering identified suspected metastases of extra-pulmonary origin, including some that were previously undetected. Accordingly, methods of the invention can play a pivotal role for gene expression analysis in lung tumor diagnosis.

[0040] Molecular Signature of Lung Adenocarcinoma Sub-Classes.

[0041] The present invention also provides methods for identifying subclasses of lung adenocarcinoma. Hierarchical and probabilistic clustering defined four distinct sub-classes of primary lung adenocarcinomas. Tumors in the C1 cluster express high levels of genes associated with cell division and proliferation (ubiquitin carrier prot.; Cks-Hs2; high-mobility group prot. 2; flap structure-specific endonuclease 1; MCM6; thymidine kinase 1; PCNA; and W27939), some of which are also expressed in the squamous cell lung carcinoma and SCLC samples in Dataset A. Relatively high-level expression of proliferation-associated genes was also seen in cluster C2.

[0042] Several neuroendocrine markers, such as dopa decarboxylase and achaete-scute homolog 1, define cluster C2 (kallikrein 11; dopa decarboxylase; achaete-scute homolog-1; achaete-scute homolog-1; calcitonin-related polypeptide a; proprotein convertase subtilisin; and carboxypeptidase E) and some of these are also expressed in SCLC and pulmonary carcinoids. However, the serine protease, kallikrein 11, is uniquely expressed in the neuroendocrine C2 adenocarcinomas, and not in other neuroendocrine lung tumors.

[0043] C3 tumors are defined by high-level expression of two sets of genes. Expression of one gene cluster (ATPase, Na+/K+ transporting; mesothelin; S100 calcium-binding prot. P; solute carrier family 16; KIAA0828; phospholipase A2, group X; progastricsin (pepsinogen C); cytokine receptor-ike factor 1; dual specificity phosphatase 4; ornithine decarboxylase 1; ornithine decarboxylase 1; TS deleted in oral cancer-related 1; ribosomal S6; sodium channel, nonvoltage-gated 1 α; DKFZP56400823; glutathione S-transferase pi; glutathione S-transferase pi; and hepsin), including ornithine decarboxylase 1 and glutathione S-transferase pi, is shared with the neuroendocrine C2 cluster. Expression of the second set of genes is shared with cluster C4 and with normal lung. Genes expressed at high levels in C4, C3 and normal lung include: surfactant, pulmonary-assoc. prot. B; ˜N acylsphingosine amidohydrolase; cytochrome b-5; cytochrome b-5; deleted in liver cancer 1; Ca+ channel, voltage-dependent; surfactant, pulmonary-assoc. prot. C; surfactant, pulmonary-assoc. prot. D; AL049963; ATP-binding cassette (ABC1); KIAA0018 gene product; cathepsin H; selenium binding protein 1; KIAA0758; leukotriene A4 hydrolase; AFO35315; leukocyte protease inhibitor; and BENE. Highest expression of type II alveolar pneumocyte markers, such as thyroid transcription factor 1, and surfactant protein B, C and D genes, was seen in cluster C4, followed by normal lung and C3 cluster. Other markers that defined cluster C4 included cytochrome b5, cathepsin H, and epithelial mucin 1.

[0044] Relation Between Gene Expression Tumor Classes, Histological Analysis and Smoking History.

[0045] Cluster C1 primarily contains poorly differentiated tumors, while C3 and C4 contains predominantly well-differentiated tumors. Adenocarcinomas of cluster C2 fell in between. Ten of the 14 C4 tumors had been identified as BACs by at least one out of three pathologists who examined the tumors; in contrast, 15 of the remaining 113 adenocarcinomas were similarly described as BACs. The presence of type 11 pneumocyte markers and the high fraction of putative BACs suggest that cluster C4 is likely to be a gene expression counterpart to BAC. All of the C4 tumors in this study were surgical-pathological stage I tumors.

[0046] Although microscopic analysis indicated that samples varied in homogeneity, contamination of normal lung cells does not seem to have overwhelmed the expression signatures. The degree to which tumors clustered with normal samples did not reflect the percentage of tumor cells in a sample in most cases. Class C4 is most similar to normal lung in both hierarchical and probabilistic clustering, yet these tumors all revealed at least an estimated 50% tumor nuclei and in most samples over 80%. In contrast, classes C2 and CM contain tumors with as few as 30% estimated tumor nuclei but are sharply distinguishable from the normal lung. Note that only adenocarcinoma specimen AD363, with an estimated 30% tumor content in the adjacent section, clustered with normal lung.

[0047] Two adenocarcinoma sub-classes were associated with lower tobacco smoking histories. The presumed metastases of colon origin (CM) and C4 adenocarcinomas with type II pneumocyte gene expression have median smoking histories of 2.5 and 23 pack-years, respectively. The entire data set had a median smoking history of 40 pack-years.

[0048] Correlation of Patient Outcome with Putative Adenocarcinoma Classes.

[0049] The present invention also provides methods for predicting patient outcome based on the analysis of lung marker gene expression. Lung cancer patient outcome was correlated with the sub-classes of lung adenocarcinomas defined herein. The neuroendocrine C2 adenocarcinomas were associated with a less favorable survival outcome than all other adenocarcinomas (FIGS. 1A, 1B). The median survival for C2 tumors was 21 months compared to 40.5 months for all non-C2 tumors (P=0.00476). When only stage I tumors are considered, the median survival for patients with C2 tumors was 20 months compared to 47.8 months for patients with non-C2 tumors; as the numbers are smaller, the P-value for this comparison is 0.0753. In contrast, C4 adenocarcinomas with type II pneumocyte gene expression (n=14) were associated with a more favorable survival outcome than non-C4 tumors. The median survival for patients with C4 tumors was 49.7 months while the median survival for patients with non-C4 tumors was 33.2 months (P=0.049; note that the non-C2 and non-C4 groups are different because of the exclusion of each group separately in the comparison). For patients with stage I tumors, the median survival in the C4 group was 49.7 months and 43.5 months in the non-C4 group (P=0.191). There was no detectable difference in prognosis between the primary lung adenocarcinomas and the metastases to the lung of colonic origin.

[0050] Arrays of Gene Expression Detection Agents.

[0051] The present invention also provides arrays of gene expression detection agents. Preferred gene expression detection agents hybridize specifically to marker genes disclosed herein. Such agents may be RNA, DNA, or PNA molecules. Preferred agents are oligonucleotides. Alternative agents bind specifically to the protein expression products of the marker genes disclosed herein. Preferred agents include antibodies and aptamers.

[0052] Agents, such as oligonucleotides, are preferably attached to a solid support in the form of an array. Oligonucleotide arrays in the form of gene chips and useful hybridization assays are known in the art and disclosed for example in U.S. Pat. Nos. 5,631,734; 5,874,219; 5,861,242; 5,858,659; 5,856,174; 5,843,655; 5,837,832; 5,834,758; 5,770,722; 5,770,456; 5,733,729; 5,556,752; 6,045,996; and 6,261,776. In a preferred embodiment, an array includes oligonucleotides for measuring the expression level of markers for a specific type or class of lung cancer. In a more preferred embodiment, an array of the invention includes a plurality of oligonucleotides that are specific for marker for several types or classes of lung cancer or adenocarcinoma.

[0053] Information about Marker Genes and Marker Gene Expression Levels.

[0054] The present invention further provides databases of marker genes and information about the marker genes, including the expression levels that are characteristic of different lung cancer types or lung adenocarcinoma subclasses. According to the invention, marker gene information is preferably stored in a memory in a computer system (FIG. 2). Alternatively, the information is stored in a removable data medium such as a magnetic disk, a CDROM, a tape, or an optical disk. In a further embodiment, the input/output of the computer system can be attached to a network and the information about the marker genes can be transmitted across the network.

[0055] Preferred information includes the identity of a predetermined number of marker genes the expression of which correlates with a particular type of lung cancer or a particular subclass of adenocarcinoma. In addition, threshold expression levels of one or more marker genes may be stored in a memory or on a removable data medium. According to the invention, a threshold expression level is a level of expression of the marker gene that is indicative of the presence of a particular type or class of lung cancer.

[0056] In a highly preferred embodiment, a computer system or removable data medium includes the identity and expression information about a plurality of marker genes for several types or classes of lung cancer disclosed herein. In addition, information about marker genes for normal lung tissue may be included.

[0057] Information stored on a computer system or data medium as described above is useful as a reference for comparison with expression data generated in an assay of lung tissue of unknown disease status.

[0058] Finally, the present invention provides methods for identifying, evaluating, and monitoring drug candidates for the treatment of different lung cancer types or adenocarcinoma subclasses. According to the invention, a candidate drug is assayed for its ability to decrease the expression of one or more markers of lung cancer. In one embodiment, a specific drug may reduce the expression of markers for a specific type or subclass of lung carcinoma described herein. Alternatively, a preferred drug may have a general effect on lung cancer and decrease the expression of different markers characteristic of different types or classes of lung carcinoma. In one embodiment, a preferred drug decreases the expression of a lung cancer marker by killing lung cancer cells or by interfering with their replication.

[0059] In one embodiment, the screening assays for drug candidates are performed on proteins encoded by the nucleic acids that are identified as having an increased expression in specific subclasses or types of lung carcinoma. In another embodiment, the screening assays for drug candidates are performed on nucleic acids that are differentially expressed in various subclasses or types of lung cancer when compared with normal samples.

[0060] In one embodiment, a candidate drug is added to cells or sample tissue prior to analysis. Preferred cells are cell lines grown from different types of cancer (e.g. different classes or subclasses of lung cancer). Alternatively, cells isolated directly from tumor tissue can be assayed. In another embodiment, the invention provides screens for a candidate drug which modulates lung cancer, modulates lung cancer gene expression and/or protein expression, modulates lung cancer genes or protein activity, binds to a lung cancer protein, or interferes with the binding of a lung cancer protein and an antibody.

[0061] The term “candidate drug” or equivalent as used herein describes any molecule, e.g., an antibody, protein, oligopeptide, fatty acid, steroid, small organic molecule, polysaccharide, polynucleotide, antisense molecule, ligand, bioactive partner and structural analogs or combinations thereof, to be tested for canditate drugs that are capable of directly or indirectly altering the lung cancer phenotype, or the expression of one or more lung cancer markers as identified herein, or overall gene and/or protein expression. Accordingly, methods of the invention include assays for monitoring the expression of nucleic acids and protein.

[0062] Preferred assays screen for candidate drugs that modulate the overall expression of specific gene clusters identified herein (for exampe, one or more genes in Tables 1-9), or the expression of specific nucleic acids or proteins within the clusters. In a particularly preferred embodiment, as assay identified a candidate drug that suppresses a lung cancer phenotype, for example to a normal lung tissue phenotype. A variety of assays can be executed for drug screening. For example, once a specific gene is identified as being differentially expressed by the methods of the invention, candidate drugs that specifically modulate expression or levels of the specific gene may be identified. For example, candidate drugs may be identified that down regulate expression of the specific gene. In one embodiment, candidate drugs may be identified that up regulate expression of the specific gene. Generally a plurality of assay mixtures are run in parallel with different drug concentrations to obtain a differential response to the various concentrations. Typically, one of these concentrations serves as a negative control, i.e., at zero concentration or below the level of detection.

[0063] The amount of gene expression can be monitored at either the gene level or the protein level, i.e., the amount of gene expression may be monitored using nucleic acid probes and methods known in the act may be used to qualify gene expression levels. Alternatively, the gene product itself can be monitored, for example through the use of antibodies to the proteins encoded by the nucleic acids identified by the methods of the invention, and in standard immunoassays.

[0064] In one embodiment, candidate drugs or agents are naturally occurring proteins or fragments of naturally occurring proteins. Thus, for example, cellular extracts containing proteins, or random or directed digests of proteinaceous cellular extracts, may be used. In this way libraries of prokaryotic and eukaryotic proteins may be made for screening by the methods of the invention. Particularly preferred in this embodiment are libraries of bacterial, fungal, viral, and mammalian proteins, with the latter being preferred, and human proteins being especially preferred.

[0065] In another embodiment, candidate drugs are peptides of from about 5 to about 30 amino acids, with from about 5 to about 20 amino acids being preferred, and from about 7 to about 15 being particularly preferred. The peptides may be digests of naturally occurring proteins as is outlined above, random peptides, or “biased” random peptides. By “random” or equivalents herein is meant that each nucleic acid and peptide consists of essentially random nucleotides and amino acids, respectively. Since generally these random peptides (or nucleic acids), are chemically synthesized, they may incorporate any nucleotide or amino acid at any position. The synthetic process can be designed to generate randomized proteins or nucleic acids, to allow the formation of all or most of the possible combinations over the length of the sequence, thus forming a library of randomized candidate proteinaceous drugs.

[0066] In another embodiment, the candidate drugs are nucleic acids. As described above generally for proteins, nucleic acid candidate drugs may be naturally occurring nucleic acids or random nucleic acids. For example, digests of prokaryotic or eukaryotic genomes may be used as is outlined above for proteins.

[0067] In a preferred embodiment, nucleic acid drug candidates are antisense molecules. Drug candidates that are antisense molecules include antisense or sense oligonucleotides comprising a single-strand nucleic acid sequence (either RNA or DNA) capable of binding to target mRNA or DNA sequences for lung cancer molecules identified by the methods of the invention. For example, a preferred antisense molecule is a molecule that binds a nucleic acid sequence encoding Kallikrein 11. The antisense molecule can either bind a full-length nucleic acid encoding Kallikrein 11, for example the full-length DNA or mRNA encoding Kallikrein 11, or a partial nucleic acid sequence for Kallikrein 11. Antisense or sense oligonuclotides, typically include a fragment of generally about 14 nucleotides, preferably about 14 to 30 nucleotides. However, it is understood that the length of the antisense or sense nucleotides will depend on the length of the target nucleic acid or a fragment thereof.

[0068] In yet another preferred embodiment, drug candidates are antibodies. An antibody used in methods for screening for a candidate drug may either bind a full length protein or a fragment thereof. In a preferred embodiment, the antibody binds a unique epitope on a target protein and shows little or no cross-reactivity. The term “antibody” is understood to include antibody fragments, as are known in the art, including Fab, Fab.sub.2, single chain antibodies (Fv for example), chimeric antibodies, etc., either produced by the modification of whole antibodies or those synthesized de novo using recombinant DNA technologies known in the art.

[0069] Antibodies as used herein as drug candidates include both polyclonal and monoclonal antibodies. Polyclonal antibodies can be raised in a mammal, for example, by one or more injections of an antigenic agent and, if desired, an adjuvant. It may be useful to conjugate the antigenic agent to a protein known to be immunogenic in the mammal being immunized. Preferred antigenic agents include cancer specific antigens, and more preferably lung cancer specific antigens. Examples of adjuvants which may be employed include Freund's complete adjuvant and MPL-TDM adjuvant (monophosphoryl Lipid A, synthetic trehalose dicorynomycolate).

[0070] The antibodies may, alternatively, be monoclonal antibodies. Monoclonal antibodies may be prepared using various hybridoma methods known in the art. For example, a mouse, hamster, or other appropriate host animal, is typically immunized with an immunizing agent to elicit lymphocytes that produce or are capable of producing antibodies that will specifically bind to a immunizing agent. Alternatively, the lymphocytes may be immunized in vitro. An immunizing agent is preferably a protein or fragment thereof that differentially expressed in subclasses or types of lung cancer. However, other known cancer specific antigens may also be used. In a preferred embodiment, the immunizing agent is the full length Kallikrein 11 protein or a homolog or derivative thereof. In another embodiment, the immunizing agent is a partial-length Kallikrein 11 protein or a homolog or derivative thereof.

[0071] Panels of available antibodies may also be screened for their effect on the expression of lung specific gene clusters (or specific genes or subsets of genes within these clusters). In one embodiment, some or all o fthe antibodies being screened are not known to be associated with any cancer specific antigen. In one embodiment, the antibodies are bispecific antibodies. Bispecific antibodies are monoclonal, preferably human or humanized, antibodies that have binding specificities for at least two different antigens.

[0072] In yet another embodiment, the candidate drugs are chemical compounds. In a preferred embodiment, the candidate drugs are small organic compounds having a molecular weight of more than 100 and less than about 2500 daltons. Candidate drugs may also include functional groups necessary for structural interaction with proteins or nucleic acids.

[0073] According to the invention, levels of marker genes disclsosed herein can be used the follow the course of a lung cancer in a patient. Methods of the invention are therefore useful to evalutate the effectiveness of a particular treatment. In addition, methods of the invention are also useful to monitor the progression of a lung cancer in a patient, for example from a C4 to a C3 to a C2 adenocarcinoma.

[0074] The identification of candidates that, alone or admixed with other suitable molecules, are competent to treat lung cancer are contemplated by the invention. Further, the production of commercially significant quantities of the aforementioned identified candidates, which are suitable for the prevention and/or treatment of lung, colon, or other cancer is contemplated. Moreover, the invention provides for the production of therapeutic grade commercially significant quantities of therapeutic agents in which any undesirable properties of the initially identified analog, such as in vivo toxicity or a tendency to degrade upon storage, are mitigated.

[0075] Methods of preventing and treating cancer, after the identification of an antibody, peptide, peptidomimetic, nucleic acid, or small molecule, include the step of administering a composition including such a compound to a patient.

[0076] Nucleic acid molecules (including DNA, RNA, and nucleic acid analogs such as PNA) which are themselves active or which code for active expressed products; peptides; proteins; antibodies; or other chemical compounds isolated and identified, or based upon or derived from ligands isolated and identified according to the invention (also referred to as active compounds or drugs) can be incorporated into pharmaceutical compositions suitable for administration. Such active compounds or drugs include inhibitors identified or constructed as a result of isolating and identifying ligands according to the invention. The drug compounds discovered according to the present invention can be administered to a mammalian host by any route. Thus, as appropriate, administration can be oral or parenteral, including intravenous and intraperitoneal routes of administration. In addition, administration can be by periodic injections of a bolus of the drug, or can be made more continuous by intravenous or intraperitoneal administration from a reservoir which is external (e.g., an i.v. bag). In certain embodiments, the drugs of the instant invention can be therapeutic-grade. That is, certain embodiments comply with standards of purity and quality control required for administration to humans. Veterinary applications are also within the intended meaning as used herein.

[0077] The formulations, both for veterinary and for human medical use, of the drugs according to the present invention typically include such drugs in association with a pharmaceutically acceptable carrier therefor and optionally other therapeutic ingredient(s). The carrier(s) can be “acceptable” in the sense of being compatible with the other ingredients of the formulations and not deleterious to the recipient thereof. Pharmaceutically acceptable carriers, in this regard, are intended to include any and all solvents, dispersion media, coatings, antibacterial and antifingal agents, isotonic and absorption delaying agents, and the like, compatible with pharmaceutical administration. The use of such media and agents for pharmaceutically active substances is known in the art. Except insofar as any conventional media or agent is incompatible with the active compound, use thereof in the compositions is contemplated. Supplementary active compounds (identified according to the invention and/or known in the art) also can be incorporated into the compositions. The formulations can conveniently be presented in dosage unit form and can be prepared by any of the methods well known in the art of pharmacy/microbiology. In general, some formulations are prepared by bringing the drug into association with a liquid carrier or a finely divided solid carrier or both, and then, if necessary, shaping the product into the desired formulation.

[0078] A pharmaceutical composition of the invention is formulated to be compatible with its intended route of administration. Examples of routes of administration include oral or parenteral, e.g., intravenous, intradermal, inhalation, transdermal (topical), transmucosal, and rectal administration. Solutions or suspensions used for parenteral, intradermal, or subcutaneous application can include the following components: a sterile diluent such as water for injection, saline solution, fixed oils, polyethylene glycols, glycerine, propylene glycol or other synthetic solvents; antibacterial agents such as benzyl alcohol or methyl parabens; antioxidants such as ascorbic acid or sodium bisulfite; chelating agents such as ethylenediaminetetraacetic acid; buffers such as acetates, citrates or phosphates and agents for the adjustment of tonicity such as sodium chloride or dextrose. pH can be adjusted with acids or bases, such as hydrochloric acid or sodium hydroxide.

[0079] Useful solutions for oral or parenteral administration can be prepared by any of the methods well known in the pharmaceutical art, described, for example, in Remington's Pharmaceutical Sciences, (Gennaro, A., ed.), Mack Pub., 1990. Formulations for parenteral administration also can include glycocholate for buccal administration, methoxysalicylate for rectal administration, or cutric acid for vaginal administration. The parenteral preparation can be enclosed in ampoules, disposable syringes or multiple dose vials made of glass or plastic. Suppositories for rectal administration also can be prepared by mixing the drug with a non-irritating excipient such as cocoa butter, other glycerides, or other compositions that are solid at room temperature and liquid at body temperatures. Formulations also can include, for example, polyalkylene glycols such as polyethylene glycol, oils of vegetable origin, hydrogenated naphthalenes, and the like. Formulations for direct administration can include glycerol and other compositions of high viscosity. Other potentially useful parenteral carriers for these drugs include ethylene-vinyl acetate copolymer particles, osmotic pumps, implantable infusion systems, and liposomes. Formulations for inhalation administration can contain as excipients, for example, lactose, or can be aqueous solutions containing, for example, polyoxyethylene-9-lauryl ether, glycocholate and deoxycholate, or oily solutions for administration in the form of nasal drops, or as a gel to be applied intranasally. Retention enemas also can be used for rectal delivery.

[0080] Formulations of the present invention suitable for oral administration can be in the form of discrete units such as capsules, gelatin capsules, sachets, tablets, troches, or lozenges, each containing a predetermined amount of the drug; in the form of a powder or granules; in the form of a solution or a suspension in an aqueous liquid or non-aqueous liquid; or in the form of an oil-in-water emulsion or a water-in-oil emulsion. The drug can also be administered in the form of a bolus, electuary or paste. A tablet can be made by compressing or moulding the drug optionally with one or more accessory ingredients. Compressed tablets can be prepared by compressing, in a suitable machine, the drug in a free-flowing form such as a powder or granules, optionally mixed by a binder, lubricant, inert diluent, surface active or dispersing agent. Moulded tablets can be made by moulding, in a suitable machine, a mixture of the powdered drug and suitable carrier moistened with an inert liquid diluent.

[0081] Oral compositions generally include an inert diluent or an edible carrier. For the purpose of oral therapeutic administration, the active compound can be incorporated with excipients. Oral compositions prepared using a fluid carrier for use as a mouthwash include the compound in the fluid carrier and are applied orally and swished and expectorated or swallowed. Pharmaceutically compatible binding agents, and/or adjuvant materials can be included as part of the composition. The tablets, pills, capsules, troches and the like can contain any of the following ingredients, or compounds of a similar nature: a binder such as microcrystalline cellulose, gum tragacanth or gelatin; an excipient such as starch or lactose; a disintegrating agent such as alginic acid, Primogel, or corn starch; a lubricant such as magnesium stearate or Sterotes; a glidant such as colloidal silicon dioxide; a sweetening agent such as sucrose or saccharin; or a flavoring agent such as peppermint, methyl salicylate, or orange flavoring.

[0082] Pharmaceutical compositions suitable for injectable use include sterile aqueous solutions (where water soluble) or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersion. For intravenous administration, suitable carriers include physiological saline, bacteriostatic water, Cremophor ELTM (BASF, Parsippany, N.J.) or phosphate buffered saline (PBS). In all cases, the composition can be sterile and can be fluid to the extent that easy syringability exists. It can be stable under the conditions of manufacture and storage and can be preserved against the contaminating action of microorganisms such as bacteria and fungi. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyetheylene glycol, and the like), and suitable mixtures thereof. The proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants. Prevention of the action of microorganisms can be achieved by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, ascorbic acid, thimerosal, and the like. In many cases, it will be preferable to include isotonic agents, for example, sugars, polyalcohols such as manitol, sorbitol, and sodium chloride in the composition. Prolonged absorption of the injectable compositions can be brought about by including in the composition an agent which delays absorption, for example, aluminum monostearate and gelatin.

[0083] Sterile injectable solutions can be prepared by incorporating the active compound in the required amount in an appropriate solvent with one or a combination of ingredients enumerated above, as required, followed by filtered sterilization. Generally, dispersions are prepared by incorporating the active compound into a sterile vehicle which contains a basic dispersion medium and the required other ingredients from those enumerated above. In the case of sterile powders for the preparation of sterile injectable solutions, methods of preparation include vacuum drying and freeze-drying which yields a powder of the active ingredient plus any additional desired ingredient from a previously sterile-filtered solution thereof.

[0084] Formulations suitable for intra-articular administration can be in the form of a sterile aqueous preparation of the drug which can be in microcrystalline form, for example, in the form of an aqueous microcrystalline suspension. Liposomal formulations or biodegradable polymer systems can also be used to present the drug for both intra-articular and ophthalmic administration.

[0085] Formulations suitable for topical administration include liquid or semi-liquid preparations such as liniments, lotions, gels, applicants, oil-in-water or water-in-oil emulsions such as creams, ointments or pasts; or solutions or suspensions such as drops. Formulations for topical administration to the skin surface can be prepared by dispersing the drug with a dermatologically acceptable carrier such as a lotion, cream, ointment or soap. In some embodiments, useful are carriers capable of forming a film or layer over the skin to localize application and inhibit removal. Where adhesion to a tissue surface is desired the composition can include the drug dispersed in a fibrinogen-thrombin composition or other bioadhesive. The drug then can be painted, sprayed or otherwise applied to the desired tissue surface. For topical administration to internal tissue surfaces, the agent can be dispersed in a liquid tissue adhesive or other substance known to enhance adsorption to a tissue surface. For example, hydroxypropylcellulose or fibrinogen/thrombin solutions can be used to advantage. Alternatively, tissue-coating solutions, such as pectin-containing formulations can be used.

[0086] For inhalation treatments, inhalation of powder (self-propelling or spray formulations) dispensed with a spray can, a nebulizer, or an atomizer can be used. Such formulations can be in the form of a finely comminuted powder for pulmonary administration from a powder inhalation device or self-propelling powder-dispensing formulations. In the case of self-propelling solution and spray formulations, the effect can be achieved either by choice of a valve having the desired spray characteristics (i.e., being capable of producing a spray having the desired particle size) or by incorporating the active ingredient as a suspended powder in controlled particle size. For administration by inhalation, the compounds also can be delivered in the form of an aerosol spray from a pressured container or dispenser which contains a suitable propellant, e.g., a gas such as carbon dioxide, or a nebulizer. Nasal drops also can be used.

[0087] Systemic administration also can be by transmucosal or transdermal means. For transmucosal or transdermal administration, penetrants appropriate to the barrier to be permeated are used in the formulation. Such penetrants generally are known in the art, and include, for example, for transmucosal administration, detergents, bile salts, and filsidic acid derivatives. Transmucosal administration can be accomplished through the use of nasal sprays or suppositories. For transdermal administration, the active compounds typically are formulated into ointments, salves, gels, or creams as generally known in the art.

