Methods of Subtyping CRC and their association with Treatment of Colon Cancer Patients With Oxaliplatin

Abstract

A gene expression signature identifies stage II colon and/or Stage III cancer patients who will receive benefit from oxaliplatin. Oxaliplatin has been shown to lengthen the survival of colon cancer patients, when it is combined with 5-fluorouracil plus leucovorin (FULV) in NSABP clinical trial C-07. Gene expression signatures are used first to classify tumors with regard to their respective subtypes, enterocyte, TA, goblet, inflammatory and stem-like and detection of expression of the enterocyte subtype directs treatment of the patient with oxaliplatin.

We claim: 
     
         1 . A method of treating a colon cancer patient comprising:
 a) obtaining a colon cancer tumor tissue sample from a patient with colon cancer,   b) contacting a genetic sample from said colon cancer tumor tissue sample with a plurality of specific genetic sequence binding targets and measuring the expression level of a panel consisting essentially of 72 genes, wherein the 72 genes are AKAP12, ANKRD44, BGN, BHLHE41, BMP7, C8orf84, CAB39L, CDKN2B, CKMT2, COL11A1, COMP, CPE, CSGALNACT1, CXCL10, CXCL11, CXCL13, CXCL2, CXCL9, CYP1B1, DAPK1, DCBLD2, DPEP1, EPB41L4B, ERAP2, F5, FAP, FGL2, FN1, FNDC1, GBP1, GBP4, GPX3, GRM8, GZMB, HGD, HOXA13, HSD17B2, ID4, IDO1, IL8, INHBA, MFAP5, MGP, MMP11, MMP28, NFIB, OAS2, PAPPA, PIGR, PLA2G12B, POU2AF1, PRAP1, PROM2, PSMB9, PTPRC, ROBO1, SDC2, SELL, SERPINE1, SFRP2, SGK2, SLC4A4, SPARC, SPP1, SSPN, STC1, TACSTD2, TGFBR3, TM4SF1, TYMS, VCAN, and VNN1,   c) obtaining a gene expression signature for said colon cancer tumor tissue from the gene expression level of the panel of 72 genes in b),   d) responsive to the gene expression signature, identifying said colon cancer tumor tissue as being a subtype responsive to oxaliplatin.   
     
     
         2 . The method of  claim 1  further comprising the step of administering oxaliplatin in combination with 5′ fluorouracil and leucovorin (FULV) to said patient with colon cancer in a). 
     
     
         3 . The method of  claim 2 , wherein the genetic sample comprises cDNA or RNA either in purified form or as a tissue lysate. 
     
     
         4 . The method of  claim 2 , wherein the identified tumor tissue subtype is of the enterocyte tissue type. 
     
     
         5 . A method for treating colon cancer in a patient with Stage II or Stage III colon cancer comprising:
 a) obtaining a colon cancer tumor tissue sample from a patient with Stage II or Stage III colon cancer,   b) isolating RNA or producing a lysate from the colon cancer tumor tissue sample,   c) contacting said RNA or said lysate with a plurality of sequence specific probes capable of determining the level of expression of a panel of 72 genes, wherein the panel of 72 genes are AKAP12, ANKRD44, BGN, BHLHE41, BMP7, C8orf84, CAB39L, CDKN2B, CKMT2, COL11A1, COMP, CPE, CSGALNACT1, CXCL10, CXCL11, CXCL13, CXCL2, CXCL9, CYP1B1, DAPK1, DCBLD2, DPEP1, EPB41L4B, ERAP2, F5, FAP, FGL2, FN1, FNDC1, GBP1, GBP4, GPX3, GRM8, GZMB, HGD, HOXA13, HSD17B2, ID4, IDO1, IL8, INHBA, MFAP5, MGP, MMP11, MMP28, NFIB, OAS2, PAPPA, PIGR, PLA2G12B, POU2AF1, PRAP1, PROM2, PSMB9, PTPRC, ROBO1, SDC2, SELL, SERPINE1, SFRP2, SGK2, SLC4A4, SPARC, SPP1, SSPN, STC1, TACSTD2, TGFBR3, TM4SF1, TYMS, VCAN, and VNN1,   d) measuring the gene expression level of the panel of 72 genes and obtaining a gene expression signature for said colon cancer tumor tissue from the gene expression level of said genes in c),   e) responsive to the gene expression signature, identifying said colon cancer tumor tissue as being a subtype responsive to oxaliplatin, and   f) administering oxaliplatin to said patient with Stage II or Stage III colon cancer.   
     
     
         6 . The method of  claim 5 , wherein the oxaliplatin is administered in combination with 5′ fluorouracil and leucovorin (FULV). 
     
     
         7 . The method of  claim 5 , wherein the colon cancer tumor tissue sample is a subtype of the enterocyte tissue type. 
     
     
         8 . The method according to  claim 1  wherein, if the colon cancer tumor tissue is not identified as being of the subtype not responsive to oxaliplatin, then oxaliplatin is not administered to the patient. 
     
     
         9 . The method according to  claim 5  wherein, if the colon cancer tumor tissue is not identified as being of the subtype not responsive to oxaliplatin, then oxaliplatin is not administered to the patient. 
     
     
         10 . The method of  claim 1 , wherein said patient is a Stage II colon cancer patient. 
     
     
         11 . The method of  claim 1 , wherein said patient is a Stage III colon cancer patient.