[0088] In one embodiment, the active compounds are prepared with carriers that will protect the compound against rapid elimination from the body, such as a controlled release formulation, including implants and microencapsulated delivery systems. Biodegradable, biocompatible polymers can be used, such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, and polylactic acid. Methods for preparation of such formulations will be apparent to those skilled in the art. The materials also can be obtained commercially from Alza Corporation and Nova Pharmaceuticals, Inc. Liposomal suspensions can also be used as pharmaceutically acceptable carriers. These can be prepared according to methods known to those skilled in the art, for example, as described in U.S. Pat. No. 4,522,811. Microsomes and microparticles also can be used.

[0089] Oral or parenteral compositions can be formulated in dosage unit form for ease of administration and uniformity of dosage. Dosage unit form refers to physically discrete units suited as unitary dosages for the subject to be treated; each unit containing a predetermined quantity of active compound calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier. The specification for the dosage unit forms of the invention are dictated by and directly dependent on the unique characteristics of the active compound and the particular therapeutic effect to be achieved, and the limitations inherent in the art of compounding such an active compound for the treatment of individuals.

[0090] Generally, the drugs identified according to the invention can be formulated for parenteral or oral administration to humans or other mammals, for example, in therapeutically effective amounts, e.g., amounts which provide appropriate concentrations of the drug to target tissue for a time sufficient to induce the desired effect. Additionally, the drugs of the present invention can be administered alone or in combination with other molecules known to have a beneficial effect on the particular disease or indication of interest. By way of example only, useful cofactors include symptom-alleviating cofactors, including antiseptics, antibiotics, antiviral and antifungal agents and analgesics and anesthetics.

[0091] Where a peptide, peptidomimetic, small molecule or other drug identified according to the invention is to be used as part of a transplant procedure (e.g. a lung transplant procedure), it can be provided to the living tissue or organ to be transplanted prior to removal of tissue or organ from the donor. The drug can be provided to the donor host.

[0092] Alternatively, or in addition, once removed from the donor, the organ or living tissue can be placed in a preservation solution containing the drug. In all cases, the drug can be administered directly to the desired tissue, as by injection to the tissue, or it can be provided systemically, either by oral or parenteral administration, using any of the methods and formulations described herein and/or known in the art.

[0093] Where the drug comprises part of a tissue or organ preservation solution, any commercially available preservation solution can be used to advantage. For example, useful solutions known in the art include Collins solution, Wisconsin solution, Belzer solution, Eurocollins solution and lactated Ringer's solution. Generally, an organ preservation solution usually possesses one or more of the following properties: (a) an osmotic pressure substantially equal to that of the inside of a mammalian cell (solutions typically are hyperosmolar and have K+ and/or Mg++ ions present in an amount sufficient to produce an osmotic pressure slightly higher than the inside of a mammalian cell); (b) the solution typically is capable of maintaining substantially normal ATP levels in the cells; and (c) the solution usually allows optimum maintenance of glucose metabolism in the cells. Organ preservation solutions also can contain anticoagulants, energy sources such as glucose, fructose and other sugars, metabolites, heavy metal chelators, glycerol and other materials of high viscosity to enhance survival at low temperatures, free oxygen radical inhibiting and/or scavenging agents and a pH indicator. A detailed description of preservation solutions and useful components can be found, for example, in U.S. Pat. No. 5,002,965, the disclosure of which is incorporated herein by reference.

[0094] The effective concentration of the drugs identified according to the invention that is to be delivered in a therapeutic composition will vary depending upon a number of factors, including the final desired dosage of the drug to be administered and the route of administration. The preferred dosage to be administered also is likely to depend on such variables as the type and extent of disease or indication to be treated, the overall health status of the particular patient, the relative biological efficacy of the drug delivered, the formulation of the drug, the presence and types of excipients in the formulation, and the route of administration. In some embodiments, the drugs of this invention can be provided to an individual using typical dose units deduced from the earlier-described mammalian studies using non-human primates and rodents. As described above, a dosage unit refers to a unitary, i.e. a single dose which is capable of being administered to a patient, and which can be readily handled and packed, remaining as a physically and biologically stable unit dose comprising either the drug as such or a mixture of it with solid or liquid pharmaceutical diluents or carriers.

[0095] In certain embodiments, organisms are engineered to produce drugs identified according to the invention. These organisms can release the drug for harvesting or can be introduced directly to a patient. In another series of embodiments, cells can be utilized to serve as a carrier of the drugs identified according to the invention.

[0096] The pharmaceutical compositions can be included in a container, pack, or dispenser together with instructions for administration.

[0097] Drugs identified by a method of the invention also include the prodrug derivatives of the compounds. The term prodrug refers to a pharmacologically inactive (or partially inactive) derivative of a parent drug molecule that requires biotransformation, either spontaneous or enzymatic, within the organism to release the active drug. Prodrugs are variations or derivatives of the compounds of the invention which have groups cleavable under metabolic conditions. Prodrugs become the compounds of the invention which are pharmaceutically active in vivo, when they undergo solvolysis under physiological conditions or undergo enzymatic degradation. Prodrug compounds of this invention can be called single, double, triple, and so on, depending on the number of biotransformation steps required to release the active drug within the organism, and indicating the number of functionalities present in a precursor-type form. Prodrug forms often offer advantages of solubility, tissue compatibility, or delayed release in the mammalian organism (see, Bundgard, Design of Prodrugs, pp. 7-9, 21-24, Elsevier, Amsterdam 1985 and Silverman, The Organic Chemistry of Drug Design and Drug Action, pp. 352-401, Academic Press, San Diego, Calif., 1992). Prodrugs commonly known in the art include acid derivatives known to practitioners of the art, such as, for example, esters prepared by reaction of the parent acids with a suitable alcohol, or amides prepared by reaction of the parent acid compound with an amine, or basic groups reacted to form an acylated base derivative. Moreover, the prodrug derivatives of drugs discovered according to this invention can be combined with other features herein taught to enhance bioavailability.

[0098] Drugs as identified by the methods described herein can be administered to individuals to treat (prophylactically or therapeutically) various stages or subclasses of cancer. In conjunction with such treatment, pharmacogenomics (i.e., the study of the relationship between an individual's genotype and that individual's response to a foreign compound or drug) can be considered. Differences in metabolism of therapeutics can lead to severe toxicity or therapeutic failure by altering the relation between dose and blood concentration of the pharmacologically active drug. Thus, a physician or clinician can consider applying knowledge obtained in relevant pharmacogenomics studies in determining whether to administer a drug as well as tailoring the dosage and/or therapeutic regimen of treatment with the drug.

[0099] Pharmacogenomics deals with clinically significant hereditary variations in the response to drugs due to altered drug disposition and abnormal action in affected persons. See e.g., Eichelbaum, M., Clin Exp Pharmacol Physiol, 1996, 23(10-11):983-985 and Linder, M. W., Clin Chem, 1997, 43(2):254-266. In general, two types of pharmacogenetic conditions can be differentiated. Genetic conditions transmitted as a single factor altering the way drugs act on the body (altered drug action) or genetic conditions transmitted as single factors altering the way the body acts on drugs (altered drug metabolism). These pharmacogenetic conditions can occur either as rare genetic defects or as naturally-occurring polymorphisms. For example, glucose-6-phosphate dehydrogenase deficiency (G6PD) is a common inherited enzymopathy in which the main clinical complication is haemolysis after ingestion of oxidant drugs (anti-malarials, sulfonamides, analgesics, nitroflirans) and consumption of fava beans.

[0100] One pharmacogenomics approach to identifying genes that predict drug response, known as “a genome-wide association,” utilizes a high-resolution map of the human genome consisting of already known gene-related markers (e.g., a “bi-allelic” gene marker map which consists of 60,000-100,000 polymorphic or variable sites on the human genome, each of which has two variants). Such a high-resolution genetic map can be compared to a map of the genome of each of a statistically significant number of patients taking part in a Phase II/III drug trial to identify markers associated with a particular observed drug response or side effect. Alternatively, such a high resolution map can be generated from a combination of some ten-million known single nucleotide polymorphisms (SNPs) in the human genome. A SNP is a common alteration that occurs in a single nucleotide base in a stretch of DNA. For example, a SNP can occur once per every 1000 bases of DNA. A SNP can be involved in a disease process, however, the vast majority can not be disease-associated. Given a genetic map based on the occurrence of such SNPs, individuals can be grouped into genetic categories depending on a particular pattern of SNPs in their individual genome. In such a manner, treatment regimens can be tailored to groups of genetically similar individuals, taking into account traits that can be common among such genetically similar individuals.

[0101] Alternatively, a method termed the “candidate gene approach,” can be utilized to identify genes that predict drug response. According to this method, if a gene that encodes a drug's target is known, all common variants of that gene can be fairly easily identified in the population and it can be determined if having one version of the gene versus another is associated with a particular drug response.

[0102] As an illustrative embodiment, the activity of drug metabolizing enzymes is a major determinant of both the intensity and duration of drug action. The discovery of genetic polymorphisms of drug metabolizing enzymes (e.g., N-acetyltransferase 2 (NAT 2) and cytochrome P450 enzymes CYP2D6 and CYP2C19) has provided an explanation as to why some patients do not obtain the expected drug effects or show exaggerated drug response and serious toxicity after taking the standard and safe dose of a drug. These polymorphisms are expressed in two phenotypes in the population, the extensive metabolizer (EM) and poor metabolizer (PM). The prevalence of PM is different among different populations. For example, the gene coding for CYP2D6 is highly polymorphic and several mutations have been identified in PM, which all lead to the absence of functional CYP2D6. Poor metabolizers of CYP2D6 and CYP2C19 quite frequently experience exaggerated drug response and side effects when they receive standard doses. If a metabolite is the active therapeutic moiety, PM show no therapeutic response, as demonstrated for the analgesic effect of codeine mediated by its CYP2D6-formed metabolite morphine. The other extreme are the so called ultra-rapid metabolizers who do not respond to standard doses. Recently, the molecular basis of ultra-rapid metabolism has been identified to be due to CYP2D6 gene amplification. Alternatively, a method termed the “gene expression profiling,” can be utilized to identify genes that predict drug response. For example, the gene expression of an animal dosed with a drug can give an indication whether gene pathways related to toxicity have been turned on.

[0103] Information generated from more than one of the above pharmacogenomics approaches can be used to determine appropriate dosage and treatment regimens for prophylactic or therapeutic treatment an individual. This knowledge, when applied to dosing or drug selection, can avoid adverse reactions or therapeutic failure and thus enhance therapeutic or prophylactic efficiency when treating a subject with a drug identified according to the invention.

EXAMPLES

Example 1

Materials and Methods

[0104] Specimens and Datasets.

[0105] A total of 203 snap-frozen lung tumors (n=186) and normal lung (n=17) specimens were used to create two datasets. Of these, 125 adenocarcinoma samples were associated with clinical data and with histological slides from adjacent sections.

[0106] The 203 specimens (Dataset A) include histologically-defined lung adenocarcinomas (n=127), squamous cell lung carcinomas (n=21), pulmonary carcinoids (n=20), SCLC (n=6) cases and normal lung (n=17) specimens. Other adenocarcinomas (n=12) were suspected to be extrapulmonary metastases based on clinical history. Dataset B, a subset of Dataset A, includes only adenocarcinomas and normal lung samples.

[0107] Tumor Bank, Clinical Information, and Pathological Analysis

[0108] The complete cohort for these studies consists of 203 patient samples that can be broken down into 139 lung adenocarcinomas (AD) that included 12 suspected metastases of extrapulmonary origin, 21 squamous (SQ) cell carcinoma cases, 20 pulmonary carcinoid (COID) tumors and 6 small cell lung cancers (SCLC), as well as 17 normal lung (NL) samples.

[0109] Tumor and normal lung specimens in this study were obtained from two independent tumor banks. The following specimens were obtained from the Thoracic Oncology Tumor Bank at the Brigham and Women's Hospital/Dana Farber Cancer Institute: 127 adenocarcinomas, 8 squamous cell carcinomas, 4 small cell carcinomas, and 14 pulmonary carcinoid samples. In addition 12 adenocarcinoma samples without associated clinical data were obtained from the Brigham/Dana-Farber tumor bank. In addition, 13 squamous cell carcinoma, 2 small cell lung carcinoma, and 6 carcinoid samples were obtained from the Massachusetts General Hospital (MGH) Tumor Bank. The snap-frozen, anonymized samples from MGH were not associated with histological sections or clinical data.

[0110] Frozen samples of resected lung tumors and parallel “normal” (grossly uninvolved) lung (protocol 91-03831) for anonymous distribution to IRB-approved research projects were obtained within 30 minutes of resection and subdivided into samples (˜100 mg). Samples intended for nucleic acid extraction was snap frozen on powdered dry ice and individually stored at −140° C. Each was associated with an immediately adjacent sample embedded for histology in Optimal Cutting Temperature (OCT) medium and stored at −80° C. Six micron frozen sections of embedded samples stained with H&E was used to confirm the post operative-pathologic diagnosis and to estimate the cellular composition of adjacent extraction samples as discussed below. Each selected sample was further characterized by examining viable tumor cells in H&E stained frozen sections comprising of at least 30% nucleated cells and low levels of tumor necrosis (<40%). In addition, at least once pulmonary pathologists (I and II) independently evaluated adjacent OCT blocks for tumor type and content. Notes were also taken for extent of fibrosis and inflammatory infiltrates.

[0111] Duplicate blocks, coupled with the identical OCT-embedded block, were also available for 36 of the adenocarcinoma samples. The majority of these duplicate blocks were within 1 to 1.5 cm from one another.

[0112] Clinical data from a prospective database and from the hospital records included the age and sex of the patient, smoking history, type of resection, post-operative pathological staging, post-operative histopathological diagnosis, patient survival information, time of last follow-up interval or time of death from the date of resection, disease status at last follow-up or death (when known), and site of disease recurrence (when known). Code numbers were assigned to samples and correlated clinical data. The linkup between the code numbers and all patient identifiers was destroyed, rendering the samples and clinical data completely anonymous.

[0113] 125 adenocarcinoma samples were associated with clinical data. Adenocarcinoma patients included 53 males and 72 females. There were 17 reported non-smokers, 51 patients reporting less than a 40 pack-year smoking history, and 54 patients reported a greater than 40 pack-year smoking history. The post-operative surgical-pathological staging of these samples included 76 stage I tumors, 24 stage II tumors, 10 stage III tumors, and 12 patients with putative metastatic tumors. Note that numbers do not always add to 125, as complete information could not be found for each case.

[0114] RNA extraction and Microarray Experiments

[0115] Briefly, tissue samples were homogenized in Trizol (Life Technologies, Gaithersburg, Md.) and RNA was extracted and purified using the RNEASY column purification kit (QIAGEN, Chatsworth, Calif.). RNA extracted from samples that were collected from two different OCT blocks was given the sample code name followed by the corresponding OCT block name. Denaturing formaldehyde gel electrophoresis followed by northern blotting using a beta-actin probe assessed RNA integrity. Samples were excluded if beta-actin was not full-length.

[0116] Preparation of in vitro transcription (IVT) products and oligonucleotide array hybridization and scanning were performed according to Affymetrix protocol (Santa Clara, Calif.). In brief, the amount of starting total RNA for each IVT reaction varied between 15 and 20 mg. First strand cDNA synthesis was generated using a T7-linked oligo-dT primer, followed by second strand synthesis. IVT reactions were performed in batches to generate cRNA targets containing biotinylated UTP and CTP, which was subsequently chemically fragmented at 95° C. for 35 minutes. Ten micrograms of the fragmented, biotinylated cRNA was mixed with MES buffer (2-[N-Morpholino]ethansulfonic acid) containing 0.5 mg/ml acetylated bovine serum albumin (Sigma, St. Louis, Mo.) and hybridized to Affymetrix (Santa Clara, Calif.) HGU95A v2 arrays at 45° C. for 16 hours. HGU95A v2 arrays contain ˜12600 genes and expressed sequence tags. Arrays were washed and stained with streptavidin-phycoerythrin (SAPE, Molecular Probes). Signal amplification was performed using a biotinylated anti-streptavidin antibody (Vector Laboratories, Burlingame, Calif.) at 3 μg/ml. A second staining with SAPE followed this. Normal goat IgG (2 mg/ml) was used as a blocking agent. Scans on arrays were performed on Affymetrix scanners and the expression value for each gene was calculated using Affymetrix GENECHIP software. Minor differences in microarray intensity were corrected using a scaling method as detailed below.

Example 2

Data Analysis

[0117] Feature Selection and Hierarchical Clustering.

[0118] For Dataset A, a standard deviation threshold of 50 expression units was used to select the 3,312 most variable transcript sequences. For Dataset B, 52 pairs of replicates (representing 36 duplicate adenocarcinomas) were used to determine the quality of the dataset, and 45 pairs having a R2 value >0.9 were used to select 675 transcript sequences (features) whose expression varied the most across all sample pairs (FIGS. 3-5).

[0119] Preprocessing and Re-scaling

[0120] The raw expression data for the first 12600 genes obtained from Affymetrix GENECHIP software was re-scaled to account for different chip intensities. Each column (sample) in the dataset was multiplied by 1/slope of a least squares linear fit of the sample vs. the reference (a sample in the dataset). The linear fit was done using only genes that have ‘Present’ calls in both the sample being re-scaled and the reference. The sample chosen as reference was a typical one (i.e. one with the number of “P” calls closer to the average over all samples in the dataset). The reference sample for the dataset was AD114T1. Scans were rejected if the scaling factor exceeded a factor of 4, fewer than 30% ‘Present’ calls, or microarray artifacts were visible. Scans that failed the above criterion were re-hybridized and re-scanned on new chips from the same fragmented cDNA.

[0121] However, linear scaling was insufficient to correct for non-linear responses that were observed, which may have resulted from saturation effects or IVT-variations from one batch to the other. Thus, a non-linear scaling was applied to adjust for such differences (FIG. 3). The 2% trimmed mean of “P” genes for all arrays after linear and non-linear rank invariant scaling (described below) are shown in box plots stratified by IVT batches. The batch differences in mean intensity may be due to the fact that a more homogenous IVT processing was applied to arrays in the same IVT batch than arrays in different batches. Also noticeable was the non-linear relationships between the scatter-plots of replicate arrays (FIG. 3) and reference RNA samples (FIG. 4), which justifies non-linear scaling methods to make expression values of genes across arrays more reasonable estimates of the actual expression values for transcripts and overall brightness of arrays.

[0122] A rank-invariant scaling method (Tseng, G. C., Oh, M. K., Rohlin, L., Liao, J. C. & Wong, W. H. (2001) Nucleic Acids Res 29, 2549-57) was used to scale all arrays towards a baseline array (AD114T1). A set of genes whose ranks in the two arrays was smaller than 50 (an empirical value chosen to make the points for selected genes naturally form a tight curve, was used to fit a smoothing spline (Venables, W. N. & Ripley, B. D. (1998) Modern applied statistics with S-PLUS (Springer, Berlin)) in the scatter-plot of the array to be normalized (X-axis) and the baseline array (Y-axis). This “Invariant Set” presumably consists of non-differentially expressed genes. The normalized values were determined by reading off the values determined by the smoothing curve for values on X-axis. After scaling the replicate arrays agree better, and batch differences were less dramatic (FIG. 3). Hence, the rank invariant-scaled data was used for all downstream analysis.

[0123] Reproducibility Statistics

[0124] Reproducibility controls included independent frozen tissue blocks for 36 adenocarcinomas resected from the lung, 16 replicates of IVT reactions or scans, and 13 reference RNA samples (Stratagene, La Jolla, Calif.). Scaled expression values for 45 of the 52 replicates compared were correlated with R2>0.9, and for 50 of the 52 replicates with R2>0.85. Examples of pairwise correlations between replicates are shown in FIG. 5.

[0125] Replication Filtering

[0126] According to the invention, technical noise may affect the measurement of some genes more than others, and the already difficult problem of adenocarcinoma sub-classification might be particularly sensitive to such noise. Accordingly, adenocarcinoma replicates were used to select only highly reproducible features (representing genes) for subsequent use in adenocarcinoma clustering. The reproducibility of 52 pairs of replicate arrays randomly selected across the adenocarcinoma samples was assessed. For each pair of replicates, a single measure of correlation (R2) was computed across all 12600 genes (FIG. 5). Forty-five replicate pairs with R2 values greater than 0.9 were used for filtering genes (below).

[0127] For each gene, a scatter plot was generated with the selected 45 pairs of replicate data points. The reproducibility of expression was assessed (Pearson correlation) between replicate pairs as well as the variability of expression values across the 45 pairs. The distribution of 45 pairwise expression datapoints was plotted for genes that were randomly selected. The correlation index of expression (a measure of a gene's variability between samples). To avoid spurious correlation measures 2-4 outliers in each dimension were removed from the calculation of correlation was obtained (cluster Incl W26626:, cor=0.0221; desmoglein 3 (pemphi, cor=0.354; phosphoglucomutase 5, cor=0.311; ATP synthase, H+tra, cor=0.137;Cluster Incl A14316, cor=0.188; Cluster Incl Y12851, cor=0.2631, solute carrier famil, cor=0.429; zinc finger protein, cor=0.179; Cluster Incl AA5866, cor=0.374; Cluster Incl AA5866, cor=0.315; Cluster Incl M34428, cor=0.351; ets variant gene 2, cor=0.187; RecQ protein-like 5, cor=0.366; Cluster Incl AJ0100, cor=0.378; one cut domain, fami, cor=0.396; hexose-6-phosphate d, cor=0.0165; Cluster Incl AL0223, cor=0.376; synovial sarcoma, X, cor=0.371; Cluster Incl S79325, cor=0.502; Cluster Incl Z84717: and cor=0.513). In addition, genes whose expression levels did not vary significantly across the 45 samples were eliminated because they were unlikely to be informative. The number of features (genes) selected by this filter varied depending on the Pearson correlation cut-off used. A clustering of adenocarcinomas was performed using 675 genes selected by a Pearson correlation threshold of 0.8. These genes have consistent expression values between replicate arrays, and their expression across all adenocarcinoma samples was variable. Selection of genes at Pearson correlation coefficients of 0.7 (1514 genes), 0.75 (1105 genes), or 0.85 (366 genes) led to roughly similar clustering. The distribution of 45 pairwise expression datapoints was plotted for selected genes that varied between the 45 adenocarcinoma replicates. The spread of the datapoints results in a correlation index that can be used to select genes that are variant between adenocarcinomas. Gene sets were selected based on their correlation cutoffs (0.7, 0.75, 0.8 and 0.85). To avoid spurious correlation measure 2-4 outliers in each dimension were removed from the calculation of correlation. The expression ranges of genes in samples that pass a replicate correlation greater than 0.85 include glyceraldehyde-3-pho, cor=0.873; glycetaldehyde-3-pho, cor=0.861; trefoil factor 3, cor=0.966; thymosin, beta 10, cor=0.862; ribosomal protein L8, cor=0.867; immunoglobulin kappa, cor=0.854; ribosomal protein S1, cor=0.882; melanoma antigen, fa, cor=0.85; epithelial protein u, cor=0.889; metallothionein IF (cor=0.88; surfactant, pulmonar, cor=0.921; UDP glycosyltransfer, cor=0.931; melanoma antigen, fa, cor=0.938; phospholipase A2, gr, cor=0.888; proline oxidase homo, cor=0.871; melanoma antigen, fa, cor=0.922; ring finger protein, cor 0.91; Cluster Incl AF0151, cor 855; tubulin, alpha, ubiq, cor=0.851, and secretory leukocyte, cor=0.934.

[0128] Hierarchical Clustering

[0129] Hierarchical clustering is an unsupervised learming method useful for dividing data into natural groups. Data are clustered hierarchically by organizing the data into a tree structure based upon the degree of correlation between features. CLUSTER (Eisen, M. B., Spellman, P. T., Brown, P. O. & Botstein, D. (1998) Proc Natl Acad Sci USA 95, 14863-8) was used to perform average linkage clustering of both genes and arrays, using median centering and normalization, and the results were displayed using TREEVIEW (Eisen, M. B., Spellman, P. T., Brown, P. O. & Botstein, D. (1998) Proc Natl Acad Sci USA 95, 14863-8). This organizes all of the data elements into a single tree with the higher levels of the tree representing the discovered classes. A threshold of 0 units was imposed before clustering because the negative values may contribute to artifacts. After this preprocessing, a set of genes was selected for clustering. For Dataset A, a variation filter was used that required a standard deviation greater than or equal to 50 expression units across samples, and 3,312 genes were selected. More stringent variation filters were selected (as few as 900 genes), which produced similar clustering results. For dataset B, 675 genes were selected based on the replicate filtering described above.

[0130] In summary, a hierarchical clustering was performed on two data sets: Dataset A, with 203 samples, and a subset, Dataset B, with 156 samples. Two distinct gene selections were used (3,312 genes selected by standard deviation in FIG. 1 versus 675 genes selected by replication filtering. To compare the results of these analyses, the clusters defined in the adenocarcinomas were mapped onto a tree generated using 3,312 genes. Clusters C2, C3 and C4 of the adenocarcinomas form consistently in both analyses.

[0131] Probabilistic Clustering

[0132] In order to validate the taxonomy obtained by hierarchical clustering, a model-based probabilistic clustering was also used (Cheeseman, P. & Stutz, J. (1996) in Advances in Knowledge Discovery and Data Mining, eds. Fayyad, U. M., Piatetsky-Shapiro, G., Smyth, P. & Uthurasamy, R. (MIT Press, Cambridge), Titterington, D. M., Smith, A. F. & Makov, U. F. (1985) Statistical Analysis of Finite Mixture Distributions (John Wiley, New York)), and the number and composition of clusters obtained by the two methods were compared. The specific program used for probabilistic clustering is AutoClass (Cheeseman, P. & Stutz, J. (1996) in Advances in Knowledge Discovery and Data Mining, eds. Fayyad, U. M., Piatetsky-Shapiro, G., Smyth, P. & Uthurasamy, R. (MIT Press, Cambridge). The method allows for the automatic selection of the number of clusters, and it performs a soft partitioning of the data, whereby each sample can be fractionally assigned to more than one cluster, thus reflecting the inherent uncertainty in the data (in practice, in all experiments samples were assigned to a cluster with probability 1). Probabilistic model-based clustering, usually referred to as finite-mixture models (Titterington, D. M., Smith, A. F. & Makov, U. F. (1985) Statistical Analysis of Finite Mixture Distributions (John Wiley, New York)), is built on the assumption that the observed data can be partitioned into sub-populations (clusters), each governed by a distinct probability distribution. Since a priori the cluster membership is not known, the resulting distribution of the observed data is a mixture of the sub-population distributions. Learning, or inducing, the probabilistic model generating the observed data thus entails determining the number of clusters (model selection), as well as the parameters of the sub-population distributions (parameter estimation). The model selection is based on a Bayesian score that measures the posterior probability of the model given the observed data. Assuming all models are a priori equally likely, this translates into searching for the model that assigns the highest probability to the observed data (i.e which best “explains” the data). It should be emphasized that the Bayesian score incorporates a component that penalizes model complexity (the higher the number of clusters, the higher the complexity of the model), thus automatically controlling for over-fitting. The parameter estimation for this type of modelling is a combinatorial optimization problem for which an exact solution is computationally infeasible. Therefore, an approximate solution needs to be adopted. AutoClass adopts the Expectation-Maximization algorithm (EM), an iterative procedure that, starting from a random initialization of the parameters, incrementally adjusts them in an attempt to find their maximum likelihood estimates (under rather general conditions, the procedure is guaranteed to converge to a local maximum) (Dempster, A. P., Laird, N. M. & Rubin, D. B. (1977) J Royal Stat Soc 39, 398-409, McLachlan, G. J. & Krishnan, T. (1997) The EM Algorithm and Extensions (John Wiley, New York). It is important to point out that because of this random component in the estimation procedure, different runs of the learning algorithms may yield different results (i.e., different parameters—and consequently, different numbers of clusters—may be selected), a variability that is accounted for in the experimental evaluation.

[0133] Experimental Evaluation of Probabilistic Clustering

[0134] A model-based probabilistic clustering was applied to a data set of 156 samples (Dataset B). For the selection of the genes, the replicate filtering method was used as described above. Two feature sets were used, the first including 675 genes (obtained by setting the correlation threshold at 0.8), and the second including 1514 genes (correlation threshold setting of 0.7). The use of different feature sets was aimed at testing for the sensitivity of the clustering procedure to the number of genes included. AutoClass was then applied to the resulting data set. For each feature set, two sets of experiments were run. In the first experiment (Experiment 1), the learning algorithms were run 200 times, with the only difference between successive runs being in the random initialization of the model parameters. The aim of this experiment was to try to account for variability due to the approximate nature of the estimation procedure. In the second experiment (Experiment 2), the learning algorithms were run 200 times on “bootstrapped” data sets, where a bootstrapped data set was obtained by randomly picking, with replacement, 156 samples from the original data set. The bootstrapped data set differs from the original one in that some of the samples may appear in it multiple times, while other samples may be missing altogether. This experiment was aimed at testing for the robustness of the clustering results to random variations in the observed data. FIG. 6 shows the distribution of the number of clusters over multiple runs for the different settings. As expected, the variability in the number of clusters over multiple iterations was higher in Experiment 2 (bootstrapping) than in Experiment 1 (random restart). This was due to the fact that in a bootstrapped data set, it often happens that the same sample is included more than once (on average, over 200 iterations, each bootstrap data set contained about 100 of the 156 samples in the original data set. In other words, on average 56 samples were duplications of samples already included). If a sample was included a sufficient number of times, the clustering algorithm may find it appropriate to define a cluster for that sample only, thus artificially inflating the number of clusters. Despite this variability, it was reassuring to see that this alternative clustering methodology selected a number of clusters mostly varying between 6 and 9, very close to the number of clusters selected by hierarchical clustering.

[0135] A visualization method was used to control for the consistency of the cluster composition over multiple runs, as well as to compare the clusters found by AutoClass with the ones obtained by hierarchical clustering. A colored matrix that is a color-based rendition of a corresponding symmetric matrix whose entries record a normalized measure of how often two samples appear in the same cluster across multiple runs. Rows and columns in this matrix were indexed by the samples in the data set, thus yielding a 156×156 matrix, with each entry taking a real value between 0 and 1. An entry set to 0 (1) indicates that the two samples indexing that entry never (always) appear in the same cluster. More specifically, given two samples, the corresponding entry in the matrix records the quantity Nmatch/Ntotal, where Ntotal is the number of iterations in which both samples are included, and Nmatch denotes the number of iterations in which the two samples are included and are clustered together. That Ntotal is equal to the total number of iterations in Experiment 1, but not in Experiment 2, where it can often happen that a sample is not selected at all in a given iteration.

[0136] Ideally, all entries in the matrix are either 0 or 1, corresponding to the situation where the cluster composition remains unchanged over multiple runs of the algorithm. Furthermore, if the samples are arranged in the matrix in the order produced by hierarchical clustering, a perfect agreement between the two clustering methodologies would translate into a block-diagonal matrix with blocks of 1's along the diagonal—each block corresponding to a different cluster—surrounded by 0's. Two-dimensional matrices were generated corresponding, respectively, to Experiment 1 (200 iterations with random restart on the original data set) and Experiment 2 (200 iterations on bootstrap data sets) for the 675-gene data set. Corresponding two-dimensional matrices were generated for the 1514-gene data set. Blocks corresponding to the candidate clusters are clearly distinguishable along the diagonal in all four of the two-dimensional matrices, thus providing supporting evidence that the selected clusters were unaffected by random variations in the data set.

[0137] K-Nearest Neighbor-based Marker Gene Selection and Supervised Learning

[0138] Following definition of “classes” and their boundaries, a k-NN algorithm was used to choose “marker” genes whose expression best correlated with each class distinction. Class definitions were based on clustering. Marker genes were chosen based on the signal-to-noise statistic (Mclass0−Mclass1)/(class0+class1), where M and represent the mean and standard deviation of expression, respectively, for each class (Golub, T. R., Slonim, D. K., Tamayo, P., Huard, C., Gaasenbeek, M., Mesirov, J. P., Coller, H., Loh, M. L., Downing, J. R., Caligiuri, M. A., et al. (1999) Science 286, 531-7).

[0139] As a further test of the relative robustness of the sample clusters, a supervised classifier was built using the following methodology. Following marker gene selection, a classifier was built and evaluated through leave-one-out cross-validation. For each round of cross-validation, one sample was withheld and the remaining samples were used to build a “k-NN” classifier (see below), from which class membership of the withheld sample was predicted. The top 25 genes selected by signal-to-noise metric for each class are shown in Table 9.

[0140] A weighted implementation of the k-NN algorithm that predicts the class of a new sample by selecting the calculating the Euclidean distance (d) of this sample to the k “nearest neighbor” samples in “expression” space in the training set was used, and the predicted class was selected to be that of the majority of the k samples (Dasarathy, V. B. (1991), (IEEE Computer Society Press, Los Alamitos, Calif.)). A marker gene selection process was performed by feeding the k-NN algorithm only the features with higher correlation with the target class. In this version of the algorithm the weight of each of the k neighbors was weighted according to 1/d.

[0141] The cross-validation step was repeated for each sample and the errors were tallied. A random 8-class classifier would be expected to give an error rate of 100-(100/8), or 87.5%. For the initial validation of clusters, classifiers were built with various numbers of marker genes selected from the 675-gene set that was used for hierarchical clustering. The best model used 100 genes (13% overall error); however, models using 75-200 genes performed with less than 20% overall error.

[0142] For testing whether the cluster definitions were highly dependent on the 675-gene set, classifiers were built from the remaining 11,925 genes. The genes were passed through a variation filter and marker genes were selected as above. A 100-gene model gave an overall error rate of 26%, with the classes that represent clusters performing better than the “other” class.

[0143] Kaplan-Meier Analysis and Permutation Testing.

[0144] Kaplan-Meier curves were generated using standard functions in S-PLUS package (Venables, W. N. & Ripley, B. D. (1998) Modern applied statistics with S-PLUS (Springer, Berlin)). Only 125 adenocarcinoma samples were used with survival information from adenocarcinoma samples. For each cluster, survival within-clusters was compared to the out-of-cluster group using the two-sample comparison based on the corresponding two K-M curves. In this way 5 K-M plots was obtained for each cluster, of which two plots have significant P-values for the comparison of the two curves, namely cluster 2 (C2, P=0.00476) and cluster 4 (C4, P=0.049). A similar analysis performed for stage I patient samples was statistically non-significant for all clusters. The small sample size (n=4) is a possible factor in the non-significance of the result for Stage I C2 patients.

[0145] These apparently significant P-values have a bias because of multiple hypothesis testing. To test for this selection bias, the cluster labels were randomly permuted among the samples and K-M significance, for each cluster, the within-cluster and out-of-cluster K-M curves and the corresponding P-values were re-computed. This randomization was repeated 1000 times. The 1000 sets of P-values were used to construct the null distributions for the test statistic T1=the smallest P-value among 5 clusters. From the 1000 permutations, the P-values for T1=0.044. This P-value is a reasonable assessment of the significance of outcome differences for the cluster C2 (FIG. 1). This statistical evidence supports the predictive value of C2 on survival.

Example 3

Gene Markers for Different Lung Cancers and Adenocarcinoma Sub-Classes

[0146] Expression data were preprocessed by setting a minimal level of 10 units and only genes that showed 5-fold change across the data set were analyzed further. Genes correlated with a particular cluster labels (e.g. “c0” or “colon”) were identified by sorting all of the genes on the array according the signal-to-noise statistic (mu_c0−mu_others)/(sd_c0+sd_others), where mu and sd represent the mean and standard deviation of expression, respectively, for each class.

[0147] Permutation of the column (sample) labels was performed to compare these correlations to what would be expected by chance. The top signal-to-noise scores for top marker genes were compared and compared with the corresponding ones for random permutation version of the cluster labels. 1000 random permutations were used to build histograms for the top marker, the second best, etc. Based on this histogram the 0.1% significance levels were estimated as compared with the values obtained for the real dataset. This test helps to assess the statistical significance of gene markers in terms of target class-correlations.

[0148] Included in the list of genes are those that exceed the 0.1% significance level for each cluster. For those clusters (colon, normal, C4) for which the lists are very long, only the top 200 genes are shown. The following Tables 1-8 present genes for the C1-C4 subclasses, normal, colorectal metastases, C0, and other subclasses. (The s2n_obs is the observed signal to noise value; the non_norm_list is the Affymetrix reference identifier; the LL_num is the LocusLink identifier; and Desc is the description of the gene or gene product.

1TABLE 1C1 MarkersClass C1UNIGENE(as ofDescPermGB/TIGRsummer(unigene/locuslinks2n_obs0.1%non_norm_listIdentifier2001)LL_numor affy)11.291.02436457_atU10860Hs.53988833guaninemonphosphatesynthetase21.250.86540117_atD84557Hs.1554624175minichromosomemaintenancedeficient (mis5, S.pombe) 631.220.79737337_atAI803447Hs.774966637small nuclearribonucleoproteinpolypeptide G41.180.7701055_g_atM87339Hs.351205984replication factor C(activator 1) 4(37 kD)51.180.76741547_atAF047472Hs.403239184BUB3 (buddinguninhibited bybenzimidazoles 3,yeast) homolog61.170.76338840_s_atL10678Hs.917475217profilin 271.120.75738065_atX62534Hs.806843148high-mobilitygroup (nonhistonechromosomal)protein 281.110.754709_atJ00314Hs.3367807280tubulin, betapolypeptide91.10.73941583_atAC004770Hs.47562237flap structure-specificendonuclease 1101.060.73140195_atX14850Hs.1470973014H2A histonefamily, member X111.050.72839109_atAB024704Hs.932922974chromosome 20open reading frame1121.050.727207_atM86752Hs.7561210963stress-induced-phosphoprotein 1(Hsp70/Hsp90-organizing protein)131.050.7221884_s_atM15796Hs.789965111proliferating cellnuclear antigen141.040.71634763_atAF020043Hs.244859126chondroitin sulfateproteoglycan 6(bamacan)151.020.71540619_atM91670Hs.17407027338ubiquitin carrierprotein161.010.7151824_s_atJ05614proliferating cellnuclear antigen(PCNA)171.010.714572_atM86699Hs.1698407272TTK proteinkinase1810.711151_s_atV00599Hs.1796612280V00599/FEATURE = mRNA/DEFINITION = HSTUB2 HumanmRNA fragmentencoding beta-tubulin. (fromclone D-beta-1)1910.7081803_atX05360Hs.184572983cell division cycle2, G1 to S and G2to M200.990.7061515_atHG4074-Rad2HT4344210.980.70434791_atX52882Hs.41126950t-complex 1220.970.70240690_atX54942Hs.837581164CDC28 proteinkinase 2230.960.70040697_atX51688Hs.85137890cyclin A2240.960.69637686_s_atY09008Hs.788537374uracil-DNAglycosylase250.960.693982_atX74795Hs.771714174minichromosomemaintenancedeficient (S.cerevisiae) 5 (celldivision cycle 46)260.950.6921505_atD00596Hs.829627298thymidylatesynthetase270.940.69038992_atX64229Hs.1107137913DEK oncogene(DNA binding)280.940.69033255_atM97856Hs.2438864678nuclearautoantigenicsperm protein(histone-binding)290.940.68836813_atU96131Hs.65669319thyroid hormonereceptor interactor13300.930.68434882_atY12065Hs.29658510528nucleolar protein(KKE/D repeat)310.910.68434715_atU74612Hs.2392305forkhead box M1320.90.683674_g_atJ04031Hs.1726654522methylenetetra-hydrofolatedehydrogenase(NADP+dependent),methenyltetra-hydrofolatecyclohydrolase,formyltetrahydro-folate synmetase330.90.68039337_atM37583Hs.1191923015H2A histonefamily, member Z340.890.67941756_atAJ010842Hs.1825911321XPA bindingprotein 1; putativeATP (GTP)-binding protein350.890.67840417_atD43950chaperonincontaining TCP1,subunit 5 (epsilon)360.890.677571_atM86667Hs.1796624673nucleosomeassembly protein1-like 1370.890.67638804_atAF053641Hs.900731434chromosomesegregation 1(yeast homolog)-like380.880.67537304_atU35451Hs.7725410951chromoboxhomolog 1(Drosophila HP1beta)390.880.67434383_atAB014458Hs.350867398ubiquitin specificprotease 1400.870.6742003_s_atU28946Hs.32482956mutS (E. coli)homolog 6410.870.67340407_atU28386Hs.1595573838karyopherin alpha2 (RAG cohort 1,importin alpha 1)420.870.67240041_atAF017790Hs.5816910403highly expressed incancer, rich inleucine heptadrepeats430.850.66841375_atAJ245416Hs.10310657819U6 snRNA-associated Sm-likeprotein440.850.6661985_s_atX73066Hs.1186384830non-metastaticcells 1, protein(NM23A)expressed in450.850.66436987_atM94362Hs.3347093999lamin B2460.840.6631782_s_atM31303Hs.819153925leukemia-associatedphosphoproteinp18 (stathmin)470.840.65935699_atAF053306Hs.36708701buddinguninhibited bybenzimidazoles 1(yeast homolog),beta480.840.65838414_atU05340Hs.82906991CDC20 (celldivision cycle 20,S. cerevisiae,homolog)490.840.65735218_atAF022385Hs.2886611235programmed celldeath 10500.840.65640726_atU37426Hs.88783832kinesin-like 1510.830.6531136_atL16991Hs.790061841deoxythymidylatekinase(thymidylatekinase)520.830.65236098_atM72709Hs.737376426splicing factor,arginine/serine-rich 1 (splicingfactor 2, alternatesplicing factor)530.830.65038350_f_atAF005392Hs.981027278tubulin, alpha 2540.830.64939374_atAL022325Hs.12255251512hypotheticalprotein FLJ10140550.830.64934314_atX59543Hs.29346240ribonucleotidereductase M1polypeptide560.830.64838473_atM63180Hs.841316897threonyl-tRNAsynthetase570.830.6471945_atM25753Hs.23960891cyclin B1580.830.64637347_atAA926959Hs.7755084722hypotheticalprotein MGC1780590.820.64540587_s_atAF054186Hs.2985819521eukaryotictranslationelongation factor 1epsilon 1600.820.64541342_atD38076Hs.247635902RAN bindingprotein 1610.820.645860_atU03911Hs.789344436mutS (E. coli)homolog 2 (coloncancer,nonpolyposis type1)620.820.64341569 atAI680675Hs.4413123234KIAA0974 protein630.820.64232610_atX93510Hs.796918572LIM domainprotein640.810.63933247_atU86782Hs.1787611021326S proteasome-associated pad1homolog650.810.63832530_atX56468Hs.7440510971tyrosine 3-monooxygenase/tryptophan 5-monooxygenaseactivation protein,theta polypeptide660.810.6381854_atX13293Hs.1797184605v-myb avianmyeloblastosisviral oncogenehomolog-like 2670.810.63737333_atX63692Hs.774621786DNA (cytosine-5-)-methyltransferase1680.80.637318_atD64142Hs.1098048971H1 histone family,member X690.80.636418_atX65550Hs.809764288antigen identifiedby monoclonalantibody Ki-67700.80.63538116_atD14657Hs.818929768KIAA0101 geneproduct710.80.63440638_atX70944Hs.1806106421splicing factorproline/glutaminerich(polypyrimidinetract-bindingprotein-associated)720.80.63336913_atU75679Hs.752577884Hairpin bindingprotein, histone730.790.63136171_atAI521453Hs.7486110923activated RNApolymerase IItranscriptioncofactor 4740.790.63138251_atAI127424Hs.903184632myosin, lightpolypeptide 1,alkali; skeletal, fast750.790.63132214_atAF003938Hs.187929352thioredoxin-like,32 kD760.790.63035312_atD21063Hs.571014171minichromosomemaintenancedeficient (S.cerevisiae) 2(mitotin)770.790.63035995 atAF067656Hs.4265011130ZW10 interactor780.790.62639677_atD80008Hs.362329837KIAA0186 geneproduct790.780.62438031_atD21853Hs.797689775KIAA0111 geneproduct800.780.62434327_atZ46606HLTF gene forhelicase-liketranscription factor/cds = UNKNOWN/gb = Z46606/gi = 575250/ug = Hs.3068/len = 5439810.780.62341322_s_atAI816034Hs.2399055651nucleolar proteinfamily A, member2 (H/ACA smallnucleolar RNPs)820.780.62236941_atU16954Hs.7582310962ALL1 -fused genefrom chromosome1q830.780.62137228_atU01038Hs.775975347polo (Drosophia)-like kinase840.780.620140_s_atU68063Hs.300356434splicing factor,arginine/serine-rich (transformer 2Drosophilahomolog) 10850.770.620149_atU90426Hs.17960610212nuclear RNAhelicase, DECDvariant of DEADbox family860.770.620349_g_atD14678Hs.208303833kinesin-like 2870.770.6191599_atL25876Hs.841131033cyclin-dependentkinase inhibitor 3(CDK2-associateddual specificityphosphatase)880.770.61939056_atX53793Hs.11795010606multifunctionalpolypeptide similarto SAICARsynthetase andAIR carboxylase890.770.61832594_atAF026291Hs.7915010575chaperonincontaining TCP1,subunit 4 (delta)900.770.61837985_atL37747lamin B1910.770.618584_s_atM30938Hs.849817520X-ray repaircomplementingdefective repair inChinese hamstercells 5 (double-strand-breakrejoining; Kuautoantigen, 80 kD)920.770.61834659_atAB018334Hs.232559631nucleoporin 155 kD930.770.61639812_atX79865Hs.1090596182mitochondrialribosomal proteinL12940.770.61541403_atAI032612Hs.1054656636small nuclearribonucleoproteinpolypeptide F950.760.61533252_atD38073Hs.1795654172minichromosomemaintenancedeficient (S.cerevisiae) 3960.760.61437738_g_atD25547Hs.791375110protein-L-isoaspartate (D-aspartate) O-methyltransferase970.760.61435916_s_atAA877215cDNA, 3 end980.750.61332843_s_atM30448casein kinase 2,beta polypeptide990.750.6131674_atM15990Hs.1941487525v-yes-1Yamaguchisarcoma viraloncogene homolog11000.740.61140842_atM60784small nuclearribonucleoproteinpolypeptide A1010.740.61038847_atD79997Hs.1843399833KIAA0175 geneproduct1020.740.60939965_atAI570572Hs.450025881ras-related C3botulinum toxinsubstrate 3 (rhofamily, small GTPbinding proteinRac3)1030.740.609351_f_atD28423pre-mRNAsplicing factorSRp20, 5″UTR1040.730.60736135_atU86602Hs.7440710969nucleolar proteinp40; homolog ofyeast EBNA1-binding protein1050.730.60739076_s_atAI991040Hs.33487910589DR1-associatedprotein 1 (negativecofactor 2 alpha)1060.730.60634878_atAB019987Hs.5075810051SMC4 (structuralmaintenance ofchromosomes 4,yeast)-like 11070.730.60441855_atAF030424Hs.133408520histoneacetyltransferase 11080.730.60438792_atAD001528Hs.897186611spermine synthase1090.720.60238123_atD14878Hs.820438872D123 gene product1100.720.60240145_atAI375913Hs.1563467153topoisomerase(DNA) II alpha(170 kD)1110.720.60139262_atU79266Hs.2364229901protein predictedby clone 236271120.720.60036107_atAA845575Hs.73851522ATP synthase, H+transporting,mitochondrial F0complex, subunitF61130.720.59937305_atU61145Hs.772562146enhancer of zeste(Drosophila)homolog 21140.720.59934380_atAC004472Hs.343930968stomatin-like 21150.720.599276_atL08069Hs.943301heat shock protein,DNAJ-like 21160.720.59934795_atU84573Hs.412705352procollagen-lysine,2-oxoglutarate 5-dioxygenase(lysinehydroxylase) 21170.710.59939969_atAA255502Hs.464238364H4 histone family,member G1180.710.59932844_atAF104913Hs.2115681981eukaryotictranslationinitiation factor 4gamma, 11190.710.59941407_atL03411Hs.1060617936RD RNA-bindingprotein1200.710.59839759_atAL031781Hs.150209444homolog of mousequaking QKI (KHdomain RNAbinding protein)1210.710.59835364_atU50939Hs.618288883amyloid betaprecursor protein-binding protein 1,59 kD1220.710.59836812_atU92715Hs.65648412breast cancer anti-estrogen resistance31230.710.59836837_atU63743Hs.6936011004kinesin-like 6(mitoticcentromere-associated kinesin)1240.710.597471_f_atU47634Hs.15915410381tubulin, beta, 41250.710.59740879_atAB014599Hs.33098823299KIAA0699 protein1260.710.596947_atD55716Hs.771524176minichromosomemaintenancedeficient (S.cerevisiae) 71270.710.595157_atU65011Hs.3074323532preferentiallyexpressed antigenin melanoma1280.70.59335200_atX92518Hs.27268091high-mobilitygroup (nonhistonechromosomal)protein isoform I-C1290.70.59232194_atM37197Hs.18476010153CCAAT-box-bindingtranscription factor1300.70.59239173_atX56597Hs.998532091fibrillarin1310.70.5901840_g_atHG1112-Ras-Like ProteinHT1112Tc41320.70.58837739_atM86737Hs.791626749structure specificrecognition protein11330.70.58734510_atAF070552Hs.12290881620DNA replicationfactor1340.70.58536536_atAF070614Hs.6149029970schwannomininteracting protein11350.70.58336863_atAF032862Hs.725503161hyaluronan-mediated motilityreceptor(RHAMM)1360.690.58334790_atS70154Hs.27854439acetyl-CoenzymeA acetyltransferase2 (acetoacetylCoenzyme Athiolase)1370.690.583527_atU14518Hs.15941058centromere proteinA (17 kD)1380.690.58138679_g_atAA733050Hs.10666635small nuclearribonucleoproteinpolypeptide E1390.690.58139984_g_atU73704Hs.4910511146FKBP-associatedprotein1400.680.58140610_atAI743507Hs.17351851663likely ortholog ofmouse zinc fingerprotein Zfr1410.680.58139792_atAF000364Hs.1526510236heterogeneousnuclearribonucleoproteinR1420.680.57933266_atAF015254Hs.1806559212serine/threoninekinase 121430.680.57831858_atX07315Hs.15173410204nuclear transportfactor 2 (placentalprotein 15)1440.680.57832340_s_atM85234Hs.744974904nuclease sensitiveelement bindingprotein 11450.680.57734099_f_atW26056Hs.343569cDNA1460.680.577831_atU28042Hs.417061662DEAD/H (Asp-Glu-Ala-Asp/His)box polypeptide 10(RNA helicase)1470.680.57637945_atU91316Hs.867911332cytosolic acylcoenzyme Athioester hydrolase1480.680.57633035_atAL021397Hs.13757626514ribosomal proteinL34 pseudogene 11490.680.57532120_atAF063308Hs.1624410615mitotic spindlecoiled-coil relatedprotein1500.680.57536104_atAA526497Hs.738187388ubiquinol-cytochrome creductase hingeprotein1510.670.57532548_atL24804Hs.27827010728unactiveprogesteronereceptor, 23 kD1520.670.57436872_atAL120559Hs.735110776cyclic AMPphosphoprotein, 19kD1530.670.57338634_atM11433Hs.1018505947retinol-bindingprotein 1, cellular1540.670.57337683_atD80012Hs.788299100ubiquitin specificprotease 101550.670.57333127_atU89942Hs.833544017lysyl oxidase-like21560.670.57241401_atU57646Hs.105261466cysteine andglycine-richprotein 21570.670.57240074_atX16396Hs.15467210797methylenetetrahydrofolatedehydrogenase(NAD+dependent),methenyltetra-hydrofolatecyclohydrolase1580.660.57241600_atU59435Hs.51815036proliferation-associated 2G4,38 kD1590.660.5711449_atD00763Hs.2515315685proteasome(prosome,macropain)subunit, alphatype, 41600.660.57037046_atAI246726Hs.769135686proteasome(prosome,macropain)subunit, alphatype, 51610.660.57034814_atAL041443Hs.431110054SUMO-1activating enzymesubunit 21620.660.57032615_atJ05032Hs.807581615aspartyl-tRNAsynthetase1630.660.56939086_g_atAA768912Hs.9236742single-strandedDNA-bindingprotein 11640.650.56939747_atU52427Hs.148395436polymerase (RNA)II (DNA directed)polypeptide G1650.650.56839009_atN98670cDNA, 5 end1660.650.56840124_atY18418Hs.2728228607RuvB (E colihomolog)-like 11670.650.56832730_atAL080059Hs.17309485453Homo sapiensmRNA forKIAA1750protein, partial cds1680.640.56738662_atAL047596Hs.30611723152KIAA0306 protein1690.640.56733679_f_atX02344Hs.25165310383tubulin, beta, 21700.640.56737302_atU30872Hs.772041063centromere proteinF (350/400 kD,mitosin)1710.640.56639704_s_atL17131Hs.1398003159high-mobilitygroup (nonhistonechromosomal)protein isoforms Iand Y1720.640.565131_atX83928Hs.831266882TATA box bindingprotein (TBP)-associated factor,RNA polymeraseII, I, 28 kD1730.640.56540779_atU59919Hs.17137422920smg GDS-ASSOCIATEDPROTEIN1740.640.56438114_atD38551Hs.818485885RAD21 (S.pombe) homolog1750.640.56432850_atZ25535Hs.2116089972nucleoporin 153 kD1760.640.5641250_atU47077Hs.1556375591protein kinase,DNA-activated,catalyticpolypeptide1770.640.56437345_atAF013759Hs.7753813calumenin1780.640.56337293_atD43948Hs.769899793KIAA0097 geneproduct1790.640.56340418_atX74262Hs.160035928retinoblastoma-binding protein 41800.640.56238158_atD79987Hs.1534799700extra spindle poles,S. cerevisiae,homolog of1810.640.562910_atM15205Hs.1050977083thymidine kinase1, soluble1820.640.56235314_atD63880Hs.57199918chromosomecondensation-related SMC-associated protein11830.640.56141601_atAA142964Hs.643116868a disintegrin andmetalloproteinasedomain 17 (tumornecrosis factor,alpha, convertingenzyme)1840.630.56141824_atAI140114Hs.615351096CGI-48 protein1850.630.56036184_atL06419Hs.750935351procollagen-lysine,2-oxoglutarate 5-dioxygenase(lysinehydroxylase,Ehlers-Danlossyndrome type VI)1860.630.56041133_atU32519Hs.22068910146Ras-GTPase-activating proteinSH3-domain-binding protein1870.630.55935694_atAB014587Hs.36289448mitogen-activatedprotein kinasekinase kinasekinase 41880.630.55939070_atU03057Hs.1184006624singed(Drosophila)-like(sea urchin fascinhomolog like)1890.630.5591801_atU76638Hs.54089580BRCA1 associatedRING domain 11900.630.55738405_atU25165Hs.827128087fragile X mentalretardation,autosomalhomolog 11910.630.55738684_atAJ010953Hs.10677827032ATPase, Ca++transporting, type2C, member 11920.630.55431832_atAB006624Hs.1491223306KIAA0286 protein1930.630.554410_s_atX57152Hs.1658431460casein kinase 2,beta polypeptide1940.620.55439060_atD38048Hs.1180655695proteasome(prosome,macropain)subunit, beta type,71950.620.55340412_atAA203476Hs.2525879232pituitary tumor-transforming 11960.620.55237729_atY08614Hs.790907514exportin 1 (CRM1,yeast, homolog)1970.620.55238863_atL07540Hs.1710755985replication factor C(activator 1) 5(36.5 kD)1980.620.55137726_atX06323Hs.7908611222mitochondrialribosomal proteinL31990.620.55141003_atU41816Hs.911615203prefoldin 42000.620.550592_atM34079Hs.2507585702proteasome(prosome,macropain) 26Ssubunit, ATPase, 3According to the invention, preferred markers are markers 1-30, preferably 1-20, and more preferably 1-10.

[0149]

2

TABLE 2

C2 Markers

Class C2

UNIGENE

(as of

Desc

Perm

GB/TIGR
summer

(unigene/locuslink

s2n_obs
0.1%
non_norm_list
Identifier
2001)
LL_num
or affy)

1
1.46
0.781
40035_at
AB012917
Hs.57771
11012
kallikrein 11

2
1.27
0.736
40544_g_at
L08424
Hs.1619
429
achaete-scute

complex

(Drosophila)

homolog-like 1

3
1.27
0.721
36606_at
X51405
Hs.75360
1363
carboxypeptidase

E

4
1.21
0.715
31477_at
L08044
Hs.82961
7033
trefoil factor 3

(intestinal)

5
1.18
0.708
36299_at
X02330

calcitonin/

calcitonin-

related

polypeptide,

alpha

6
1.17
0.699
40649_at
X64810
Hs.78977
5122
proprotein

convertase

subtilisin/kexin

type 1

7
1.16
0.684
442_at
X15187
Hs.82689
7184
tumor rejection

antigen (gp96) 1

8
1.05
0.660
36300_at
X15943
Hs.37058
796
calcitonin/

calcitonin-

related

polypeptide,

alpha

9
1.02
0.658
39332_at
AF035316
Hs.336780
7280
tubulin, beta

polypeptide

10
0.97
0.651
39756_g_at
Z93930
Hs.149923
7494
X-box binding

protein 1

11
0.96
0.647
39135_at
AB018310
Hs.95180
23151
KIAA0767

protein

12
0.95
0.645
34785_at
AB028948
Hs.4084
23389
KIAA1025

protein

13
0.92
0.644
37617_at
U90912
Hs.81897
54462
KIAA1128

protein

14
0.85
0.630
1788_s_at
U48807
Hs.2359
1846
dual specificity

phosphatase 4

15
0.85
0.630
37928_at
AA621555
Hs.84928
4801
nuclear

transcription

factor Y, beta

16
0.84
0.625
37141_at
U39840
Hs.299867
3169
hepatocyte

nuclear factor 3,

alpha

17
0.84
0.623
35995 at
AF067656
Hs.42650
11130
ZW10 interactor

18
0.83
0.622
40201_at
M76180
Hs.150403
1644
dopa

decarboxylase

(aromatic L-

amino acid

decarboxylase)

19
0.82
0.620
35800_at
D63391
Hs.6793
5050
platelet-

activating factor

acetylhydrolase,

isoform Ib,

gamma subunit

(29 kD)

20
0.8
0.618
33543_s_at
U77718
Hs.44499
5411
pinin,

desmosome

associated

protein

21
0.8
0.615
1822_at
HG4677-

Oncogene

HT5102

Ret/Ptc2, Fusion

Activated

22
0.79
0.613
35343_at
M37400
Hs.597
2805
glutamic-

oxaloacetic

transaminase 1,

soluble

(aspartate

aminotransferase

1)

23
0.78
0.610
41403_at
AI032612
Hs.105465
6636
small nuclear

ribonucleoprotein

polypeptide F

24
0.78
0.606
37426_at
U80736
Hs.110826
27324
trinucleotide

repeat

containing 9

25
0.77
0.605
39113_at
AI262789
Hs.93659
9601
protein disulfide

isomerase

related protein

(calcium-

binding protein,

intestinal-

related)

26
0.77
0.604
40881_at
X64330
Hs.174140
47
ATP citrate

lyase

27
0.77
0.603
32137_at
AF029778
Hs.166154
3714
jagged 2

28
0.77
0.600
34690_at
U66616
Hs.236030
6601
SWI/SNF

related, matrix

associated, actin

dependent

regulator of

chromatin,

subfamily c,

member 2

29
0.77
0.599
41395_at
AB003791
Hs.104576
8534
carbohydrate

(keratan sulfate

Gal-6)

sulfotransferase

1

30
0.76
0.599
39891_at
AI246730
Hs.126901

cDNA, 3 end

31
0.76
0.598
41250_at
U24169
Hs.301613
7965
JTV1 gene

32
0.76
0.598
37545_at
W22110
Hs.7934
9314
Kruppel-like

factor 4 (gut)

33
0.75
0.597
41146_at
J03473
Hs.177766
142
ADP-

ribosyltransferase

(NAD+; poly

(ADP-ribose)

polymerase)

34
0.74
0.597
40865_at
U51166
Hs.173824
6996
thymine-DNA

glycosylase

35
0.74
0.597
35147_at
AB002360
Hs.25515
23263
MCF.2 cell line

derived

transforming

sequence-like

36
0.74
0.591
36847_r_at
AA121509
Hs.70830
51690
U6 snRNA-

associated Sm-

like protein

LSm7

37
0.73
0.588
37293_at
D43948
Hs.76989
9793
KIAA0097 gene

product

38
0.73
0.587
36482_s_at
Y15724
Hs.5541
489
ATPase, Ca++

transporting,

ubiquitous

39
0.72
0.586
38654_at
X65488
Hs.103804
3192
heterogeneous

nuclear

ribonucleoprotein

U (scaffold

attachment

factor A)

40
0.72
0.583
37359_at
D14658
Hs.77665
9789
KIAA0102 gene

product

41
0.72
0.582
37638_at
D50857
Hs.82295
1793
dedicator of

cyto-kinesis 1

42
0.72
0.582
39824_at
AI391564
Hs.110820

cDNA, 3 end

43
0.71
0.580
37019_at
J00129
Hs.7645
2244
fibrinogen, B

beta polypeptide

44
0.71
0.578
40074_at
X16396
Hs.154672
10797
methylene

tetrahydrofolate

dehydrogenase

(NAD+

dependent),

methenyltetra-

hydrofolate

cyclohydrolase

45
0.71
0.576
40584_at
Y08612
Hs.172108
4927
nucleoporin

88 kD

46
0.7
0.576
33266_at
AF015254
Hs.180655
9212
serine/threonine

kinase 12

47
0.69
0.575
36008_at
AF041434
Hs.43666
11156
protein tyrosine

phosphatase

type IVA,

member 3

48
0.69
0.574
37333_at
X63692
Hs.77462
1786
DNA (cytosine-

5-)-

methyltransferase

1

49
0.69
0.574
1660_at
D83004
Hs.75355
7334
ubiquitin-

conjugating

enzyme E2N

(homologous to

yeast UBC13)

50
0.69
0.573
36149_at
D78014
Hs.74566
1809
dihydro-

pyrimidinase-

like 3

51
0.68
0.573
39692_at
AL080209
Hs.13659
64764
hypothetical

protein

DKFZp586F2423

52
0.68
0.570
40317_at
U57352
Hs.6517
40
amiloride-

sensitive cation

channel 1,

neuronal

(degenerin)

53
0.67
0.568
31906_at
AF068754
Hs.250899
3281
heat shock

factor binding

protein 1

54
0.67
0.567
149_at
U90426
Hs.179606
10212
nuclear RNA

helicase, DECD

variant of

DEAD box

family

55
0.67
0.567
38978_at
AF013758
Hs.109643
10605
polyadenylate

binding protein-

interacting

protein 1

56
0.67
0.565
35566_f_at
AF015128
Hs.301365

IgG heavy chain

variable region

(Vh26)

57
0.66
0.564
36745_at
AF035308
Hs.167036

clone 23798 and

23825

58
0.66
0.563
36133_at
AL031058
Hs.74316
1832
desmoplakin

(DPI, DPII)

59
0.66
0.563
35966_at
X71125
Hs.79033
25797
glutaminyl-

peptide

cyclotransferase

(glutaminyl

cyclase)

60
0.66
0.562
37955_at
AB015631
Hs.8752
10330
transmembrane

protein 4

61
0.65
0.562
40846_g_at
U10324
Hs.256583
3609
interleukin

enhancer

binding factor 3,

90 kD

62
0.65
0.560
37101_at
AL050008
Hs.306186
25855
DKFZP564A063

protein

63
0.65
0.559
40580_r_at
M24398
Hs.171814
5763
parathymosin

64
0.65
0.559
36489_at
D00860
Hs.56
5631
phosphoribosyl

pyrophosphate

synthetase 1

65
0.65
0.558
37133_at
AF027406
Hs.104865
26576
serine/threonine

kinase 23

66
0.64
0.557
33714_at
Y10043
Hs.19114
3149
high-mobility

group

(nonhistone

chromosomal)

protein 4

67
0.64
0.557
35351_at
U89505
Hs.6106
5936
RNA binding

motif protein 4

68
0.64
0.557
41829_at
AB018274
Hs.6214
23367
KIAA0731

protein

69
0.64
0.555
39158_at
AB021663
Hs.9754
22809
activating

transcription

factor 5

70
0.64
0.555
35163_at
AB028964
Hs.26023
22887
KIAA1041

protein

71
0.64
0.555
36406_at
AA401397
Hs.165296
26085
kallikrein 13

72
0.63
0.554
32149_at
AA532495
Hs.183752
4477
microsemino-

protein, beta-

73
0.63
0.554
32825_at
Y10805
Hs.20521
3276
HMT1 (hnRNP

methyltransferase,

S. cerevisiae
)-

like 2

74
0.63
0.553
35590_s_at
X81832

gastric

inhibitory

polypeptide

receptor

75
0.63
0.553
36636_at
M12267
Hs.75485
4942
ornithine

aminotransferase

(gyrate

atrophy)

76
0.63
0.553
37944_at
U19523
Hs.86724
2643
GTP

cyclohydrolase

1 (dopa-

responsive

dystonia)

77
0.63
0.552
41083_at
AC006276
Hs.99093

chromosome 19,

cosmid R28379

78
0.62
0.550
39317_at
D86324
Hs.24697
8418
cytidine

monophosphate-

N-

acetylneuraminic

acid

hydroxylase

(CMP-N-

acetylneuraminate

monooxygenase)

79
0.62
0.550
33162_at
X02160
Hs.89695
3643
insulin receptor

80
0.62
0.549
31586_f_at
X72475
Hs.156110
3514
immunoglobulin

kappa constant

81
0.62
0.549
34289_f_at
D50920
Hs.23106
9862
KIAA0130 gene

product

82
0.62
0.549
36615_at
M83751
Hs.75412
7873
Arginine-rich

protein

83
0.62
0.546
904_s_at
L47276

(cell line HL-

60) alpha

topoisomerase

truncated-form

mRNA, 3 UTR

84
0.62
0.545
39791_at
M23114
Hs.1526
488
ATPase, Ca++

transporting,

cardiac muscle,

slow twitch 2

85
0.62
0.544
36203_at
X16277
Hs.75212
4953
ornithine

decarboxylase 1

86
0.61
0.544
1582_at
M29540
Hs.220529
1048
carcinoembryonic

antigen-

related cell

adhesion

molecule 5

87
0.61
0.544
38456_s_at
AL049650
Hs.83753
6628
small nuclear

ribonucleoprotein

polypeptides

B and B1

88
0.61
0.544
39610_at
X16665
Hs.2733
3212
homeo box B2

89
0.61
0.544
37272_at
X57206
Hs.78877
3707
inositol 1,4,5-

trisphosphate 3-

kinase B

90
0.61
0.544
36185_at
D32050
Hs.75102
16
alanyl-tRNA

synthetase

91
0.61
0.544
38435_at
U25182
Hs.83383
10549
thioredoxin

peroxidase

(antioxidant

enzyme)

92
0.6
0.544
32447_at
U76388
Hs.157037
2516
nuclear receptor

subfamily 5,

group A,

member 1

93
0.6
0.544
38753_at
AF039022
Hs.85951
11260
exportin, tRNA

(nuclear export

receptor for

tRNAs)

94
0.6
0.543
38248_at
AB011124
Hs.90232
9762
KIAA0552 gene

product

95
0.6
0.543
38719_at
U03985
Hs.108802
4905
N-

ethylmaleimide-

sensitive factor

96
0.6
0.543
34105_f_at
AI147237
Hs.300697
3502
immunoglobulin

heavy constant

gamma 3 (G3m

marker)

97
0.6
0.543
40840_at
M80254
Hs.173125
10105
peptidylprolyl

isomerase F

(cyclophilin F)

98
0.6
0.542
1745_at
HG4679-

Oncogene

HT5104

Ret/Ptc, Fusion

Activated

99
0.59
0.542
1884_s_at
M15796
Hs.78996
5111
proliferating

cell nuclear

antigen

100
0.59
0.542
31935_s_at
U75968
Hs.27424
1663
DEAD/H (Asp-

Glu-Ala-

Asp/His) box

polypeptide 11

(S. cerevisiae

CHL1-like

helicase)

101
0.59
0.542
34933_at
AJ238381
Hs.132576
5083
paired box gene

9

102
0.59
0.542
33304_at
U88964
Hs.183487
3669
interferon

stimulated gene

(20 kD)

103
0.59
0.542
38340_at
AB014555
Hs.96731
9026
huntingtin

interacting

protein- 1-

related

104
0.58
0.542
1796_s_at
U05681

B-cell

CLL/lymphoma

3

105
0.58
0.542
34726_at
U07139
Hs.250712
784
calcium

channel,

voltage-

dependent, beta

3 subunit

106
0.58
0.541
35253_at
AB011143
Hs.30687
9846
GRB2-

associated

binding protein

2

107
0.58
0.541
35151_at
AF089814
Hs.25664
10263
tumor

suppressor

deleted in oral

cancer-related 1

108
0.58
0.541
38635_at
Z69043
Hs.102135
6748
signal sequence

receptor, delta

(translocon-

associated

protein delta)

109
0.58
0.541
39040_at
W28360
Hs.184325
51632
CGI-76 protein

110
0.57
0.541
38860_at
U66346
Hs.189
5143
phosphodiesterase

4C, cAMP-

specific (dunce

(Drosophila)-

homolog

phosphodiesterase

E1)

111
0.57
0.541
1432_s_at
D16105
Hs.210
4058
leukocyte

tyrosine kinase

112
0.57
0.541
36851_g_at
U42360

Putative

prostate cancer

tumor

suppressor

113
0.57
0.540
37985_at
L37747

lamin B1

114
0.57
0.540
38708_at
AF054183
Hs.10842
5901
RAN, member

RAS oncogene

family

115
0.57
0.540
32404_at
AF065314
Hs.234785
1261
cyclic

nucleotide gated

channel alpha 3

116
0.57
0.540
36970_at
D80004
Hs.75909
23199
KIAA0182

protein

117
0.57
0.540
32646_at
AB007918
Hs.169182
23046
KIAA0449

protein

118
0.57
0.539
32485_at
X00371
Hs.118836
4151
myoglobin

119
0.57
0.538
37774_at
AI819942
Hs.90998
23157
septin 2

120
0.57
0.538
36153_at
L13848
Hs.74578
1660
DEAD/H (Asp-

Glu-Ala-

Asp/His) box

polypeptide 9

(RNA helicase

A, nuclear DNA

helicase II;

leukophysin)

121
0.57
0.538
288_s_at
L25931
Hs.152931
3930
lamin B

receptor

122
0.56
0.538
33347_at
AA883868
Hs.216354
6048
ring finger

protein 5

123
0.56
0.538
33399_at
AA142942
Hs.241507
6194
ribosomal

protein S6

124
0.56
0.538
1888_s_at
X06182
Hs.81665
3815
v-kit Hardy-

Zuckerman 4

feline sarcoma

viral oncogene

homolog

125
0.56
0.538
1846_at
L78132
Hs.4082
3964
prostate

carcinoma

tumor antigen

(pcta-1)/lectin

126
0.56
0.537
34338_at
D49738
Hs.31053
1155
cytoskeleton-

associated

protein 1

127
0.56
0.537
41241_at
D84273
Hs.181311
4677
asparaginyl-

tRNA

synthetase

128
0.56
0.536
35670_at
M37457

ATPase,

Na+/K+

transporting,

alpha 3

polypeptide

129
0.56
0.536
41399_at
AB029034
Hs.285641
23133
KIAA1111

protein

130
0.55
0.536
36676_at
AL031659
Hs.75722
6185
growth hormone

releasing

hormone

131
0.55
0.536
39927_at
U17032
Hs.267831
394
Rho GTPase

activating

protein 5

132
0.55
0.536
1257_s_at
L42379
Hs.77266
5768
quiescin Q6

133
0.55
0.535
37576_at
U52969
Hs.80296
5121
Purkinje cell

protein 4

134
0.55
0.535
34987_s_at
X79536
Hs.249495
3178
heterogeneous

nuclear

ribonucleoprotein

A1

135
0.55
0.535
1798_at
U41060
Hs.79136
25800
LIV-1 protein,

estrogen

regulated

136
0.55
0.535
40674_s_at
S82986
Hs.820
3223
homeo box C6

137
0.55
0.535
39342_at
X94754
Hs.279946
4141
methionine-

tRNA

synthetase

138
0.55
0.535
38707_r_at
S75174
Hs.108371
1874
E2F

transcription

factor 4,

p107/p130-

binding

139
0.55
0.535
34648_at
Z12830
Hs.250773
6745
signal sequence

receptor, alpha

(translocon-

associated

protein alpha)

140
0.54
0.535
40653_at
U32439
Hs.79348
6000
regulator of G-

protein

signalling 7

141
0.54
0.534
34827_at
AF045458
Hs.47061
8408
unc-51 (C.

elegans
)-like

kinase 1

142
0.54
0.534
36178_at
U23143
Hs.75069
6472
serine

hydroxymethyl-

transferase 2

(mitochondrial)

143
0.54
0.534
34264_at
AB026894
Hs.226499
23623
nesca protein

144
0.54
0.534
41750_at
D49489
Hs.182429
10130
protein disulfide

isomerase-

related protein

145
0.54
0.534
36971_at
D87446
Hs.75912
23505
KIAA0257

protein

146
0.54
0.534
38399_at
AL034428
Hs.82575
6629
small nuclear

ribonucleoprotein

polypeptide

B″

147
0.54
0.534
32190_at
AL050118
Hs.184641
9415
fatty acid

desaturase 2

148
0.54
0.534
38835_at
U94831
Hs.91586
10548
transmembrane

9 superfamily

member 1

149
0.54
0.533
37316_r_at
AI057607
Hs.7731
55837
uncharacterized

bone marrow

protein BM036

The C2 class is a robust class of markers. According to the invention, preferred markers are markers 1-30, preferably 1-20, and more preferably 1-10. Highly preferred markers are kallikrein 11, achaete-scute complex (Drosophila) homolog-like 1, carboxypeptidase E, trefoil factor 3 (intestinal), calcitonin/calcitonin-related polypeptide alpha, proprotein convertase, dual specificity phosphatase 4, and dopa decarboxylase.

[0150]

3

TABLE 3

C3 Markers

Class C3

UNIGENE

(as of

Desc

s2n_o
Perm

GB/TIGR
summer

(unigene/locuslink

bs
0.1%
non_norm_list
Identifier
2001)
LL_num
or affy)

1
1.42
0.866
37669_s_at
U16799
Hs.78629
481
ATPase, Na+/K+

transporting, beta 1

polypeptide

2
1.2
0.724
36066_at
AB020635
Hs.4984
23382
KIAA0828 protein

3
1.17
0.707
33699_at
M18667

progastricsin

(pepsinogen C)

4
1.06
0.706
1081_at
M33764
Hs.75212
4953
ornithine

decarboxylase 1

5
1.06
0.688
33396_at
U12472
Hs.226795
2950
glutathione S-

transferase pi

6
1.06
0.679
34319_at
AA131149
Hs.2962
6286
S100 calcium-

binding protein P

7
1.02
0.674
40409_at
U46689
Hs.159608
224
aldehyde

dehydrogenase 10

(fatty aldehyde

dehydrogenase)

8
1.02
0.673
32805_at
U05861

aldo-keto reductase

family 1, member

C1 (dihydrodiol

dehydrogenase 1;

20-alpha (3-alpha)-

hydroxysteroid

dehydrogenase)

9
0.99
0.667
33383_f_at
AI820718
Hs.250505
5914
retinoic acid

receptor, alpha

10
0.98
0.663
35207_at
X76180
Hs.2794
6337
sodium channel,

nonvoltage-gated 1

alpha

11
0.98
0.655
33052_at
U95301
Hs.144442
8399
phospholipase A2,

group X

12
0.98
0.649
38526_at
U02882
Hs.172081
5144
phosphodiesterase

4D, cAMP-specific

(dunce

(Drosophila)-

homolog

phosphodiesterase

E3)

13
0.97
0.646
38066_at
M81600

diaphorase

(NADH/NADPH)

(cytochrome b-5

reductase)

14
0.93
0.644
1882_g_at
HG4058-

Oncogene Aml1-

HT4328

Evi-1, Fusion

Activated

15
0.93
0.643
37779_at
Y08134
Hs.123659
27293
acid

sphingomyelinase-

like

phosphodiesterase

16
0.92
0.641
38773_at
AB003151
Hs.88778
873
carbonyl reductase

1

17
0.9
0.639
700_s_at
HG371-

Mucin 1,

HT26388

Epithelial, Alt.

Splice 9

18
0.89
0.639
37004_at
J02761
Hs.76305
6439
surfactant,

pulmonary-

associated protein B

19
0.88
0.639
38986_at
Z49835
Hs.289101
2923
glucose regulated

protein, 58 kD

20
0.88
0.638
40685_at
U10868
Hs.83155
221
aldehyde

dehydrogenase 7

21
0.87
0.636
35938_at
M72393
Hs.211587
5321
phospholipase A2,

group IV A

(cytosolic, calcium-

dependent)

22
0.87
0.632
41267_at
AB028972
Hs.227835
22980
KIAA1049 protein

23
0.86
0.628
34839_at
AB029027
Hs.279039
22910
KIAA1104 protein

24
0.85
0.627
38784_g_at
J05581
Hs.89603
4582
mucin 1,

transmembrane

25
0.83
0.627
33439_at
D15050
Hs.232068
6935
transcription factor

8 (represses

interleukin 2

expression)

26
0.82
0.627
38429_at
U29344
Hs.83190
2194
fatty acid synthase

27
0.82
0.626
39248_at
N74607
Hs.234642
360
aquaporin 3

28
0.8
0.625
1563_s_at
M58286
Hs.159
7132
tumor necrosis

factor receptor

superfamily,

member 1A

29
0.8
0.623
39260_at
U59185
Hs.23590
9122
solute carrier family

16 (monocarboxylic

acid transporters),

member 4

30
0.79
0.623
38801_at
AI742846
Hs.9006
9218
VAMP (vesicle-

associated

membrane protein)-

associated protein A

(33 kD)

31
0.79
0.622
37311_at
AF010400

transaldolase 1

32
0.78
0.622
36200_at
X69838
Hs.75196
10919
ankyrin repeat-

containing protein

33
0.78
0.620
36938_at
U70063
Hs.75811
427
N-acylsphingosine

amidohydrolase

(acid ceramidase)

34
0.77
0.618
41051_at
X95073
Hs.96247
7257
translin-associated

factor X

35
0.77
0.618
32072_at
U40434
Hs.155981
10232
mesothelin

36
0.76
0.618
41402_at
AL080121
Hs.105460
25849
DKFZP564O0823

protein

37
0.76
0.617
39392_at
AJ002190
Hs.12482
8443
glyceronephosphate

O-acyltransferase

38
0.75
0.617
1346_at
S72043
Hs.73133
4504
metallothionein 3

(growth inhibitory

factor

(neurotrophic))

39
0.74
0.617
34798_at
Z35491
Hs.41714
573
BCL2-associated

athanogene

40
0.72
0.616
35151_at
AF089814
Hs.25664
10263
tumor suppressor

deleted in oral

cancer-related 1

41
0.72
0.616
41772_at
M68840
Hs.183109
4128
monoamine oxidase

A

42
0.72
0.613
40223_r_at
AI677689
Hs.296406
9701
KIAA0685 gene

product

43
0.71
0.612
37399_at
D17793
Hs.78183
8644
aldo-keto reductase

family 1, member

C3 (3-alpha

hydroxysteroid

dehydrogenase,

type II)

44
0.71
0.611
37748_at
D86985
Hs.79276
9778
KIAA0232 gene

product

45
0.7
0.610
39689_at
AI362017
Hs.135084
1471
cystatin C (amyloid

angiopathy and

cerebral

hemorrhage)

46
0.7
0.610
38827_at
AF038451
Hs.91011
10551
anterior gradient 2

(Xenepus laevis)

homolog

47
0.7
0.609
36945_at
X94910
Hs.75841
10961
endoplasmic

reticulum lumenal

protein

48
0.7
0.608
1662_r_at
HG2261-

Antigen, Prostate

HT2351

Specific, Alt. Splice

Form 2

49
0.69
0.608
38482_at
AJ011497
Hs.278562
1366
claudin 7

50
0.68
0.606
33325_at
W26667
Hs.184581

cDNA

51
0.68
0.606
35311_at
AF084523
Hs.5710
8804
cellular repressor of

E1A-stimulated

genes

52
0.67
0.604
38063_at
U00952
Hs.8068
57326
hematopoietic

PBX-interacting

protein

53
0.67
0.604
33863_at
U65785
Hs.277704
10525
oxygen regulated

protein (150 kD)

54
0.66
0.604
38790_at
L25879
Hs.89649
2052
epoxide hydrolase

1, microsomal

(xenobiotic)

55
0.66
0.602
35214_at
AF061016
Hs.28309
7358
UDP-glucose

dehydrogenase

56
0.66
0.602
37279_at
U10550
Hs.79022
2669
GTP-binding

protein

overexpressed in

skeletal muscle

57
0.65
0.602
37639_at
X07732
Hs.823
3249
hepsin

(transmembrane

protease, serine 1)

58
0.64
0.602
33730_at
AF095448
Hs.194691
9052
retinoic acid

induced 3

59
0.64
0.602
37003_at
X62654
Hs.76294
967
CD63 antigen

(melanoma 1

antigen)

60
0.64
0.601
36959_at
U49278
Hs.75875
7335
ubiquitin-

conjugating enzyme

E2 variant 1

61
0.64
0.601
36488_at
AB011542
Hs.5599
1955
EGF-like-domain,

multiple 5

62
0.64
0.601
37552_at
U33632
Hs.79351
3775
potassium channel,

subfamily K,

member 1 (TWIK-

1)

63
0.64
0.601
36540_at
AB018260
Hs.62113
23221
KIAA0717 protein

64
0.63
0.600
40031_at
M74542
Hs.575
218
aldehyde

dehydrogenase 3

65
0.63
0.599
34485_r_at
M21868
Hs.118249
10564
brefeldin A-

inhibited guanine

nucleotide-

exchange protein 2

66
0.63
0.599
206_at
M84424

cathepsin E

67
0.63
0.599
38376_at
L46590
Hs.82208
37
acyl-Coenzyme A

dehydrogenase,

very long chain

68
0.63
0.599
36644_at
D29963
Hs.75564
977
CD151 antigen

69
0.63
0.599
36963_at
U30255
Hs.75888
5226
phosphogluconate

dehydrogenase

70
0.62
0.599
271_s_at
J05036
Hs.1355
1510
cathepsin E

71
0.62
0.599
36647_at
AA526812
Hs.262823
55699
hypothetical protein

FLJ10326

72
0.62
0.599
32081_at
AB023166
Hs.15767
11113
citron (rho-

interacting,

serine/threonine

kinase 21)

73
0.62
0.598
691_g_at
J02783
Hs.75655
5034
procollagen-proline,

2-oxoglutarate 4-

dioxygenase

(proline 4-

hydroxylase), beta

polypeptide (protein

disulfide isomerase;

thyroid hormone

binding protein

p55)

74
0.62
0.598
34835_at
D87442
Hs.4788
23385
nicastrin

75
0.62
0.598
38642_at
Y10183
Hs.10247
214
activated leucocyte

cell adhesion

molecule

76
0.62
0.598
32892_at
X85106
Hs.301664
6196
ribosomal protein

S6 kinase, 90 kD,

polypeptide 2

77
0.62
0.597
1826_at
M12174
Hs.204354
388
ras homolog gene

family, member B

78
0.61
0.597
38816_at
AF095791
Hs.272023
10579
transforming, acidic

coiled-coil

containing protein 2

79
0.61
0.597
39379_at
AL049397
Hs.12314

clone

DKFZp586C1019

80
0.61
0.595
38385_at
S65738
Hs.82306
11034
destrin (actin

depolymerizing

factor)

81
0.61
0.595
39698_at
U51712
Hs.13775
84525
hypothetical protein

SMAP31

82
0.61
0.595
36151_at
U60644
Hs.74573
23646
similar to vaccinia

virus HindIII K4L

ORF

83
0.61
0.595
32747_at
X05409
Hs.195432
217
aldehyde

dehydrogenase 2,

mitochondrial

84
0.6
0.594
39512_s_at
AA457029
Hs.342682

clone RP11-

127K18

According to the invention, preferred markers are markers 1-30, preferably 1-20, and more preferably 1-10.

[0151]

4

TABLE 4

C4 Markers

Class C4

UNIGENE

(as of

Desc

Perm

GB/TIGR
summer

(unigene/locuslink or

s2n_obs
0.1%
non_norm_list
Identifier
2001)
LL_num
affy)

1
1.07
0.786
1411_at
D16154

cytochrome P-450c11

2
1.04
0.704
37021_at
X16832
Hs.288181
1512
cathepsin H

3
1.02
0.701
534_s_at
U20391
Hs.73769
2348
folate receptor 1

(adult)

4
0.95
0.655
38394_at
D42047
Hs.82432
23171
KIAA0089 protein

5
0.94
0.653
1460_g_at
M68941
Hs.73826
5775
protein tyrosine

phosphatase, non-

receptor type 4

(megakaryocyte)

6
0.92
0.650
33331_at
U17077
Hs.185055
7851
BENE protein

7
0.91
0.648
38336_at
AB023230
Hs.96427
23150
KIAA1013 protein

8
0.89
0.647
31883_at
AF025794
Hs.153792
4552
5-

methyltetrahydro-

folate-homocysteine

methyltransferase

reductase

9
0.88
0.641
35016_at
M13560

Ia-associated

invariant gamma-

chain gene

10
0.87
0.635
1629_s_at
HG3187-

Tyrosine

HT3366

Phosphatase 1, Non-

Receptor, Alt. Splice

3

11
0.87
0.632
37512_at
U89281
Hs.11958
8630
oxidative 3 alpha

hydroxysteroid

dehydrogenase;

retinol

dehydrogenase; 3-

hydroxysteroid

epimerase

12
0.86
0.631
38459_g_at
L39945

cytochrome b-5

13
0.86
0.631
36965_at
U13616
Hs.75893
288
ankyrin 3, node of

Ranvier (ankyrin G)

14
0.85
0.630
593_s_at
M34353
Hs.1041
6098
v-ros avian UR2

sarcoma virus

oncogene homolog 1

15
0.85
0.615
821_s_at
U78793

folate receptor 1

(adult)

16
0.84
0.611
130_s_at
X82850
Hs.197764
7080
thyroid transcription

factor 1

17
0.83
0.610
33278_at
AC004381
Hs.181345
6296
SA (rat hypertension-

associated) homolog

18
0.82
0.608
33967_at
M31525
Hs.342656
3111
major

histocompatibility

complex, class II, DN

alpha

19
0.82
0.605
35792_at
U67963
Hs.6721
11343
lysophospholipase-

like

20
0.81
0.599
33584_at
U35146
Hs.158512
8999
cyclin-dependent

kinase-like 2 (CDC2-

related kinase)

21
0.8
0.598
38785_at
X52228
Hs.89603
4582
mucin 1,

transmembrane

22
0.8
0.597
34198_at
U12128
Hs.211595
5783
protein tyrosine

phosphatase, non-

receptor type 13

(APO-1/CD95 (Fas)-

associated

phosphatase)

23
0.8
0.595
33249_at
M16801
Hs.1790
4306
nuclear receptor

subfamily 3, group C,

member 2

24
0.79
0.592
40310_at
AF051152
Hs.63668
7097
toll-like receptor 2

25
0.79
0.587
37189_at
AL023553
Hs.75835
5372
phosphomannomutase

1

26
0.79
0.587
37038_at
X83467
Hs.76781
5825
ATP-binding cassette,

sub-family D (ALD),

member 3

27
0.77
0.583
37218_at
D64110
Hs.77311
10950
BTG family, member

3

28
0.77
0.582
34823_at
X60708
Hs.44926
1803
dipeptidylpeptidase

IV (CD26, adenosine

deaminase

complexing protein 2)

29
0.77
0.579
715_s_at
D87002
Hs.284380
2678
similar to rat integral

membrane

glycoprotein

POM121

30
0.77
0.578
38984_at
AB007896
Hs.110
9581
putative L-type

neutral amino acid

transporter

31
0.77
0.577
38627_at
M95585
Hs.250692
3131
hepatic leukemia

factor

32
0.77
0.576
39419_at
AB011088
Hs.129872
9043
sperm associated

antigen 9

33
0.76
0.575
34760_at
D14664
Hs.2441
9936
KIAA0022 gene

product

34
0.76
0.572
554_at
U03634
Hs.301946
3928
lymphoid blast crisis

oncogene

35
0.76
0.571
34996_at
U75329
Hs.318545
7113
transmembrane

protease, serine 2

36
0.75
0.570
35232_f_at
AI056696
Hs.29463
1070
centrin, EF-hand

protein, 3 (CDC31

yeast homolog)

37
0.75
0.570
37886_at
AB015332
Hs.96200
26993
neighbor of A-kinase

anchoring protein 95

38
0.74
0.570
36252_at
U43030
Hs.25537
1489
cardiotrophin 1

39
0.74
0.569
1709_g_at
U07620
Hs.151051
5602
mitogen-activated

protein kinase 10

40
0.73
0.568
35221_at
X91648
Hs.29117
5813
purine-rich element

binding protein A

41
0.73
0.568
33933_at
X63187
Hs.2719
10406
epididymis-specific,

whey-acidic protein

type, four-disulfide

core; putative ovarian

carcinoma marker

42
0.73
0.567
33561_at
X80031
Hs.530
1285
collagen, type IV,

alpha 3 (Goodpasture

antigen)

43
0.73
0.566
41809_at
AI656421
Hs.322404
79161
hypothetical protein

MGC4175

44
0.73
0.566
36511_at
AB020658
Hs.5867
22908
KIAA0851 protein

45
0.73
0.565
41109_at
M31452
Hs.1012
722
complement

component 4-binding

protein, alpha

46
0.72
0.562
32893_s_at
M30474
Hs.289098
2679
gamma-

glutamyltransferase 2

47
0.72
0.561
39345_at
AI525834
Hs.119529
10577
Niemann-Pick

disease, type C2 gene

48
0.72
0.559
39115_at
AL050275
Hs.9383
25982
DKFZP566D213

protein

49
0.72
0.558
40508_at
AF025887
Hs.169907
2941
glutathione S-

transferase A4

50
0.71
0.557
1137_at
L20852
Hs.10018
6575
solute carrier family

20 (phosphate

transporter), member

2

51
0.71
0.557
40101_g_at
U72206
Hs.337774
9181
rho/rac guanine

nucleotide exchange

factor (GEF) 2

52
0.7
0.556
711_at
HG2339-

Nuclear Factor 1,

HT2435

Variant Hepatic

53
0.7
0.555
40834_at
AB002298
Hs.173035
23037
KIAA0300 protein

54
0.7
0.554
41302_at
R59606
Hs.4113
10768
S-

adenosylhomocysteine

hydrolase-like 1

55
0.69
0.552
1922_g_at
HG2510-

Ras-Specific Guanine

HT2606

Nucleotide-Releasing

Factor

56
0.69
0.552
37579_at
L47738
Hs.258503
26999
p53 inducible protein

57
0.69
0.551
32902_at
U28281
Hs.2199
6344
secretin receptor

58
0.69
0.548
704_at
HG4167-

Nuclear Factor 1, A

HT4437

Type

59
0.69
0.547
37676_at
AF056490
Hs.78746
5151
phosphodiesterase 8A

60
0.69
0.547
33621_at
X71348

transcription factor 2,

hepatic; LF-B3;

variant hepatic

nuclear factor

61
0.69
0.547
38252_s_at
U84007
Hs.904
178
amylo-1,6-

glucosidase, 4-alpha-

glucanotransferase

(glycogen

debranching enzyme,

glycogen storage

disease type III)

62
0.68
0.544
34213_at
AB020676
Hs.21543
23286
KIAA0869 protein

63
0.68
0.544
37405_at
U29091
Hs.334841
8991
selenium binding

protein 1

64
0.68
0.543
34767_at
AI670788
Hs.24719
64112
modulator of

apoptosis 1

65
0.68
0.542
35955_at
S80864
Hs.262219
25835
cytochrome c-like

antigen

66
0.68
0.541
38790_at
L25879
Hs.89649
2052
epoxide hydrolase 1,

microsomal

(xenobiotic)

67
0.68
0.540
36508_at
AF030186
Hs.58367
2239
glypican 4

68
0.68
0.540
33942_s_at
AF004563
Hs.239356
6812
syntaxin binding

protein 1

69
0.67
0.540
37629_at
M55268
Hs.82201
1459
casein kinase 2, alpha

prime polypeptide

70
0.67
0.539
32822_at
J02966
Hs.2043
291
solute carrier family

25 (mitochondrial

carrier; adenine

nucleotide

translocator), member

4

71
0.67
0.538
35472_at
Y10745
Hs.17287
3772
potassium inwardly-

rectifying channel,

subfamily J, member

15

72
0.67
0.537
34163_g_at
D84111
Hs.80248
11030
RNA-binding protein

gene with multiple

splicing

73
0.67
0.536
31925_s_at
L26584
Hs.169350
5923
Ras protein-specific

guanine nucleotide-

releasing factor 1

74
0.67
0.536
32854_at
AB014596
Hs.21229
23291
f-box and WD-40

domain protein 1B

75
0.67
0.535
35645_at
AL050148
Hs.31834

clone

DKFZp586G1520

76
0.66
0.535
1986_at
X74594
Hs.79362
5934
retinoblastoma-like 2

(p130)

77
0.66
0.533
1938_at
K03218

v-src avian sarcoma

(Schmidt-Ruppin A-

2) viral oncogene

homolog

78
0.66
0.532
1616_at
D14838
Hs.111
2254
fibroblast growth

factor 9 (glia-

activating factor)

79
0.66
0.532
41440_at
D82061
Hs.288354
7923
FabG (beta-ketoacyl-

[acyl-carrier-protein]

reductase, E coli) like

80
0.66
0.530
41129_at
D26067
Hs.174905
23027
KIAA0033 protein

81
0.66
0.530
40209_at
U72671
Hs.151250
7087
intercellular adhesion

molecule 5,

telencephalin

82
0.65
0.529
32676_at
M93405
Hs.293970
4329
methylmalonate-

semialdehyde

dehydrogenase

83
0.65
0.528
36557_at
M92303
Hs.635
782
calcium channel,

voltage-dependent,

beta 1 subunit

84
0.65
0.528
35228_at
Y08682
Hs.29331
1375
carnitine

palmitoyltransferase

I, muscle

85
0.65
0.527
1667_s_at
J02871
Hs.687
1580
cytochrome P450,

subfamily IVB,

polypeptide 1

86
0.65
0.526
40701_at
U75362
Hs.85482
8975
ubiquitin specific

protease 13

(isopeptidase T-3)

87
0.65
0.525
40343_at
AJ005814
Hs.70954
3204
homeo box A7

88
0.65
0.524
39301_at
X85030
Hs.40300
825
calpain 3, (p94)

89
0.65
0.524
35435_s_at
AF001903
Hs.8110
3033
L-3-hydroxyacyl-

Coenzyme A

dehydrogenase, short

chain

90
0.64
0.523
34235_at
AB018301
Hs.22039
23282
KIAA0758 protein

91
0.64
0.523
37344_at
X62744
Hs.77522
3108
major

histocompatibility

complex, class II, DM

alpha

92
0.64
0.522
41120_at
D14686

aminomethyltransferase

(glycine cleavage

system protein T)

93
0.64
0.522
40673_at
U12778
Hs.81934
36
acyl-Coenzyme A

dehydrogenase,

short/branched chain

94
0.63
0.521
34353_at
AB014548
Hs.31921
23244
KIAA0648 protein

95
0.63
0.520
35285_at
AF007216
Hs.5462
8671
solute carrier family

4, sodium bicarbonate

cotransporter,

member 4

96
0.63
0.520
40822_at
L41067
Hs.172674
4775
nuclear factor of

activated T-cells,

cytoplasmic,

calcineurin-dependent

3

97
0.63
0.519
41331_at
R93981
Hs.24279
9860
KIAA0806 gene

product

98
0.63
0.519
40278_at
AB029003
Hs.155546
23062
KIAA1080 protein;

Golgi-associated,

gamma-adaptin ear

containing, ARF-

binding protein 2

99
0.63
0.519
36828_at
AB002324
Hs.301094
23361
KIAA0326 protein

100
0.63
0.519
40128_at
D79993
Hs.132853
9685
KIAA0171 gene

product

101
0.63
0.519
35382_at
AF043244
Hs.278439
8996
nucleolar protein 3

(apoptosis repressor

with CARD domain)

102
0.63
0.518
40217_s_at
U65887
Hs.152981
1040
CDP-diacylglycerol

synthase

(phosphatidate

cytidylyltransferase)

1

103
0.63
0.518
38095_i_at
M83664
Hs.814
3115
major

histocompatibility

complex, class II, DP

beta 1

104
0.62
0.518
34555_at
X63755
Hs.2743
3846
keratin, cuticle,

ultrahigh sulphur 1

105
0.62
0.517
33263_at
X67098

rTS beta protein

106
0.62
0.517
33267_at
AF035315
Hs.180737

clone 23664 and

23905

107
0.62
0.517
1594_at
J05448
Hs.79402
5432
polymerase (RNA) II

(DNA directed)

polypeptide C (33 kD)

108
0.62
0.516
40013_at
Y12696
Hs.54570
1193
chloride intracellular

channel 2

109
0.62
0.516
32122_at
L31573
Hs.16340
6821
sulfite oxidase

110
0.62
0.515
34800_at
AL039458
Hs.4193
26018
ortholog of mouse

integral membrane

glycoprotein LIG-1

111
0.62
0.515
41723_s_at
M32578
Hs.180255
3123
major

histocompatibility

complex, class II, DR

beta 1

112
0.62
0.515
38683_s_at
AB029008
Hs.301226
57450
KIAA1085 protein

113
0.62
0.514
32235_at
AB011116
Hs.284251
23295
KIAA0544 protein

114
0.62
0.514
41689_at
R16035
Hs.12701
51090
plasmolipin

115
0.62
0.514
38318_at
AL050128
Hs.95260
51439
Autosomal Highly

Conserved Protein

116
0.61
0.513
1619_g_at
D21241

cytochrome P-450

aromatase

117
0.61
0.513
39266_at
AF070632
Hs.23729

clone 24405

118
0.61
0.513
40711_at
AL049340
Hs.86405

clone

DKFZp564P056

119
0.61
0.512
39247_at
U66689
Hs.274260
368
ATP-binding cassette,

sub-family C

(CFTR/MRP),

member 6

120
0.61
0.512
39820_at
AF001549
Hs.110103
54700
RNA polymerase I

transcription factor

RRN3

121
0.61
0.511
39974_at
AF039917
Hs.47042
956
ectonucleoside

triphosphate

diphosphohydrolase 3

122
0.61
0.511
37704_at
Z14093
Hs.78950
593
branched chain keto

acid dehydrogenase

E1, alpha polypeptide

(maple syrup urine

disease)

123
0.61
0.510
34521_at
AB001872
Hs.21291
9175
mitogen-activated

protein kinase kinase

kinase 13

124
0.6
0.509
38072_at
AL031432
Hs.8084
57035
hypothetical protein

dJ465N24.2.1

125
0.6
0.509
40149_at
AL049924
Hs.15744
25970
SH2-B homolog

126
0.6
0.509
39138_g_at
X80878
Hs.95262
4798
nuclear factor related

to kappa B binding

protein

127
0.6
0.508
38064_at
X79882
Hs.80680
9961
major vault protein

128
0.6
0.508
34473_at
AF051151
Hs.114408
7100
toll-like receptor 5

129
0.6
0.508
36755_s_at
M75914
Hs.68876
3568
Interleukin 5 receptor,

alpha

130
0.6
0.507
41686_s_at
AL042668
Hs.337629

cDNA, 5 end

131
0.6
0.507
41424_at
L48516
Hs.296259
5446
paraoxonase 3

132
0.6
0.507
903_at
L42373
Hs.155079
5525
protein phosphatase

2, regulatory subunit

B (B56), alpha

isoform

133
0.6
0.506
35408_i_at
X16281
Hs.278480
7595
zinc finger protein 44

(KOX 7)

134
0.59
0.506
1270_at
M64788
Hs.75151
5909
RAP1, GTPase

activating protein 1

135
0.59
0.506
1087_at
M60459
Hs.89548
2057
erythropoietin

receptor

136
0.59
0.505
33290_at
M74161
Hs.182577
3633
inositol

polyphosphate-5-

phosphatase, 75 kD

137
0.59
0.505
39408_at
Z80345
Hs.127610
35
acyl-Coenzyme A

dehydrogenase, C-2

to C-3 short chain

138
0.59
0.505
40766_at
U24578
Hs.278625
721
complement

component 4B

139
0.59
0.505
39612_at
AL050061
Hs.27371

clone DKFZp566J123

140
0.59
0.504
38850_at
M11119
Hs.272951

endogenous retrovirus

envelope region

mRNA (PL1)

141
0.59
0.504
34529 at
W26760
Hs.336635

cDNA

142
0.59
0.504
40394_at
L17128
Hs.77719
2677
gamma-glutamyl

carboxylase

143
0.59
0.503
37811_at
AF042792
Hs.127436
9254
calcium channel,

voltage-dependent,

alpha 2/delta subunit

2

144
0.58
0.503
37150_at
AB026190
Hs.106290
27252
Kelch motif

containing protein

145
0.58
0.503
41346_at
AJ007583
Hs.25220
9215
like-

glycosyltransferase

146
0.58
0.502
37609_at
U01833
Hs.81469
4682
nucleotide binding

protein 1 (E. coli

MinD like)

147
0.58
0.502
35988_i_at
AI417075
Hs.42343
84148
hypothetical protein

FLJ14040

148
0.58
0.501
32427_at
U66583
Hs.72911
1421
crystallin, gamma D

149
0.58
0.501
37151_at
AF052120
Hs.106334

clone 23836

150
0.58
0.501
37172_at
M75106
Hs.75572
1361
carboxypeptidase B2

(plasma)

151
0.58
0.500
35815_at
AL049470
Hs.306184
25767
Huntingtin interacting

protein B

152
0.58
0.499
37722_s_at
U26266
Hs.79064
1725
deoxyhypusine

synthase

153
0.58
0.499
40600_at
AW024467
Hs.172847
3338
DnaJ (Hsp40)

homolog, subfamily

C, member 4

154
0.57
0.499
38086_at
AB007935
Hs.81234
3321
immunoglobulin

superfamily, member

3

155
0.57
0.499
38285_at
AF039397

crystallin, mu

156
0.57
0.499
41381_at
AB002306
Hs.10351
23337
KIAA0308 protein

157
0.57
0.498
34716_at
AF067730
Hs.3530
63902
TLS-associated

serine-arginine

protein 2

158
0.57
0.498
38492_at
D55639
Hs.169139
8942
kynureninase (L-

kynurenine

hydrolase)

159
0.57
0.497
39438_at
AF039081
Hs.13313
1389
cAMP responsive

element binding

protein-like 2

160
0.57
0.497
36997_at
J04809
Hs.76240
203
adenylate kinase 1

161
0.57
0.497
32076_at
D83407
Hs.156007
10231
Down syndrome

critical region gene 1-

like 1

162
0.57
0.497
32185_at
U00946
Hs.184592
65125
protein kinase, lysine

deficient 1

163
0.57
0.496
36538_at
AB018314
Hs.6162
23368
KIAA0771 protein

164
0.56
0.496
41339_at
AF043117
Hs.24594
10277
ubiquitination factor

E4B (homologous to

yeast UFD2)

165
0.56
0.495
32144_at
AL050135
Hs.166891
5993
regulatory factor X, 5

(influences HLA

class II expression)

166
0.56
0.495
37402_at
D26129
Hs.78224
6035
ribonuclease, RNase

A family, 1

(pancreatic)

167
0.56
0.494
700_s_at
HG371-

Mucin 1, Epithelial,

HT26388

Alt. Splice 9

168
0.56
0.494
33521_at
M63962
Hs.36992
495
ATPase, H+/K+

exchanging, alpha

polypeptide

169
0.56
0.494
34934_at
L29376
Hs.132807

(clone 3.8-1) MHC

class I

170
0.56
0.494
41018_at
AL050015
Hs.92700
25864
DKFZP564O243

protein

171
0.56
0.493
37539_at
AB023176
Hs.79219
23179
RalGDS-like gene;

KIAA0959 protein

172
0.56
0.493
36626_at
X87176
Hs.75441
3295
hydroxysteroid (17-

beta) dehydrogenase

4

173
0.56
0.493
36012_at
Y09631
Hs.43913
10464
PIBF1 gene product

174
0.56
0.493
41491_s_at
AB028944
Hs.29189
23250
ATPase, Class VI,

type 11A

175
0.56
0.493
32746_at
AF015451
Hs.195175
8837
CASP8 and FADD-

like apoptosis

regulator

176
0.56
0.492
40833_r_at
AL050126
Hs.234265
26092
DKFZP586G011

protein

177
0.56
0.492
34256_at
AB018356
Hs.225939
8869
sialyltransferase 9

(CMP-

NeuAc: lactosyl-

ceramide alpha-2,3-

sialyltransferase;

GM3 synthase)

178
0.56
0.491
AFFX-
L38424

B subtilis dapB, jojF,

DapX-M_at

jojG genes

corresponding to

nucleotides 1358-

3197 of L38424

(−5, −M,

−3 represent

transcript regions 5

prime, Middle, and 3

prime respectively)

179
0.55
0.491
40547_at
AI688516
Hs.163867
4695
NADH

dehydrogenase

(ubiquinone) 1 alpha

subcomplex, 2 (8 kD,

B8)

180
0.55
0.491
41488_at
AC002394
Hs.144852

hypothetical protein

A-211C6.1

181
0.55
0.491
41501_at
AF004849
Hs.30148
10114
homeodomain-

interacting protein

kinase 3

182
0.55
0.490
35287_at
AF046888
Hs.54673
8741
tumor necrosis factor

(ligand) superfamily,

member 13

183
0.55
0.490
33284_at
M19507
Hs.1817
4353
myeloperoxidase

184
0.55
0.490
40152_r_at
Z48054
Hs.158084
5830
peroxisome receptor

1

185
0.55
0.490
34001_at
AF033199
Hs.8198
7754
zinc finger protein

204

186
0.55
0.489
1527_s_at
U50527
Hs.22174

BRCA2 region

187
0.55
0.489
34141_at
AL109681
Hs.226017

clone EUROIMAGE

112333

188
0.55
0.489
34116_at
AF038852
Hs.21903
785
calcium channel,

voltage-dependent,

beta 4 subunit

189
0.55
0.488
36806_at
X83877
Hs.289104
11256
Alu-binding protein

with zinc finger

domain

190
0.55
0.488
39557_at
AI625844
Hs.295963

cDNA, 3 end

191
0.55
0.487
40595_at
AI345337
Hs.301266
6949
Treacher Collins-

Franceschetti

syndrome 1

192
0.55
0.487
39993_at
D11466
Hs.51
5277
phosphatidylinositol

glycan, class A

(paroxysmal

nocturnal

hemoglobinuria)

193
0.55
0.487
39947_at
AJ006352
Hs.42331
1945
ephrin-A4

194
0.55
0.487
785_at
U96114
Hs.315493
11060
Nedd-4-like

ubiquitin-protein

ligase

195
0.55
0.487
33569_at
D50532
Hs.54403
10462
macrophage lectin 2

(calcium dependent)

196
0.54
0.486
39171_at
W21787
Hs.99816
56998
beta-catenin-

interacting protein

ICAT

197
0.54
0.486
39678_at
D10511

acetyl-Coenzyme A

acetyltransferase 1

(acetoacetyl

Coenzyme A

thiolase)

198
0.54
0.486
881_at
M35198
Hs.123125
3694
integrin, beta 6

199
0.54
0.485
40064_at
AB011121
Hs.154248
66008
amyotrophic lateral

sclerosis 2 (juvenile)

chromosome region,

candidate 3

200
0.54
0.485
33800_at
AF036927
Hs.20196
115
adenylate cyclase 9

According to the invention, preferred markers are markers 1-30, preferably 1-20, and more preferably 1-10. Highly preferred markers are cathepsin H, folate receptor 1 (adult), BENE protein, and cytochrome b-5.

[0152]

5

TABLE 5

Normal Lung Markers

Class Norm

UNIGENE

(as of

Desc

Perm

GB/TIGR
summer

(unigene/locuslink or

s2n_obs
0.1%
non_norm_list
Identifier
2001)
LL_num
affy)

1
1.97
0.677
32542_at
AF063002
Hs.239069
2273
four and a half LIM

domains 1

2
1.85
0.631
1815_g_at
D50683
Hs.82028
7048
transforming growth

factor, beta receptor II

(70-80 kD)

3
1.82
0.626
36119_at
AF070648
Hs.74034

clone 24651

4
1.75
0.603
35868_at
M91211
Hs.184
177
advanced

glycosylation end

product-specific

receptor

5
1.71
0.600
39031_at
AA152406
Hs.114346
1346
cytochrome c oxidase

subunit VIIa

polypeptide 1 (muscle)

6
1.7
0.594
37398_at
AA100961
Hs.78146
5175
platelet/endothelial

cell adhesion molecule

(CD31 antigen)

7
1.7
0.592
40331_at
AF035819
Hs.67726
8685
macrophage receptor

with collagenous

structure

8
1.7
0.589
40607_at
U97105
Hs.173381
1808
dihydropyrimidinase-

like 2

9
1.7
0.588
40841_at
AF049910
Hs.173159
6867
transforming, acidic

coiled-coil containing

protein 1

10
1.69
0.587
38454_g_at
X15606
Hs.83733
3384
intercellular adhesion

molecule 2

11
1.65
0.582
36569_at
X64559
Hs.65424
7123
tetranectin

(plasminogen-binding

protein)

12
1.63
0.578
39066_at
L38486
Hs.296049
4239
microfibrillar-

associated protein 4

13
1.6
0.576
40282_s_at
M84526
Hs.155597
1675
D component of

complement (adipsin)

14
1.6
0.575
34320_at
AL050224
Hs.29759
22939
polymerase I and

transcript release

factor

15
1.6
0.574
37027_at
M80899
Hs.301417
195
AHNAK

nucleoprotein

(desmoyokin)

16
1.58
0.574
33328_at
W28612
Hs.296326

cDNA

17
1.58
0.573
35985_at
AB023137
Hs.42322
11217
A kinase (PRKA)

anchor protein 2

18
1.57
0.572
770_at
D00632
Hs.336920
2878
glutathione peroxidase

3 (plasma)

19
1.55
0.570
38177_at
AJ001015
Hs.155106
10266
receptor (calcitonin)

activity modifying

protein 2

20
1.54
0.568
39760_at
AL031781
Hs.15020
9444
homolog of mouse

quaking QKI (KH

domain RNA binding

protein)

21
1.54
0.567
268_at
L34657

platelet/endothelial

cell adhesion molecule

(CD31 antigen)

22
1.53
0.567
33756_at
U39447
Hs.198241
8639
amine oxidase, copper

containing 3 (vascular

adhesion protein 1)

23
1.51
0.567
32562_at
X72012
Hs.76753
2022
endoglin (Osler-

Rendu-Weber

syndrome 1)

24
1.51
0.566
40419_at
X85116
Hs.160483
2040
erythrocyte membrane

protein band 7.2

(stomatin)

25
1.48
0.565
40994_at
L15388
Hs.211569
2869
G protein-coupled

receptor kinase 5

26
1.48
0.564
38430_at
AA128249
Hs.83213
2167
fatty acid binding

protein 4, adipocyte

27
1.47
0.564
36155_at
D87465
Hs.74583
9806
KIAA0275 gene

product

28
1.47
0.564
39631_at
U52100
Hs.29191
2013
epithelial membrane

protein 2

29
1.45
0.563
36627_at
X86693
Hs.75445
8404
SPARC-like 1 (mast9,

hevin)

30
1.45
0.562
35730_at
X03350
Hs.4
125
alcohol dehydrogenase

2 (class I), beta

polypeptide

31
1.42
0.561
34708_at
D88587
Hs.333383
8547
ficolin

(collagen/fibrinogen

domain-containing) 3

(Hakata antigen)

32
1.42
0.560
39775_at
X54486
Hs.151242
710
serine (or cysteine)

proteinase inhibitor,

clade G (C1 inhibitor),

member 1

33
1.41
0.560
38239_at
AI312905
Hs.16762

cDNA, 3 end

34
1.41
0.559
35261_at
W07033
Hs.5210
9535
glia maturation factor,

gamma

35
1.4
0.559
39350_at
U50410
Hs.119651
2719
glypican 3

36
1.39
0.559
40560_at
U28049
Hs.168357
6909
T-box 2

37
1.39
0.559
607_s_at
M10321
Hs.110802
7450
von Willebrand factor

38
1.36
0.557
1596_g_at
L06139
Hs.89640
7010
TEK tyrosine kinase,

endothelial (venous

malformations,

multiple cutaneous and

mucosal)

39
1.36
0.557
38653_at
D11428
Hs.103724
5376
peripheral myelin

protein 22

40
1.35
0.557
36577_at
Z24725
Hs.75260
10979
mitogen inducible 2

41
1.33
0.555
37976_at
AL034397
Hs.8904
11326
Ig superfamily protein

42
1.33
0.554
34210_at
N90866
Hs.276770
1043
CDW52 antigen

(CAMPATH-1

antigen)

43
1.33
0.554
38508_s_at
U89337
Hs.169886
7148
DIR1 protein

44
1.32
0.553
32780_at
AB018271
Hs.198689
26029
KIAA0728 protein

45
1.31
0.553
39634_at
AB017168
Hs.29802
9353
slit (Drosophila)

homolog 2

46
1.31
0.552
38995_at
AF000959
Hs.110903
7122
claudin 5

(transmembrane

protein deleted in

velocardiofacial

syndrome)

47
1.3
0.552
37099_at
AI806222
Hs.100194
241
arachidonate 5-

lipoxygenase-

activating protein

48
1.3
0.552
37196_at
X79981
Hs.76206
1003
cadherin 5, type 2,

VE-cadherin (vascular

epithelium)

49
1.29
0.552
36958_at
X95735
Hs.75873
7791
zyxin

50
1.28
0.552
38685_at
AL035306
Hs.106823
84295
hypothetical protein

MGC14797

51
1.28
0.551
37307_at
X04828
Hs.77269
2771
guanine nucleotide

binding protein (G

protein), alpha

inhibiting activity

polypeptide 2

52
1.27
0.551
38704_at
AB007934
Hs.108258
23499
actin binding protein;

macrophin

(microfilament and

actin filament cross-

linker protein)

53
1.27
0.551
32166_at
AB028950
Hs.18420
7094
KIAA1027 protein

54
1.26
0.550
34874_at
AJ004832
Hs.5038
10908
neuropathy target

esterase

55
1.26
0.549
36937_s_at
U90878
Hs.75807
9124
PDZ and LIM domain

1 (elfin)

56
1.25
0.549
37247_at
AF047419
Hs.78061
6943
transcription factor 21

57
1.25
0.549
39541_at
W52003
Hs.10491
57493
KIAA1237 protein

58
1.25
0.547
590_at
M32334

intercellular adhesion

molecule 2

59
1.24
0.547
37168_at
AB013924
Hs.10887
27074
similar to lysosome-

associated membrane

glycoprotein

60
1.23
0.547
39038_at
AF093118
Hs.11494
10516
fibulin 5

61
1.23
0.547
40456_at
AL049963
Hs.284205
64116
up-regulated by BCG-

CWS

62
1.23
0.546
40202_at
D31716
Hs.150557
687
basic transcription

element binding

protein 1

63
1.21
0.546
31856_at
Z24680
Hs.151641
2615
glycoprotein A

repetitions

predominant

64
1.2
0.545
32321_at
X56841
Hs.181392
3133
major

histocompatibility

complex, class I, E

65
1.19
0.545
37042_at
U09577
Hs.76873
8692
hyaluronoglucos-

aminidase 2

66
1.19
0.545
1897_at
L07594
Hs.79059
7049
transforming growth

factor, beta receptor III

(betaglycan, 300 kD)

67
1.18
0.544
35783_at
H93123
Hs.66708
9341
vesicle-associated

membrane protein 3

(cellubrevin)

68
1.17
0.544
32052_at
L48215
Hs.155376
3043
hemoglobin, beta

69
1.17
0.544
33862_at
AF017786
Hs.173717
8613
phosphatidic acid

phosphatase type 2B

70
1.16
0.543
32812_at
AB029025
Hs.202949
22998
KIAA1102 protein

71
1.16
0.543
36452_at
AB028952
Hs.5307
11346
synaptopodin

72
1.15
0.542
37407_s_at
AF013570
Hs.78344
4629
myosin, heavy

polypeptide 11,

smooth muscle

73
1.15
0.541
38406_f_at
AI207842
Hs.8272
5730
prostaglandin D2

synthase (21 kD, brain)

74
1.14
0.541
216_at
M98539

prostaglandin D2

synthase (21 kD, brain)

75
1.14
0.541
38700_at
M33146
Hs.108080
1465
cysteine and glycine-

rich protein 1

76
1.13
0.541
39182_at
U87947
Hs.9999
2014
epithelial membrane

protein 3

77
1.13
0.541
39315_at
D13628
Hs.2463
284
angiopoietin 1

78
1.13
0.540
36207_at
D67029
Hs.75232
6397
SEC14 (S. cerevisiae)-

like 1

79
1.13
0.540
38338_at
AI201108
Hs.9651
6237
related RAS viral (r-

ras) oncogene

homolog

80
1.11
0.540
38691_s_at
J03553
Hs.1074
6440
surfactant, pulmonary-

associated protein C

81
1.11
0.539
32109_at
AA524547
Hs.160318
5348
FXYD domain-

containing ion

transport regulator 1

(phospholemman)

82
1.11
0.539
38044_at
AF035283
Hs.8022
11170
TU3A protein

83
1.1
0.537
40567_at
X01703
Hs.272897
7846
Tubulin, alpha, brain-

specific

84
1.1
0.537
36908_at
M93221

mannose receptor, C

typel

85
1.1
0.537
35183_at
U78735
Hs.26630
21
ATP-binding cassette,

sub-family A (ABC1),

member 3

86
1.09
0.537
538_at
S53911
Hs.85289
947
CD34 antigen

87
1.09
0.536
33283_at
AF106941
Hs.18142
409
arrestin, beta 2

88
1.08
0.536
33295_at
X85785
Hs.183
2532
Duffy blood group

89
1.08
0.536
38972_at
AF052169
Hs.109438

clone 24775

90
1.07
0.536
33137_at
Y13622
Hs.85087
8425
latent transforming

growth factor beta

binding protein 4

91
1.07
0.535
39588_at
AF055872
Hs.26401
8742
tumor necrosis factor

(ligand) superfamily,

member 12

92
1.06
0.535
38786_at
AL079279
Hs.8963

clone EUROIMAGE

248114

93
1.06
0.535
33833_at
J05243
Hs.77196
6709
spectrin, alpha, non-

erythrocytic 1 (alpha-

fodrin)

94
1.06
0.534
35164_at
AF084481
Hs.26077
7466
Wolfram syndrome 1

(wolframin)

95
1.05
0.534
37718_at
D43636
Hs.79025
23182
KIAA0096 protein

96
1.05
0.534
1780_at
M19722
Hs.1422
2268
Gardner-Rasheed

feline sarcoma viral

(v-fgr) oncogene

homolog

97
1.05
0.534
36668_at
M28713

diaphorase (NADH)

(cytochrome b-5

reductase)

98
1.05
0.534
41338_at
AI951946
Hs.21907
11143
histone

acetyltransferase

99
1.04
0.533
32527_at
AI381790
Hs.74120
10974
adipose specific 2

100
1.04
0.533
34363_at
Z11793
Hs.3314
6414
selenoprotein P,

plasma, 1

101
1.04
0.533
37743_at
U60060
Hs.79226
9638
fasciculation and

elongation protein zeta

1 (zygin I)

102
1.03
0.533
32838_at
S67247
Hs.296842

smooth muscle myosin

heavy chain isoform

SMemb [human,

umbilical cord, fetal

aorta,

103
1.03
0.533
40739_at
M83670
Hs.89485
762
carbonic anhydrase IV

104
1.03
0.533
39057_at
L04733
Hs.117977
3831
kinesin 2 (60-70 kD)

105
1.03
0.532
35625_at
X94630
Hs.3107
976
CD97 antigen

106
1.03
0.531
40742_at
M16591
Hs.89555
3055
hemopoietic cell

kinase

107
1.03
0.531
38717_at
AL050159
Hs.288771
25840
DKFZP586A0522

protein

108
1.03
0.531
32254_at
AL050223
Hs.194534
6844
vesicle-associated

membrane protein 2

(synaptobrevin 2)

109
1.03
0.531
38026_at
U01244
Hs.79732
2192
fibulin 1

110
1.02
0.530
37958_at
AL049257
Hs.8769
83604
hypothetical protein

DKFZp761J17121

111
1.02
0.530
37598_at
D79990
Hs.80905
9770
Ras association

(RalGDS/AF-6)

domain family 2

112
1.02
0.530
39145_at
J02854
Hs.9615
10398
myosin regulatory

light chain 2, smooth

muscle isoform

113
1.02
0.530
40775_at
AL021786
Hs.17109
9452
integral membrane

protein 2A

114
1.02
0.529
35282_r_at
M33680
Hs.54457
975
CD81 antigen (target

of antiproliferative

antibody 1)

115
1.02
0.529
37023_at
J02923
Hs.76506
3936
lymphocyte cytosolic

protein 1 (L-plastin)

116
1.02
0.529
38748_at
U76421
Hs.85302
104
adenosine deaminase,

RNA-specific, B1

(homolog of rat

RED1)

117
1.01
0.529
41198_at
AF055008
Hs.180577
2896
granulin

118
1
0.528
34194_at
AL049313
Hs.21103

clone DKFZp564B076

119
1
0.528
33158_at
M97252
Hs.89591
3730
Kallmann syndrome 1

sequence

120
0.99
0.528
31525_s_at
J00153

hemoglobin, alpha 2

121
0.99
0.527
32847_at
U48959
Hs.211582
4638
myosin, light

polypeptide kinase

122
0.98
0.527
38110_at
AF000652
Hs.8180
6386
syndecan binding

protein (syntenin)

123
0.98
0.527
39220_at
T92248
Hs.2240
7356
uteroglobin

124
0.98
0.527
38119_at
X12496
Hs.81994
2995
glycophorin C

(Gerbich blood group)

125
0.98
0.527
40936_at
AI651806
Hs.19280
51232
cysteine-rich motor

neuron 1

126
0.98
0.527
37194_at
M68891
Hs.334695
2624
GATA-binding protein

2

127
0.97
0.526
41620_at
AB018259
Hs.118140
9732
KIAA0716 gene

product

128
0.96
0.526
37951_at
AF035119
Hs.8700
10395
deleted in liver cancer

1

129
0.95
0.526
657_at
L11373
Hs.284180
5098
protocadherin gamma

subfamily C, 3

130
0.95
0.525
37009_at
AL035079
Hs.76359
847
catalase

131
0.95
0.525
33390_at
AA203487
Hs.314363

CD68

132
0.95
0.525
40434_at
U97519
Hs.16426
5420
podocalyxin-like

133
0.95
0.525
37022_at
U41344

proline arginine-rich

end leucine-rich repeat

protein

134
0.95
0.525
31792_at
M20560
Hs.1378
306
annexin A3

135
0.94
0.524
38113_at
AB018339
Hs.8182
23345
synaptic nuclei

expressed gene 1b

136
0.94
0.524
35152_at
AJ001016
Hs.25691
10268
receptor (calcitonin)

activity modifying

protein 3

137
0.93
0.524
1879_at
M14949

related RAS viral (r-

ras) oncogene

homolog

138
0.93
0.524
41734_at
AB020677
Hs.18166
22898
KIAA0870 protein

139
0.92
0.524
36495_at
U21931

fructose-1,6-

bisphosphatase 1

140
0.92
0.524
1370_at
M29696
Hs.237868
3575
interleukin 7 receptor

141
0.92
0.523
1598_g_at
L13720
Hs.78501
2621
growth arrest-specific

6

142
0.92
0.523
38363_at
W60864
Hs.9963
7305
TYRO protein tyrosine

kinase binding protein

143
0.92
0.523
32035_at
M16942
Hs.318720

MHC class II HLA-

DRw53-associated

glycoprotein beta-

chain

144
0.92
0.523
41209_at
M15856
Hs.180878
4023
lipoprotein lipase

145
0.92
0.523
1612_s_at
X56681
Hs.2780
3727
jun D proto-oncogene

146
0.91
0.523
34091_s_at
Z19554
Hs.297753
7431
vimentin

147
0.91
0.522
479_at
U53446
Hs.81988
1601
disabled (Drosophila)

homolog 2 (mitogen-

responsive

phosphoprotein)

148
0.91
0.522
39615_at
AB028949
Hs.27742
23254
KIAA1026 protein

149
0.9
0.522
692_s_at
J02947
Hs.2420
6649
superoxide dismutase

3, extracellular

150
0.9
0.521
36065_at
AF052389
Hs.4980
9079
LIM domain binding 2

151
0.9
0.521
40570_at
AF032885
Hs.170133
2308
forkhead box O1A

(rhabdomyosarcoma)

152
0.9
0.521
37148_at
AF025533
Hs.105928
11025
leukocyte

immunoglobulin-like

receptor, subfamily B

(with TM and ITIM

domains), member 3

153
0.89
0.521
41288_at
AL036744
Hs.279009
4256
matrix Gla protein

154
0.89
0.521
32811_at
X98507
Hs.286226
4641
myosin IB

155
0.88
0.521
37384_at
D13640
Hs.278441
9647
KIAA0015 gene

product

156
0.88
0.520
41325_at
AF006823
Hs.24040
3777
potassium channel,

subfamily K, member

3 (TASK)

157
0.88
0.520
40322_at
D12763
Hs.66
9173
interleukin 1 receptor-

like 1

158
0.88
0.520
32905_s_at
M30038
Hs.334455
7176
tryptase, alpha

159
0.87
0.520
34873_at
Y16241
Hs.5025
10529
nebulette

160
0.87
0.520
610_at
M15169
Hs.2551
154
adrenergic, beta-2-,

receptor, surface

161
0.87
0.520
41644_at
AB018333
Hs.12002
23328
KIAA0790 protein

162
0.87
0.520
36894_at
AL031846

chromobox homolog 7

163
0.87
0.520
33891_at
AL080061
Hs.25035
25932
chloride intracellular

channel 4

164
0.87
0.520
40147_at
U18009
Hs.157236
10493
membrane protein of

cholinergic synaptic

vesicles

165
0.87
0.520
38796_at
X03084
Hs.8986
713
complement

component 1, q

subcomponent, beta

polypeptide

166
0.87
0.520
36856_at
W28743
Hs.7159
80301
hypothetical protein

PP1628

167
0.87
0.520
1038_s_at
U19247

interferon gamma

receptor 1

168
0.86
0.519
34637_f_at
M12963
Hs.73843
124
alcohol dehydrogenase

1 (class I), alpha

polypeptide

169
0.85
0.519
38747_at
M81945

CD34 antigen

170
0.84
0.519
32747_at
X05409
Hs.195432
217
aldehyde

dehydrogenase 2,

mitochondrial

171
0.84
0.519
32749_s_at
AL050396
Hs.195464
2316
filamin A, alpha

(actin-binding protein-

280)

172
0.84
0.519
38087_s_at
W72186
Hs.81256
6275
S100 calcium-binding

protein A4 (calcium

protein, calvasculin,

metastasin, murine

placental homolog)

173
0.84
0.518
38095_i_at
M83664
Hs.814
3115
major

histocompatibility

complex, class II, DP

beta 1

174
0.84
0.518
40203_at
AJ012375
Hs.150580
10209
putative translation

initiation factor

175
0.84
0.518
34224_at
AC004770
Hs.21765
3995
flap structure-specific

endonuclease 1

176
0.83
0.518
307_at
J03600
Hs.89499
240
arachidonate 5-

lipoxygenase

177
0.83
0.518
38968_at
AB005047
Hs.109150
9467
SH3-domain binding

protein 5 (BTK-

associated)

178
0.83
0.517
39114_at
AB022718
Hs.93675
11067
decidual protein

induced by

progesterone

179
0.83
0.517
41385_at
AB023204
Hs.103839
23136
differentially

expressed in

adenocarcinoma of the

lung

180
0.83
0.517
39400_at
AB028978
Hs.126084
23102
KIAA1055 protein

181
0.83
0.517
39081_at
AI547258
Hs.118786
4502
metallothionein 2A

182
0.82
0.517
33813_at
AI813532
Hs.256278
7133
tumor necrosis factor

receptor superfamily,

member 1B

183
0.82
0.517
31775_at
X65018

surfactant, pulmonary-

associated protein D

184
0.82
0.517
32855_at
L00352

low density lipoprotein

receptor (familial

hypercholesterolemia)

185
0.82
0.516
40480_s_at
M14333
Hs.169370
2534
FYN oncogene related

to SRC, FOR, YES

186
0.81
0.516
36156_at
U41518
Hs.74602
358
aquaporin 1 (channel-

forming integral

protein, 28 kD)

187
0.81
0.516
41439_at
AJ001381
Hs.121576

incomplete cDNA for

a mutated allele of a

myosin class I, myh-1c

188
0.81
0.516
774_g_at
D10667

myosin, heavy

polypeptide 11,

smooth muscle

189
0.81
0.516
924_s_at
J03805
Hs.80350
5516
protein phosphatase 2

(formerly 2A),

catalytic subunit, beta

isoform

190
0.81
0.516
40771_at
Z98946
Hs.170328
4478
moesin

191
0.81
0.515
38833_at
X00457
Hs.914

SB classII

histocompatibility

antigen alpha-chain

192
0.81
0.515
41143_at
U12022

calmodulin 1

(phosphorylase kinase,

delta)

193
0.8
0.515
37176_at
U96078
Hs.75619
3373
hyaluronoglucos-

aminidase 1

194
0.8
0.515
36447_at
S80990

ficolin

(collagen/fibrinogen

domain-containing) 1

195
0.8
0.515
1052_s_at
M83667
Hs.76722
1052
CCAAT/enhancer

binding protein

(C/EBP), delta

196
0.8
0.515
41723_s_at
M32578
Hs.180255
3123
major

histocompatibility

complex, class II, DR

beta 1

197
0.8
0.515
38404_at
M55153
Hs.8265
7052
transglutaminase 2 (C

polypeptide, protein-

glutamine-gamma-

glutamyltransferase)

198
0.8
0.515
34760_at
D14664
Hs.2441
9936
KIAA0022 gene

product

199
0.79
0.515
32569_at
L13385
Hs.77318
5048
platelet-activating

factor acetylhydrolase,

isoform Ib, alpha

subunit (45 kD)

200
0.79
0.514
505_at
U43077
Hs.160958
11140
CDC37 (cell division

cycle 37, S. cerevisiae,

homolog)

According to the invention, preferred markers are markers 1-30, preferably 1-20, and more preferably 1-10. Highly preferred markers are transforming growth factor beta receptor II, dihydropyrimidinase-like 2, and tetranectin.

[0153]

6

TABLE 6

Colorectal Matastasis Markers

Class: Colon

UNIGENE

(as of

Desc

Perm

GB/TIGR
summer

(unigene/locuslink

s2n_obs
0.1%
non_norm_list
Identifier
2001)
LL_num
or affy)

1
2.33
0.914
40392_at
U51096
Hs.77399
1045
caudal type homeo

box transcription

factor 2

2
1.58
0.728
40736_at
X83228
Hs.89436
1015
cadherin 17, LI

cadherin (liver-

intestine)

3
1.55
0.719
37124_i_at
J04813
Hs.104117
1577
cytochrome P450,

subfamily IIIA

(niphedipine

oxidase),

polypeptide 5

4
1.52
0.715
169_at
U51095
Hs.1545
1044
caudal type homeo

box transcription

factor 1

5
1.45
0.701
40043_at
X71345
Hs.58247
5647
protease, serine, 4

(trypsin 4, brain)

6
1.4
0.698
35644 at
AB014598
Hs.31720
9843
hephaestin

7
1.37
0.688
38586_at
M10050
Hs.5241
2168
fatty acid binding

protein 1, liver

8
1.37
0.682
32972_at
Z83819
Hs.132370
27035
NADPH oxidase 1

9
1.34
0.679
39951_at
L20826
Hs.430
5357
plastin 1 (I isoform)

10
1.3
0.677
1229_at
U78556
Hs.166066
10903
cisplatin resistance

associated

11
1.3
0.677
988_at
X16354
Hs.50964
634
carcinoembryonic

antigen-related cell

adhesion molecule

1 (biliary

glycoprotein)

12
1.3
0.669
37415_at
AB018258
Hs.109358
23120
ATPase, Class V,

type 10B

13
1.25
0.668
41708_at
AB028957
Hs.12896
23314
KIAA1034 protein

14
1.22
0.656
765_s_at
AB006781
Hs.5302
3960
lectin, galactoside-

binding, soluble, 4

(galectin 4)

15
1.21
0.654
39697_at
U26726
Hs.1376
3291
hydroxysteroid (11-

beta)

dehydrogenase 2

16
1.2
0.650
33559_at
U61412

PTK6 protein

tyrosine kinase 6

17
1.2
0.649
33904_at
AB000714
Hs.25640
1365
claudin 3

18
1.19
0.649
41266_at
X53586
Hs.227730
3655
integrin, alpha 6

19
1.19
0.648
36170_at
D83198
Hs.7486
23474
protein expressed in

thyroid

20
1.18
0.648
37847_at
AB006955
Hs.132945
10083
PDZ-73 protein

21
1.16
0.646
34595_at
AF105424
Hs.5394
4640
myosin, heavy

polypeptide-like

(110 kD)

22
1.16
0.644
40694_at
X73502
Hs.84905
54474
cytokeratin 20

23
1.14
0.639
35415_at
X12901
Hs.166068
7429
villin 1

24
1.14
0.638
899_at
L38517
Hs.69351
3549
Indian hedgehog

(Drosophila)

homolog

25
1.11
0.638
37875_at
U79725
Hs.143131
10223
glycoprotein A33

(transmembrane)

26
1.11
0.635
41678_at
AF025304
Hs.125124
2048
EphB2

27
1.1
0.632
32649_at
X59871
Hs.169294
6932
transcription factor

7 (T-cell specific,

HMG-box)

28
1.08
0.629
35114_at
AF084645
Hs.118138
8856
nuclear receptor

subfamily 1, group

I, member 2

29
1.07
0.629
36832_at
AB015630
Hs.69009
10331
transmembrane

protein 3

30
1.07
0.627
41396 at
AB006629
Hs.104717
7461
cytoplasmic linker 2

31
1.07
0.624
35256_at
AL096737
Hs.5167

clone

DKFZp434F152

32
1.07
0.620
33436_at
Z46629
Hs.2316
6662
SRY (sex

determining region

Y)-box 9

(campomelic

dysplasia,

autosomal sex-

reversal)

33
1.05
0.620
33789_at
AF088219
Hs.272493
6359
small inducible

cytokine subfamily

A (Cys-Cys),

member 23

34
1.05
0.619
34450_at
M73489
Hs.1085
2984
guanylate cyclase

2C (heat stable

enterotoxin

receptor)

35
1.04
0.619
31355_at
U77629
Hs.135639
430
achaete-scute

complex

(Drosophila)

homolog-like 2

36
1.03
0.618
39732_at
X73882
Hs.146388
9053
microtubule-

associated protein 7

37
1.03
0.617
40061_at
D83784
Hs.154104
5326
pleiomorphic

adenoma gene-like

2

38
1.03
0.617
38469_at
M35252
Hs.84072
7103
transmembrane 4

superfamily

member 3

39
1.03
0.615
246_at
M25629
Hs.123107
3816
kallikrein 1,

renal/pancreas/salivary

40
1.03
0.613
36742_at
U34249
Hs.337461
89870
ring finger protein 9

41
1.02
0.613
36816_s_at
M28668
Hs.663
1080
cystic fibrosis

transmembrane

conductance

regulator, ATP-

binding cassette

(sub-family C,

member 7)

42
1.01
0.612
38495_s_at
U27328
Hs.169238
2525
fucosyltransferase 3

(galactoside 3(4)-L-

fucosyltransferase,

Lewis blood group

included)

43
1.01
0.611
1973_s_at
V00568
Hs.79070
4609
v-myc avian

myelocytomatosis

viral oncogene

homolog

44
1.01
0.611
37857_at
AL080188
Hs.137556
92211
MT-protocadherin

45
1
0.610
40198_at
L06132
Hs.149155
7416
voltage-dependent

anion channel 1

46
0.99
0.607
33824_at
X74929
Hs.242463
3856
keratin 8

47
0.99
0.607
38160_at
AF011333
Hs.153563
4065
lymphocyte antigen

75

48
0.99
0.607
34280_at
Y09765
Hs.22785
2564
gamma-

aminobutyric acid

(GABA) A

receptor, epsilon

49
0.98
0.606
31608_g_at
AJ002428
Hs.201553
10065
voltage-dependent

anion channel 1

pseudogene

50
0.98
0.606
820_at
U77604
Hs.81874
4258
microsomal

glutathione S-

transferase 2

51
0.98
0.606
34176_at
AF091087
Hs.206501
57228
hypothetical protein

from clone 643

52
0.98
0.605
40647_at
Z32684
Hs.78919
7504
Kell blood group

precursor (McLeod

phenotype)

53
0.98
0.604
36655_at
L27476
Hs.75608
9414
tight junction

protein 2 (zona

occludens 2)

54
0.97
0.604
37050_r_at
AI130910
Hs.76927
10953
translocase of outer

mitochondrial

membrane 34

55
0.97
0.604
32324_at
X57346
Hs.279920
7529
tyrosine 3-

monooxygenase/try

ptophan 5-

monooxygenase

activation protein,

beta polypeptide

56
0.96
0.604
41715_at
Y11312
Hs.132463
5287
phosphoinositide-3-

kinase, class 2, beta

polypeptide

57
0.96
0.604
40492_at
AB020633
Hs.169600
23045
KIAA0826 protein

58
0.96
0.603
575_s_at
M93036

tumor-associated

calcium signal

transducer 1

59
0.95
0.603
1756_f_at
D00003
Hs.329704
1575
cytochrome P450,

subfamily IIIA

(niphedipine

oxidase),

polypeptide 3

60
0.95
0.603
37950_at
X74496
Hs.86978
5550
prolyl

endopeptidase

61
0.95
0.603
35489_at
M82962
Hs.179704
4224
meprin A, alpha

(PABA peptide

hydrolase)

62
0.95
0.603
39721_at
U09303
Hs.144700
1947
ephrin-B1

63
0.94
0.602
34803_at
AF022789
Hs.42400
9959
ubiquitin specific

protease 12

64
0.94
0.602
32587_at
U07802
Hs.78909
678
butyrate response

factor 2 (EGF-

response factor 2)

65
0.94
0.602
41359_at
Z98265
Hs.26557
11187
plakophilin 3

66
0.93
0.602
1291_s_at
L03840
Hs.165950
2264
fibroblast growth

factor receptor 4

67
0.93
0.602
37253_at
X92493
Hs.78406
8395
phosphatidylinositol-

4-phosphate 5-

kinase, type I, beta

68
0.92
0.601
38005_at
AJ005866
Hs.90078
11046
nucleotide-sugar

transporter similar

to C. elegans sqv-7

69
0.92
0.601
41448_at
AC004080
Hs.110637
3206
even-skipped

homeo box 1

(homolog of

Drosophila)

70
0.91
0.600
39748_at
AL050021
Hs.14846

clone

DKFZp564D016

71
0.91
0.600
35276_at
AB000712
Hs.5372
1364
claudin 4

72
0.9
0.599
37244_at
AA746355
Hs.77917
7347
ubiquitin carboxyl-

terminal esterase L3

(ubiquitin

thiolesterase)

73
0.9
0.599
41530_at
D16294
Hs.32500
10449
acetyl-Coenzyme A

acyltransferase 2

(mitochondrial 3-

oxoacyl-Coenzyme

A thiolase)

74
0.9
0.598
36289_f_at
U27333
Hs.32956
2528
fucosyltransferase 6

(alpha (1,3)

fucosyltransferase)

75
0.9
0.598
36846_s_at
AA121509
Hs.70830
51690
U6 snRNA-

associated Sm-like

protein LSm7

76
0.89
0.597
35262_at
AF022229
Hs.5215
3692
integrin beta 4

binding protein

77
0.89
0.597
41816_at
AL049851
Hs.57973
29775
hypothetical protein

78
0.89
0.597
38739_at
AF017257
Hs.85146
2114
v-ets avian

erythroblastosis

virus E26 oncogene

homolog 2

79
0.89
0.596
1936_s_at
HG3523-

Proto-Oncogene C-

HT4899

Myc, Alt. Splice 3,

Orf 114

80
0.89
0.596
31948_at
X79563
Hs.1948
6227
ribosomal protein

S21

81
0.88
0.596
36687_at
N50520
Hs.75752
1349
cytochrome c

oxidase subunit

VIIb

82
0.88
0.595
2042_s_at
M15024
Hs.1334
4602
v-myb avian

myeloblastosis viral

oncogene homolog

83
0.87
0.595
38375_at
AF112219
Hs.82193
2098
esterase

D/formylglutathione

hydrolase

84
0.86
0.594
35961_at
AL049390
Hs.22689

clone

DKFZp586O1318

85
0.86
0.594
1582_at
M29540
Hs.220529
1048
carcinoembryonic

antigen-related cell

adhesion molecule 5

86
0.86
0.594
37888_at
D87449
Hs.82635
23169
KIAA0260 protein

87
0.86
0.594
266_s_at
L33930
Hs.286124
934
CD24 antigen

(small cell lung

carcinoma cluster 4

antigen)

88
0.86
0.593
31845_at
U32645
Hs.151139
2000
E74-like factor 4

(ets domain

transcription factor)

89
0.86
0.593
37211_at
M93107
Hs.76893
622
3-hydroxybutyrate

dehydrogenase

(heart,

mitochondrial)

90
0.86
0.592
35345_at
X83618
Hs.59889
3158
3-hydroxy-3-

methylglutaryl-

Coenzyme A

synthase 2

(mitochondrial)

91
0.86
0.592
41236_at
U79252
Hs.240062
29787
hypothetical protein

92
0.86
0.592
37698_at
X97335
Hs.78921
8165
A kinase (PRKA)

anchor protein 1

93
0.85
0.591
32585_at
AF027299
Hs.7857
2037
erythrocyte

membrane protein

band 4.1-like 2

94
0.85
0.590
38808_at
D64154
Hs.90107
11047
cell membrane

glycoprotein,

110000M (r)

(surface antigen)

95
0.85
0.590
37104_at
L40904
Hs.100724
5468
peroxisome

proliferative

activated receptor,

gamma

96
0.85
0.590
1317_at
X70040
Hs.2942
4486
macrophage

stimulating 1

receptor (c-met-

related tyrosine

kinase)

97
0.84
0.590
37413_at
J05257
Hs.109
1800
dipeptidase 1

(renal)

98
0.84
0.589
36345_g_at
U34038
Hs.154299
2150
coagulation factor II

(thrombin)

receptor-like 1

99
0.84
0.589
38036_at
L35035
Hs.79886
22934
ribose 5-phosphate

isomerase A (ribose

5-phosphate

epimerase)

100
0.84
0.589
39765_at
AB002318
Hs.150443
23079
KIAA0320 protein

101
0.84
0.588
36363_at
U30930
Hs.158540
7368
UDP

glycosyltransferase

8 (UDP-galactose

ceramide

galactosyltransferase)

102
0.84
0.587
1031_at
U09564
Hs.75761
6732
SFRS protein

kinase 1

103
0.84
0.587
35913_at
U88047
Hs.198515
1820
dead ringer

(Drosophila)-like 1

104
0.83
0.587
39119_s_at
AA631972
Hs.943
9235
natural killer cell

transcript 4

105
0.83
0.587
37896_at
AI474125
Hs.82961
7033
trefoil factor 3

(intestinal)

106
0.83
0.587
33892_at
X97675
Hs.25051
5318
plakophilin 2

107
0.83
0.587
1506_at
D11086
Hs.84
3561
interleukin 2

receptor, gamma

(severe combined

immunodeficiency)

108
0.83
0.587
1237_at
S81914
Hs.76095
8870
immediate early

response 3

109
0.82
0.586
35194_at
X53463
Hs.2704
2877
glutathione

peroxidase 2

(gastrointestinal)

110
0.82
0.586
36650 at
D13639
Hs.75586
894
cyclin D2

111
0.82
0.586
2075_s_at
L36719
Hs.180533
5606
mitogen-activated

protein kinase

kinase 3

112
0.82
0.586
40182_s_at
AF055027
Hs.143696
10498
coactivator-

associated arginine

methyltransferase-1

113
0.82
0.586
786_at
X06745
Hs.267289
5422
polymerase (DNA

directed), alpha

114
0.82
0.585
901_g_at
L41349
Hs.283006
5332
phospholipase C,

beta 4

115
0.82
0.585
41200_at
Z22555
Hs.180616
949
CD36 antigen

(collagen type I

receptor,

thrombospondin

receptor)-like 1

116
0.82
0.585
39339_at
AB018335
Hs.119387
9725
KIAA0792 gene

product

117
0.81
0.584
41355_at
N95229
Hs.130881
53335
B-cell

CLL/lymphoma

11A (zinc finger

protein)

118
0.81
0.584
40002_r_at
AI935442
Hs.53542
23230
chorein

119
0.81
0.584
40404_s_at
U18291
Hs.1592
8881
CDC16 (cell

division cycle 16, S.

cerevisiae
,

homolog)

120
0.81
0.583
40893_at
AF058953
Hs.182217
8803
succinate-CoA

ligase, ADP-

forming, beta

subunit

121
0.8
0.583
34840_at
AI700633
Hs.288232

cDNA, 3 end

122
0.8
0.583
36123_at
D87292
Hs.248267
7263
thiosulfate

sulfurtransferase

(rhodanese)

123
0.8
0.583
33248_at
H94842
Hs.17882

EST

124
0.8
0.582
34866_at
AF055029
Hs.4988

clone 24711

125
0.8
0.582
34255_at
AF059202
Hs.288627
8694
diacylglycerol O-

acyltransferase

(mouse) homolog

126
0.8
0.582
37186_s_at
U11863
Hs.75741
26
amiloride binding

protein 1 (amine

oxidase (copper-

containing))

127
0.8
0.582
41223_at
M22760
Hs.181028
9377
cytochrome c

oxidase subunit Va

128
0.79
0.581
34335_at
AI765533
Hs.30942
1948
ephrin-B2

129
0.79
0.581
34712_at
AB023227
Hs.23860
23268
KIAA1010 protein

130
0.79
0.581
1350_at
U02388
Hs.101
8529
cytochrome P450,

subfamily IVF,

polypeptide 2

131
0.79
0.580
34829_at
U59151
Hs.4747
1736
dyskeratosis

congenita 1,

dyskerin

132
0.79
0.580
40527_at
AF000571
Hs.156115
3784
potassium voltage-

gated channel,

KQT-like

subfamily, member 1

133
0.79
0.580
37757_at
L23959
Hs.79353
7027
transcription factor

Dp-1

134
0.79
0.580
37926_at
D14520
Hs.84728
688
Kruppel-like factor

5 (intestinal)

135
0.79
0.580
38048_at
D84110
Hs.80248
11030
RNA-binding

protein gene with

multiple splicing

136
0.78
0.579
1562_g_at
U27193
Hs.41688
1850
dual specificity

phosphatase 8

137
0.78
0.579
36059_at
AB011540
Hs.4930
4038
low density

lipoprotein

receptor-related

protein 4

138
0.78
0.579
36580_at
AL050139
Hs.75277
64795
hypothetical protein

FLJ13910

139
0.78
0.579
37263_at
U55206
Hs.78619
8836
gamma-glutamyl

hydrolase

(conjugase,

folylpolygammaglut

amyl hydrolase)

140
0.78
0.579
38381_at
U32315
Hs.82240
6809
syntaxin 3A

141
0.78
0.579
37534_at
Y07593
Hs.79187
1525
coxsackie virus and

adenovirus receptor

142
0.77
0.578
34998_at
AF059531
Hs.152337
10196
protein arginine N-

methyltransferase

3 (hnRNP

methyltransferase S.

cerevisiae
)-like 3

143
0.77
0.578
35492_at
AC004523
Hs.180570
66002
hypothetical protein

similar to rat

CYP4F1

144
0.77
0.578
2089_s_at
H06628
Hs.199067
2065
v-erb-b2 avian

erythroblastic

leukemia viral

oncogene homolog 3

145
0.77
0.578
39362_r_at
AF043906
Hs.121068
7105
transmembrane 4

superfamily

member 6

146
0.77
0.578
37690_at
U61263
Hs.78880
10994
ilvB (bacterial

acetolactate

synthase)-like

147
0.77
0.577
35029_at
Y07828
Hs.91096
11074
ring finger protein

148
0.77
0.577
31849_at
AB011136
Hs.151385
23078
KIAA0564 protein

149
0.77
0.577
40333_at
U43842
Hs.68879
652
bone

morphogenetic

protein 4

150
0.77
0.577
1827_s_at
M13929U37122
Hs.324470
120
c-myc-P64 mRNA,

151
0.76
0.577
33103_s_at

initiating from

promoter P0,

(HLmyc2.5)

adducin 3 (gamma)

152
0.76
0.576
38247_at
U67058
Hs.168102

Coagulation factor

II (thrombin)

receptor-like 1

153
0.76
0.576
31854_at
AF035582
Hs.151469
8573
calcium/calmodulin-

dependent serine

protein kinase

(MAGUK family)

154
0.76
0.576
35932_at
AF081507

left-right

determination,

factor B

155
0.76
0.576
39540_at
AF000561
Hs.104640
51341
HFV-1 inducer of

short transcripts

binding protein

156
0.76
0.576
41713_at
U09848
Hs.132390
7586
zinc finger protein

36 (KOX 18)

157
0.76
0.576
35444_at
AC004030
Hs.71779

Cosmid F21856

158
0.75
0.576
39219_at
U20240
Hs.2227
1054
CCAAT/enhancer

binding protein

(C/EBP), gamma

159
0.75
0.575
37672_at
Z72499
Hs.78683
7874
ubiquitin specific

protease 7 (herpes

virus-associated)

160
0.75
0.575
32502_at
AL041124
Hs.6748
81544
hypothetical protein

PP1665

161
0.75
0.574
37423_at
U30246
Hs.110736
6558
solute carrier family

12

(sodium/potassium/

chloride

transporters),

member 2

162
0.75
0.574
37720_at
M22382
Hs.79037
3329
heat shock 60 kD

protein 1

(chaperonin)

163
0.75
0.574
1445_at
AF014958
Hs.302043
9034
chemokine (C-C

motif) receptor-like

2

164
0.75
0.574
36821_at
AL050367
Hs.66762

clone

DKFZp564A026

165
0.75
0.573
37188_at
X92720
Hs.75812
5106
phosphoenolpyruvate

carboxykinase 2

(mitochondrial)

166
0.75
0.573
37177_at
Y00636
Hs.75626
965
CD58 antigen,

(lymphocyte

function-associated

antigen 3)

167
0.75
0.573
31669_s_at
AF039307
Hs.249171
3207
homeo box A11

168
0.75
0.573
35673_at
U02082
Hs.334
7984
Rho guanine

nucleotide

exchange factor

(GEF) 5

169
0.75
0.573
283_at
L16842
Hs.119251
7384
ubiquinol-

cytochrome c

reductase core

protein I

170
0.75
0.572
35727_at
AI249721
Hs.39850
54963
hypothetical protein

FLJ20517

171
0.74
0.572
40445_at
AF017307
Hs.166096
1999
E74-like factor 3

(ets domain

transcription factor,

epithelial-specific)

172
0.74
0.572
1943_at
X51688
Hs.85137
890
cyclin A2

173
0.74
0.572
39801_at
AF046889
Hs.153357
8985
procollagen-lysine,

2-oxoglutarate 5-

dioxygenase 3

174
0.74
0.572
288_s_at
L25931
Hs.152931
3930
lamin B receptor

175
0.74
0.571
32320_at
Z11502
Hs.181107
312
annexin A13

176
0.74
0.571
3750 l_at
Y07707
Hs.119018
55922
transcription factor

NRF

177
0.73
0.571
476_s_at
U50079
Hs.88556
3065
histone deacetylase

1

178
0.73
0.571
864_at
U07664

homeo box HB9

179
0.73
0.570
34046_at
Z83844
Hs.97858
23616
hypothetical protein

dJ37E16.5

180
0.73
0.570
1385_at
M77349
Hs.118787
7045
transforming

growth factor, beta-

induced, 68 kD

181
0.73
0.570
31887_at
J04469
Hs.153998
1159
creatine kinase,

mitochondrial 1

(ubiquitous)

182
0.73
0.570
36764_at
AC004125
Hs.7235
10368
calcium channel,

voltage-dependent,

gamma subunit 3

183
0.73
0.570
35140_at
R59697
Hs.25283
1024
cyclin-dependent

kinase 8

184
0.73
0.570
367_at
Z29067
Hs.2236
4752
NIMA (never in

mitosis gene a)-

related kinase 3

185
0.73
0.569
41276_at
W27641
Hs.23964
10284
sin3-associated

polypeptide, 18 kD

186
0.73
0.569
37562_at
L11370
Hs.79769
5097
protocadherin 1

(cadherin-like 1)

187
0.73
0.569
38630_at
AL080192
Hs.101282

clone

DKFZp434B102)

188
0.73
0.569
40123_at
D87435
Hs.155499
8729
golgi-specific

brefeldin A

resistance factor 1

189
0.73
0.569
32601_s_at
AC004382
Hs.279832
55715
small inducible

cytokine subfamily

A (Cys-Cys),

member 17

190
0.72
0.569
33573_at
AB009426

apolipoprotein B

mRNA editing

enzyme, catalytic

polypeptide 1

191
0.72
0.569
35656_at
AJ010346
Hs.32597
6049
ring finger protein

(C3H2C3 type) 6

192
0.72
0.569
39876_at
AL035252
Hs.12330
955
ectonucleoside

triphosphate

diphosphohydrolase

6 (putative

function)

193
0.72
0.569
2064_g_at
L20046
Hs.48576
2073
excision repair

cross-

complementing

rodent repair

deficiency,

complementation

group 5 (xeroderma

pigmentosum,

complementation

group G (Cockayne

syndrome))

194
0.72
0.569
40067_at
M82882
Hs.154365
1997
E74-like factor 1

(ets domain

transcription factor)

195
0.72
0.568
34339_at
AB009282
Hs.79103
80777
cytochrome b5

outer mitochondrial

membrane

precursor

196
0.72
0.568
38518_at
Y18004
Hs.171558
10389
sex comb on midleg

(Drosophila)-like 2

197
0.71
0.567
37809_at
U41813
Hs.127428
3205
homeo box A9

198
0.71
0.567
36613_at
U09585
Hs.315177
7866
interferon-related

developmental

regulator 2

199
0.71
0.567
31324_at
U82303
Hs.123080

unknown protein

mRNA

200
0.71
0.567
308_f_at
J03756
Hs.65149
2689
growth hormone 2

According to the invention, preferred markers are markers 1-30, preferably 1-20, and more preferably 1-10. Highly preferred markers are cytokeratin 20 and villin 1.

[0154]

7

TABLE 7

C0 Markers

According to the invention, preferred markers are markers 1-30, preferably 1-20,

and more preferably 1-10.

Class: C0

UNIGENE

(as of

Desc

Perm

GB/TIGR
summer

(unigene/locuslink

s2n_obs
0.1%
non_norm_list
Identifier
2001)
LL_num
or affy)

1
0.81
0.681
493_at
U29171
Hs.75852
1453
casein kinase 1, delta

2
0.8
0.620
39431_at
AJ132583
Hs.293007
9520
Aminopeptidase

puromycin sensitive

3
0.78
0.599
1953_at
AF024710
Hs.73793
7422
vascular endothelial

growth factor

4
0.75
0.584
34678_at
AL096713
Hs.234680
26509
fer-1 (C. elegans)-

like 3 (myoferlin)

5
0.73
0.570
32919_at
AC004010
Hs.121520

BAC clone

GS099H08

6
0.72
0.545
884_at
M59911
Hs.265829
3675
integrin, alpha 3

(antigen CD49C,

alpha 3 subunit of

VLA-3 receptor)

7
0.71
0.531
38261_at
AF085692
Hs.90786
8714
ATP-binding

cassette, sub-family

C (CFTR/MRP),

member 3

8
0.7
0.528
33889_s_at
D79985
Hs.2491
9993
DiGeorge syndrome

critical region gene 2

9
0.7
0.524
31888_s_at
AF001294
Hs.154036
7262
tumor suppressing

subtransferable

candidate 3

10
0.69
0.522
38127_at
Z48199
Hs.82109
6382
syndecan 1

11
0.66
0.514
38132_at
M88338
Hs.148101
11135
serum constituent

protein

12
0.65
0.511
2017_s_at
M64349
Hs.82932
893
cyclin D1 (PRAD1:

parathyroid

adenomatosis 1)

13
0.64
0.510
36101_s_at
M63978

vascular endothelial

growth factor

14
0.64
0.509
33354_at
AA630312
Hs.194477
64750
E3 ubiquitin ligase

SMURF2

15
0.64
0.507
32206_at
AB007920
Hs.18586
9876
KIAA0451 gene

product

16
0.61
0.499
168_at
U50196
Hs.94382
132
adenosine kinase

17
0.61
0.492
39962_at
U59305
Hs.44708
8476
Ser-Thr protein

kinase related to the

myotonic dystrophy

protein kinase

18
0.6
0.489
33944_at
S60099
Hs.279518
334
amyloid beta (A4)

precursor-like

protein 2

19
0.6
0.488
32094_at
AB017915
Hs.158304
9469
carbohydrate

(chondroitin

6/keratan)

sulfotransferase 3

20
0.6
0.486
40504_at
AF001601
Hs.169857
5445
paraoxonase 2

21
0.59
0.485
36117_at
L13616
Hs.740
5747
PTK2 protein

tyrosine kinase 2

22
0.58
0.480
34256_at
AB018356
Hs.225939
8869
sialyltransferase 9

(CMP-

NeuAc: lactosylcer-

amide alpha-2,3-

sialyltransferase;

GM3 synthase)

23
0.57
0.477
35212_at
AF064801
Hs.28285
11236
patched related

protein translocated

in renal cancer

24
0.57
0.476
34796_at
X63679
Hs.4147
23471
translocating chain-

associating

membrane protein

25
0.56
0.475
40229_at
AJ010071
Hs.153504
10040
target of myb1

(chicken) homolog-

like 1

26
0.55
0.473
34793_s_at
M22299
Hs.4114
5358
plastin 3 (T isoform)

27
0.55
0.473
38643_at
W87466
Hs.246885
55041
hypothetical protein

FLJ20783

28
0.55
0.472
35350_at
AB011170
Hs.6079
51363
B cell RAG

associated protein

29
0.55
0.471
38028_at
AL050152
Hs.301914
55885
clone

DKFZp586K1220

30
0.55
0.471
1030_s_at
U07806
Hs.317
7150
topoisomerase

(DNA) I

31
0.54
0.469
37741_at
M77836
Hs.79217
5831
pyrroline-5-

carboxylate

reductase 1

32
0.54
0.469
35294_at
M25077
Hs.554
6738
Sjogren syndrome

antigen A2 (60 kD,

ribonucleoprotein

autoantigen SS-

A/Ro)

33
0.53
0.468
38306_at
AA477576
Hs.94631
10565
brefeldin A-inhibited

guanine nucleotide-

exchange protein 1

34
0.53
0.467
33128_s_at
W68521
Hs.83393
1474
cystatin E/M

35
0.53
0.463
40471_at
Y09048
Hs.168670
5824
peroxisomal

farnesylated protein

36
0.52
0.462
31680_at
M55630

topoisomerase I

pseudogene 2

37
0.52
0.460
41140_at
U05875
Hs.177559
3460
interferon gamma

receptor 2

(interferon gamma

transducer 1)

38
0.52
0.459
33931_at
X71973
Hs.2706
2879
glutathione

peroxidase 4

(phospholipid

hydroperoxidase)

39
0.52
0.459
393_s_at
X90976
Hs.129914
861
runt-related

transcription factor 1

(acute myeloid

leukemia 1; aml1

oncogene)

40
0.52
0.459
36036_at
J05500
Hs.47431
6710
spectrin, beta,

erythrocytic

(includes

spherocytosis,

clinical type I)

41
0.51
0.459
39411_at
AL080156
Hs.12813
25976
DKFZP434J214

protein

42
0.51
0.459
33454_at
AF016903
Hs.273330
180
agrin

43
0.51
0.458
33121_g_at
AF045229
Hs.82280
6001
regulator of G-

protein signalling 10

44
0.5
0.458
40093_at
X83425
Hs.155048
4059
Lutheran blood

group (Auberger b

antigen included)

45
0.5
0.456
977_s_at
Z35402
Hs.194657
999
cadherin 1, type 1,

E-cadherin

(epithelial)

46
0.5
0.456
33421_s_at
AB016247
Hs.288031
6309
sterol-C5-desaturase

(fungal ERG3, delta-

5-desaturase)-like

47
0.5
0.455
39712_at
AI541308
Hs.14331
6284
S100 calcium-

binding protein A13

48
0.49
0.452
33894_at
AJ010046
Hs.25155
10276
neuroepithelial cell

transforming gene 1

49
0.49
0.451
38042_at
X03674
Hs.80206
2539
glucose-6-phosphate

dehydrogenase

50
0.49
0.450
32715_at
N90862
Hs.172684
8673
vesicle-associated

membrane protein 8

(endobrevin)

51
0.49
0.448
41273_at
AL046940
Hs.250723
79086
hypothetical protein

MGC2747

52
0.49
0.448
40303_at
U85658
Hs.61796
7022
transcription factor

AP-2 gamma

(activating enhancer-

binding protein 2

gamma)

53
0.49
0.446
39277_at
U60805
Hs.238648
9180
oncostatin M

receptor

54
0.48
0.446
35597_at
AJ000480
Hs.7837
10221
phosphoprotein

regulated by

mitogenic pathways

55
0.48
0.444
38423_at
L38935
Hs.83086

GT212 mRNA

56
0.48
0.444
291_s_at
J04152
Hs.23582
4070
tumor-associated

calcium signal

transducer 2

57
0.48
0.444
34885_at
AJ002308
Hs.5097
9144
synaptogyrin 2

58
0.48
0.444
37001_at
M23254
Hs.76288
824
calpain 2, (m/II)

large subunit

59
0.48
0.443
40928_at
W26496
Hs.187991
26118
DKFZP564A122

protein

60
0.48
0.443
41078_at
D63484
Hs.98508
23144
KIAA0150 protein

61
0.47
0.443
32034_at
AF041259
Hs.155040
7764
zinc finger protein

217

62
0.47
0.442
37912_at
X80200
Hs.8375
9618
TNF receptor-

associated factor 4

63
0.47
0.442
36933_at
D87953
Hs.75789
10397
N-myc downstream

regulated

64
0.47
0.442
35442_at
AB007958
Hs.169431
57243
KIAA0489 protein

65
0.47
0.442
33754_at
U43203
Hs.197764
7080
thyroid transcription

factor 1

66
0.47
0.442
34823_at
X60708
Hs.44926
1803
dipeptidylpeptidase

IV (CD26, adenosine

deaminase

complexing protein

2)

67
0.47
0.441
35276_at
AB000712
Hs.5372
1364
claudin 4

68
0.47
0.441
40088_at
X84373
Hs.155017
8204
nuclear receptor

interacting protein 1

69
0.46
0.440
1274_s_at
L22005
Hs.76932
997
cell division cycle 34

70
0.46
0.440
39698_at
U51712
Hs.13775
84525
hypothetical protein

SMAP31

71
0.46
0.440
37103_at
AF070610
Hs.100543

clone 24505

72
0.46
0.439
39382_at
AB011089
Hs.12372
23321
KIAA0517 protein

73
0.46
0.439
37360_at
U66711
Hs.77667
4061
lymphocyte antigen

6 complex, locus E

74
0.46
0.439
32640_at
M24283
Hs.168383
3383
intercellular

adhesion molecule 1

(CD54), human

rhinovirus receptor

75
0.45
0.438
38762_at
AF083255
Hs.8765
11325
RNA helicase-

related protein

76
0.45
0.438
39021_at
AB020684
Hs.11217
23333
KIAA0877 protein

77
0.45
0.437
35326_at
AF004876
Hs.5809
10897
putative

transmembrane

protein; homolog of

yeast Golgi

membrane protein

Yif1p (Yip1p-

interacting factor)

78
0.45
0.437
33942_s_at
AF004563
Hs.239356
6812
syntaxin binding

protein 1

79
0.45
0.435
32830_g_at
X97544
Hs.20716
10440
translocase of inner

mitochondrial

membrane 17 (yeast)

homolog A

80
0.44
0.435
33448_at
AB000095
Hs.233950
6692
serine protease

inhibitor, Kunitz

type 1

81
0.44
0.434
36201_at
D13315
Hs.75207
2739
glyoxalase I

82
0.44
0.434
2035_s_at
M55914
Hs.284127
4346
MYC promoter-

binding protein 1

83
0.44
0.433
34759_at
U68494
Hs.24385

hbc647 mRNA

sequence

84
0.44
0.433
38819_at
U33635
Hs.90572
5754
PTK7 protein

tyrosine kinase 7

[0155]

8

TABLE 8

Other Markers

Class: Other

UNIGENE

(as of

Desc

GB/TIGR
summer

(unigene/locuslink

s2n_obs
Perm 0.1%
non_norm_list
Identifier
2001)
LL_num
or affy)

1
0.46
0.436
608_at
M12529
Hs.169401
348
apolipoprotein E

2
0.45
0.427
1665_s_at
HG544-

Endothelial Cell

HT544

Growth Factor 1

3
0.45
0.373
35820_at
X62078

GM2 ganglioside

activator protein

4
0.45
0.369
33338_at
M97936
Hs.21486
6772
transcription factor

ISGF-3

5
0.44
0.362
37219_at
X72755
Hs.77367
4283
monokine induced

by gamma interferon

6
0.43
0.362
33956_at
AB018549
Hs.69328
23643
MD-2 protein

7
0.42
0.355
34663_at
M28696
Hs.278443
2213
low-affinity IgG Fcreceptor

(beta-Fc-gamma-RII)

8
0.42
0.355
36879_at
M63193
Hs.73946
1890
endothelial cell

growth factor 1

(platelet-derived)

9
0.41
0.354
36659_at
X15525
Hs.75589
53
acid phosphatase 2,

lysosomal

10
0.41
0.353
37542_at
D86961
Hs.79299
10184
lipoma HMGIC

fusion partner-like 2

11
0.4
0.351
33143_s_at
U81800
Hs.85838
9123
solute carrier family

16 (monocarboxylic

acid transporters),

member 3

12
0.4
0.350
36753_at
AF072099
Hs.67846
11006
leukocyte

immunoglobulin-like

receptor, subfamily

B (with TM and

ITIM domains),

member 4

13
0.39
0.349
34342_s_at
AF052124
Hs.313
6696
secreted

phosphoprotein 1

(osteopontin, bone

sialoprotein I, early

T-lymphocyte

activation 1)

14
0.38
0.347
37310_at
X02419
Hs.77274
5328
plasminogen

activator, urokinase

15
0.38
0.346
39008_at
M13699
Hs.296634
1356
ceruloplasmin

(ferroxidase)

16
0.37
0.344
35714_at
U89606
Hs.38041
8566
pyridoxal

(pyridoxine, vitamin

B6) kinase

17
0.37
0.344
36661_s_at
X06882
Hs.75627
929
CD 14 antigen

18
0.36
0.342
38077_at
X52022
Hs.80988
1293
collagen, type VI,

alpha 3

19
0.36
0.340
32488_at
X14420
Hs.119571
1281
collagen, type III,

alpha 1 (Ehlers-

Danlos syndrome

type IV, autosomal

dominant)

20
0.36
0.340
39945_at
U09278
Hs.418
2191
fibroblast activation

protein, alpha

21
0.36
0.339
128_at
X82153
Hs.83942
1513
cathepsin K

(pycnodysostosis)

22
0.36
0.336
31859_at
J05070
Hs.151738
4318
matrix

metalloproteinase 9

(gelatinase B, 92 kD

gelatinase, 92 kD

type IV collagenase)

23
0.36
0.335
32306_g_at
J03464
Hs.179573
1278
collagen, type I,

alpha 2

24
0.35
0.334
40297_at
AC005053
Hs.61635
26872
six transmembrane

epithelial antigen of

the prostate

25
0.35
0.333
771_s_at
D00749

CD7 antigen (p41)

26
0.35
0.331
40496_at
J04080
Hs.169756
716
complement

component 1, s

subcomponent

27
0.35
0.329
1184_at
D45248
Hs.179774
5721
proteasome

(prosome,

macropain) activator

subunit 2 (PA28

beta)

28
0.34
0.329
1717_s_at
U45878
Hs.127799
330
baculoviral IAP

repeat-containing 3

29
0.34
0.329
1039_s_at
U22431
Hs.197540
3091
hypoxia-inducible

factor 1, alpha

subunit (basic helix-

loop-helix

transcription factor)

30
0.34
0.328
32193_at
AF030339
Hs.286229
10154
plexin C1

31
0.34
0.328
464_s_at
U72882
Hs.50842
3430
interferon-induced

protein 35

32
0.34
0.325
41471_at
W72424
Hs.112405
6280
S100 calcium-

binding protein A9

(calgranulin B)

33
0.33
0.325
368_at
Z29083
Hs.82128
10860
5T4 oncofetal

trophoblast

glycoprotein

34
0.33
0.323
195_s_at
U28014
Hs.74122
837
caspase 4, apoptosis-

related cysteine

protease

35
0.33
0.323
34386_at
AF072250
Hs.35947
8930
methyl-CpG binding

domain protein 4

36
0.33
0.322
38631_at
M92357
Hs.101382
7127
tumor necrosis

factor, alpha-induced

protein 2

37
0.33
0.321
37220_at
M63835

Fc fragment of IgG,

high affinity Ia,

receptor for (CD64)

38
0.33
0.321
32700_at
M55543
Hs.171862
2634
guanylate binding

protein 2, interferon-

inducible

39
0.32
0.320
32434_at
D10522
Hs.75607
4082
myristoylated

alanine-rich protein

kinase C substrate

(MARCKS, 80K-L)

40
0.32
0.320
34666_at
X07834
Hs.318885
6648
superoxide

dismutase 2,

mitochondrial

41
0.32
0.320
1633_g_at
U77735
Hs.80205
11040
pim-2 oncogene

42
0.32
0.319
39827_at
AA522530
Hs.111244
54541
hypothetical protein

43
0.32
0.319
231_at
M55153
Hs.8265
7052
transglutaminase 2

(C polypeptide,

protein-glutamine-

gamma-

glutamyltransferase)

44
0.32
0.319
35474_s_at
Y15915
Hs.172928
1277
collagen, type I,

alpha 1

45
0.32
0.318
40712_at
D26579
Hs.86947
101
a disintegrin and

metalloproteinase

domain 8

46
0.32
0.317
1042_at
U27185
Hs.82547
5918
retinoic acid receptor

responder

(tazarotene induced) 1

47
0.32
0.317
37922_at
L02648
Hs.84232
6948
transcobalamin II;

macrocytic anemia

48
0.32
0.316
35816_at
U46692
Hs.695
1476
cystatin B (stefin B)

49
0.32
0.315
38111_at
X15998
Hs.81800
1462
chondroitin sulfate

proteoglycan 2

(versican)

[0156]

9

TABLE 9

Group 1

s2n v. s2n v.
Genbank—

Rank
Feature
or_tigi
Description

1
0.89 0.57 493_at
U29171
casein kinase 1, delta

2
0.80 0.53 39431_a
AJ132583
puromycin sensitive amino-

3
0.78 0.52 1953_at
AF024710
peptidase vascular

endothelial growth factor

(VEGF)

4
0.75 0.52 34678_at
AL096713
fer-1 (C. elegans)-like 3

(myoferlin)

5
0.74 0.51 36100_at
AF022375
vascular endothelial growth

factor (VEGF)

6
0.73 0.51 32919_at
AC004010
BAC clone GS099H08

7
0.72 0.50 884_at
M59911
integrin, alpha 3 (CD49C

antigen)

8
0.71 0.49 38261_at
AF085692
ATP-binding cassette, sub-

family C (CFTR/MRP)

9
0.70 0.49 31888_s_at
AF001294
tumor suppressing subtrans-

ferable condidate 3

10
0.69 0.48 38127_at
Z48199
syndecan 1

11
0.69 0.46 33889_s_at
D79985
DiGeorge syndrome critical

region gene 2

12
0.66 0.46 38132_at
M88338
serum constituent protein

13
0.65 0.45 2017_s_at
M64349
cyclin D1 (PRAD1:

parathyroid adenomatosis

1)

14
0.64 0.45 36101_s_at
M63978
vascular endothelial growth

factor (VEGF)

15
0.64 0.45 33354_at
AA630312
E3 ubiquitin ligase

SMURF2

16
0.64 0.45 32206_at
AB007920
KIAA0450 gene product

17
0.64 0.44 1930_at
U83659
ATP-binding cassette, sub-

family C (CFTR/MRP)

18
0.64 0.44 40237_at
AF035444
tumor suppressing subtrans-

ferable candidate 3

19
0.61 0.44 168_at
U50196
Adenosine kinase

20
0.61 0.44 39962_at
U59305
ser-thr protein kinase

PK428

21
0.60 0.44 33944_at
S60099
Amyloid beta (A4)

precursor-like protein 2

22
0.60 0.44 32094_at
AB017915
condoroitin 6-

sulfotransferase

23
0.60 0.44 40504_at
AF001601
paraoxoriase 2

24
0.59 0.44 36117_at
L13616
PTK2, focal adhesion

kinase

25
0.59 0.44 40229_at
AJ010071
target of myb1-like

[0157]

10

Class-CM

Genbank

Rank
s2n v. s2n v Feature
or tigi
Description

1
2.29 0.84 40392 at
U51096
caudal type homeo box

transcription factor 2

2
1.99 0.64 170_at
U51096
caudal type homeo box

transcription factor 2

3
1.60 0.64 40736_at
X83228
cadherini 17, LI cadherin

(liver-intestine)

4
1.55 0.63 37124_i_at
J04813
cytochrome P450, subfamily

IIIA (niphedipine oxidase)

5
1.53 0.61 169_at
U51095
caudal type homeo box

transcription factor 1

6
1.48 0.60 40043_at
X71345
serine protease, trypsinogen

IV

7
1.40 0.59 35644_at
AB014598
Hephaestin

8
1.38 0.59 32972_at
Z83819
NADPH oxidase 1

9
1.38 0.59 38586_at
M10050
fatty acid binding protein 1,

liver

10
1.33 0.58 39951_at
L20826
plastin 1 (I isoform)

11
1.30 0.57 988_at
X16354
Carcineombryonic antigen-

related cell adhesion molecule

1

12
1.30 0.57 1229_at
U785566
Cisplatin resistance associated

13
1.30 0.57 37415_at
AB018258
ATPase, Class V, type 10B

14
1.27 0.57 41708_at
AB028957
KIAA1034 protein

15
1.22 0.56 765_s_at
AB006781
galectin 4

16
1.22 0.56 40694_at
X73502
cytokeratin 20

17
1.20 0.56 39697_at
U26726
hydroxysteroid (11-beta)

dehydrogenase 2

18
1.20 0.56 33904_at
AB000714
claudin 3

19
1.20 0.56 33559_at
U61412
protein tyrosine kinase PTK6

20
1.19 0.56 41266_at
X53586
Integrin, alpha 6

21
1.19 0.55 35415_at
X12901
villin 1

22
1.19 0.55 36170_at
D83198
protein expressed in thyroid

23
1.18 0.55 37847_at
AB006955
PDZ-73 protein

24
1.16 0.55 34595_at
AF105424
myosin IA

25
1.16 0.55 37125_f_at
J04813
cytochrome P450, subfamily

IIIA (niphedipine oxidase)

[0158]

11

Class-C1

Genbank—

Rank
s2n v: s2n v Feature
or_tigi
Description

1
1.29 0.85 36457_at
U10860
guanine monophosphate

synthetase

2
1.25 0.79 40117_at
D84557
Minichromosome mainte-

nance deficient (mis5, 6.

Pombe) 6

3
1.22 0.75 37337_at
A1803447
small nuclear ribonucleo-

protein polypeptide G

4
1.21 0.73 41547_at
AF047472
BUB3 homolog

5
1.17 0.69 1055_g_at
M87339
replication factor C

6
1.17 0.69 38840_s_at
L10678
profilin 2

7
1.14 0.68 33839_at
AL096719
profilin 2

8
1.12 0.68 38065_at
X62534
high-mobility group protein 2

9
1.11 0.68 709_at
J00314
tubulin, beta polypeptide

10
1.09 0.67 41583_at
AC004770
flap structure-specific

endonuclease 1

11
1.07 0.67 34783_s_at
AF047473
BUB3 homolog

12
1.06 0.67 1824_s_at
J05614
proliferating cell nuclear

antigen (PCNA)

13
1.05 0.65 40195_a:
X14850
H2A histone family, member

X

14
1.05 0.65 39109_a
AB024704
chromosome 20 open reading

frame 1

15
1.05 0.65 207_at
M86752
stress-induced-phosphoprotien

1 (Hsp70/Hsp90 organizing

protein)

16
1.04 0.65 1884_s_at
M15796
proliferating cell nuclear

antigen (PCNA)

17
1.03 0.64 34763_a
AF020043
chondroitin sulfate

proteoglycan 6 (bamacan)

18
1.03 0.64 572_at
M86699
TTK protein kinase

19
1.02 0.64 40619_a
M91670
ubiquitin carrier protein

20
1.00 0.63 151_s_at
V00599
FK506-binding protein 1A

(12 kD)

21
1.00 0.63 1803_at
X05360
cell division cycle 2, G1 to S

and G2 to M

22
0.99 0.63 1515_at
HG4074-
Rad2

HT4344

23
0.98 0.63 34791_a
X52882
t-complex 1

24
0.97 0.63 40690_a
X54942
CDC28 protein kinase 2

25
0.96 0.63 37686_s_at
Y09008
uracil-DNA glycosylse

[0159]

12

Class-C2

S2n v. S2n v.
Genebank—

Rank
Feature
or_tigi
Description

1
1.46 0.77 40035_a
AB012917
kallikrein 11

2
1.28 0.65 40544_g_at
L08424
achaete-acute comlex

homolog-like 1

3
1.27 0.59 36606_a
X51405
carboxypeptidase E

4
1.21 0.59 31477_a
L08044
trefoil factor 3 (Intestinal)

5
1.19 0.58 36299_a
X02330
calcitonin/calcitonin-related

polypeptide

6
1.17 0.57 40649_a
X64810
proprotein convertase

subtilisin/kexin type 1

7
1.16 0.57 40543_a
L08424
achaete-acute complex

homolog-like 1

8
1.16 0.57 442_at
X15187
tumor rejection antigen

(gp96)1

9
1.11 0.56 37897_s_at
AI985964
trefoil factor 3 (Intestinal)

10
1.06 056 36300_a
X15943
calcitonin/calcitonin-related

polypeptide

11
1.02 0.56 39332_a
AF035316
tubulin, beta polypeptide

12
0.97 0.55 39756_g_at
Z93930
X-box binding protein 1

13
0.96 0.54 39135_a
AB018310
KIAA0767 protein

14
0.95 0.54 34785_a
AB028948
KIAA1025 protein

15
0.92 0.53 37617_a
U90912
KIAA1128 protein

16
0.87 0.53 39755_a
Z93930
X-box binding protein 1

17
0.85 0.53 37928_a
AA621555
nuclear transcription factor

Y, beta

18
0.85 0.53 1788_s_at
U48807
dual specificity phosphatase

4

19
0.84 0.53 35995_a
AF067656
ZW10 Interactor

20
0.84 0.53 37141_a
U39840
hepatocyte nuclear factor 3,

alpha

21
0.83 0.53 40201_a
M76180
dopa decarboxylase

22
0.82 0.52 1823_g_at
HG4677-
Oncogene Ret/Ptc2

HT5102

23
0.82 0.52 35800_at
D63391
platelet-activating factor

acetylhydrolase

24
0.81 0.52 1822_at
HG4677-
Oncogen Ret/Ptc2

HT5102

25
0.81 0.52 37426_at
U80736
trinuclectide repeat

containing 9

[0160]

13

Class C3

Genebank—

Rank
52n v. 52n v Feature
or_tigi
Description

1
1.42 0.67 37669_s_at
U16799
Na+/K+ transporting

ATPase

2
1.20 0.61 36066_a:
AB020635
KIAA0828 protein

3
1.17 0.60 33699_a:
M18667
pepsinogen C gene

4
1.06 0.58 1081_at
M33764
Ornithine decarboxylase 1

5
1.06 0.57 33396_a:
U12472
Glutathione S-transferase pi

6
1.06 0.57 34319_a:
AA131149
S100 calcium-binding

protein P

7
1.04 0.56 829_s_a:
U21689
Glutathione S-transferase

pl

8
1.02 0.55 37004_a:
J02761
Pulmonary-associated

surfactant

9
1.02 0.55 40409_a:
U46689
Aldehyde dehydrogenase 3

family

10
1.02 0.52 32805_a:
U05861
aldo-ketb reductase family

1

11
1.00 0.52 36203_a:
X16277
Ornithine decarboxylase 1

12
0.99 0.52 33383_f-at
A1820718
Retinoic acid receptor

13
0.99 0.51 33052_a:
U95301
Phospholipase A2

14
0.98 0.51 35207_a:
X76180
Sodium channel,

nonvoltage-gated 1 alpha

15
0.98 0.51 38526_a:
U02882
CAMP-specific

phosphodiesterase

16
0.97 0.51 38066_a:
M81600
NAD(P)H-quinone

oxireductase

17
0.93 0.51 1882_g_at
HA4058-
Fusion activated Oncogene

HT4328
Aml1-Evi-1

18
.093 0.51 37779_at
Y08134
acid sphingomyelinase-like

phosphodiesterase

19
0.92 0.50 38773_at
AB003151
carbonyl reductase 1

20
0.90 0.50 700_s_at
HG371-
Mucin 1, Epithellial

HT26388

21
0.89 0.50 35938_at
M72393
phospholipase A2, group

IVA

22
0.88 0.50 38986_at
Z49835
glucose regulated protein,

58 kD

23
0.88 0.50 40685_at
U10868
aldehyde dehydrogenase 3

family, member B1

24
0.87 0.49 41267_at
AB028972
KIAA1049 protein

25
0.86 0.49 34839_at
AB029027
KIAA1104 protein

[0161]

14

Class NL

s2n v. s2n v.
Genbank—

Rank
Feature
or_tigi
Description

1
1.97 0.61 32542_at
AF063002
four and a half LIM

domains 1

2
1.92 0.59 1815_g_at
D50683
TGF-beta II receptor

3
1.82 0.58 36119_at
AF070648
clone 24651 mRNA

4
1.75 0.57 35868_at
M91211
advanced glycosylation end

product-specific receptor

5
1.71 0.56 39031_at
AA152406
Cytochrome c oxidase

6
1.70 0.56 37398_at
AA100961
CD31 antgen

7
1.70 0.56 40607_at
U97105
Dihydropyrimidinase-like 2

8
1.70 0.56 40841_at
AF049910
Transforming, acidic

coiled-coil containing

protein 1

9
1.69 0.55 40331_at
AF035819
Macrophage receptor with

collagenous structure

10
1.68 0.55 38454_g_at
X15606
Intercellular adhesion

molecule 2

11
1.65 0.55 36569_at
X64559
tetranectin (plasminogen-

binding protein)

12
1.63 0.55 39066_at
L38486
Microfibrillar-associated

protein 4

13
1.60 0.54 40282_s_at
M84526
adipsin/complement factor

D

14
1.60 0.54 34320_at
AL050224
polymerase I and transcript

release factor

15
1.60 0.54 37027_at
M80899
AHNAK nucleoprotein

(desmoyokin)

16
1.58 0.54 33328_at
W28612
EST

17
1.58 0.54 1814_at
D50683
TGF-beta II receptor

18
1.58 0.54 35985_at
AB023137
A kinase (PRKA) anchor

protein 2

19
1.57 0.53 38177_at
AJ001015
RAMP2

20
1.57 0.53 39775_at
X54488
C1-Inhibitor

21
1.57 0.53 770_at
D00632
glutathione peroxidase 3

22
1.54 0.53 39760_at
AL031781
KH domain RNA binding

protein

23
1.54 0.53 268_at
L34657
platelet/endothelial cell

adhesion molecule-1

(PECAM-1)

24
1.53 0.52 33756_at
U39447
amine oxidase (vascular

adhesion protein 1)

25
1.52 0.52 40419_at
X85116
erythrocyte membrane

protein band 7.2 (stomatin)

[0162]

15

Class-C5

Genbank

Rank
s2n v. s2n v Feature
or tigi
Description

1
1.06 0.73 1411_at
D16154
P-450c11

2
1.04 0.70 37021_at
X16832
Cathepsin H

3
1.02 0.70 534_s_at
U20391
folate receptor 1 (adult)

4
0.95 0.69 38394_at
D42047
KIAA0089 protein

5
0.94 0.67 1460_g_at
M68941
Protein tyrosine phosphatase

6
0.92 0.67 33331_at
U17077
BENE protein

7
0.91 0.65 38336_at
AB023230
K1AA1013 protein

8
0.89 0.65 31883_at
AF025794
Methionine synthase reductase

(MTRR)

9
0.88 0.65 35016_at
M13560
1a-associated invariant

gamma-chain

10
0.88 0.65 37512_at
U89281
Oxidative 3 alpha hydroxy-

steroid dehydrogenase

11
0.87 0.64 1629_s_at
HG3187-
Tyrosine Phosphatase 1, Non-

HT3366
Receptor

12
0.86 0.64 38459_g_at
L39945
Cytochrome b5 (CYB5) gene

13
0.86 0.64 34139_at
AL049651
Somatostatin receptor 4

14
0.86 0.63 36965_at
U13616
Ankyrin G (ANK-3)

15
0.85 0.63 130_s_at
X82850
Thyroid transcription factor 1

16
0.85 0.63 593_s_at
M34353
v-ros avian UR2 sarcoma

virus oncogene homolog 1

17
0.85 0.63 33278_at
AC004381
SA (rat hypertension-

associated) homolog

18
0.85 0.63 821_s_at
U78793
folate receptor alpha (hFR)

19
0.82 0.63 40617_at
AC004381
Hypothetical protein

FLJ20274

20
0.82 0.63 35792_at
U67963
Lysophospholipase-like

21
0.80 0.63 38785_at
X52228
mucin 1, transmembrane

22
0.80 0.63 33967_at
M31525
major histocompatibility

complex, class II

23
0.80 0.63 34198_at
U12128
APO-1/CD95 (Fas)-associated

phosphatase

24
0.80 0.62 33584_at
U35146
CDC2-related kinase

25
0.80 0.62 33249_at
M16801
Nuclear receptor subfamily 3,

group C, member 2

[0163] The invention may be embodied in other specific forms without departing from the spirit or essential characteristics thereof. The foregoing embodiments are therefore to be considered in all respects illustrative rather then limiting on the invention described herein. Scope of the invention is thus indicated by the appended claims rather than by the foregoing description, and all changes which come within the meaning and range of equivalency of the claims are intended to be embraced therein.

[0164] Each of the patent documents and scientific publications disclosed hereinabove is incorporated by reference herein in its entirety.

Classification of lung carcinomas using gene expression analysis

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Date Filed

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Inventors

CPC

US Classifications

International Classifications

Abstract

Description

Claims

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