Gene expression markers for prediction of patient response to chemotherapy

Abstract

The present invention relates to gene sets useful in assessing prognosis and/or predicting the response of cancer, e.g. colorectal cancer to chemotherapy. In addition, the invention relates to a clinically validated cancer test, e.g. colorectal test, for assessment of prognosis and/or prediction of patient response to chemotherapy, using expression analysis. The present invention accommodates the use of archived paraffin embedded biopsy material for assay of all markers in the relevant gene sets and therefore is compatible with the most widely available type of biopsy material.

What is claimed: 
     
         1 . A method of predicting a likelihood that a human patient diagnosed with cancer will exhibit a positive clinical response to treatment with chemotherapy, comprising:
 determining an expression level of at least one gene listed in Table 5 or a co-expressed gene thereof, in a tumor sample obtained from said patient,   using the expression level to calculate a likelihood of a positive clinical response to chemotherapy, wherein
 increased expression of one or more of the genes selected from the group consisting of AURKB, Axin 2, BIK, BRAF, BRCA2, BUB1, C20 orf1, C20ORF126, CASP9, CCNE2 variant 1, CDC2, CDC4, CENPA, CENPF, CLIC1, CYR61, Cdx2, Chk1, DLC1, DUSP1, E2F1, EGR3, EI24, ESPL1, FBXO5, FGF2, FOS, FUT6, GSK3B, Grb10, HES6, HLA-G, HNRPAB, HOXB13, HSPE1, KIF22, KIFC1, KLRK1, Ki-67, LAT, LMYC, MAD2L1, MSH2, MSH3, NR4A1, PDGFA, PRDX2, RAB32, RAD54L, RANBP2, RCC1, ROCK2, RhoB, S100P, SAT, SOD1, SOS1, STK15, TCF-1, TOP2A, TP53BP1, UBE2C, VCP, and cMYC, or their corresponding expression products, is positively correlated with an increased likelihood of a positive response to chemotherapy; and 
 increased expression of one or more of the genes selected from the group consisting of ABCB1, AMFR, ANXA1, APC, B-Catenin, BGN, CALD1, CD44E, CD44s, CD44v6, CD68, CDH11, CHFR, CLDN1, CLTC, COL1A1, COL1A2, CREBBP, CTSB, CTSL, CXCL12, EFNB2, ENO1, EPAS1, FGF18, FOXO3A, FPGS, FZD1, GJB2, GPX1, HIF1A, HNRPD, HSD17B2, HoxA5, IGFBP3, IGFBP5, IGFBP7, IL6ST, ITGA5, KLF5, KLK10, KRT8, LEF, LOX, MADH7, MCM3, MCP1, MMP1, MMP2, Maspin, NRP1, PDGFC, PDGFD, PDGFRa, PFN2, PKR2, RUNX1, SEMA4B, SIAT4A, SKP2, SPARC, SPRY1, THBS1, TIMP1, UPP1, and VDAC2, or their corresponding products, is negatively correlated with a likelihood of a positive response to chemotherapy; and 
   generating a report based on the likelihood of a positive clinical response to chemotherapy.   
     
     
         2 . The method of  claim 1  wherein said method is a PCR-based method. 
     
     
         3 . The method of  claim 1  wherein said method is an array-based method. 
     
     
         4 . The method of  claim 1  wherein said expression level is normalized relative to the expression levels of one or more reference genes, or their expression products. 
     
     
         5 . The method of  claim 1  wherein said cancer is colorectal cancer. 
     
     
         6 . The method of  claim 5 , wherein the colorectal cancer Dukes B (stage II) or Dukes C (stage III) colorectal cancer. 
     
     
         7 . The method of  claim 1  wherein said cancer is colon cancer. 
     
     
         8 . The method of  claim 7 , wherein said colon cancer is Duke B (stage II) or Dukes C (stage III) colon cancer. 
     
     
         9 . The method of  claim 1  comprising determining the expression levels of at least two of said genes, or their expression products. 
     
     
         10 . The method of  claim 1  comprising determining the expression levels of at least three of said genes, or their expression products. 
     
     
         11 . The method of  claim 1  comprising determining the expression levels of at least four of said genes, or their expression products. 
     
     
         12 . The method of  claim 1  comprising determining the expression levels of at least five of said genes, or their expression products. 
     
     
         13 . The method of  claim 1  wherein the chemotherapy is a 5-fluorouracil (5-FU) therapy. 
     
     
         14 . A method for analyzing a colorectal cancer tissue sample to deterimine whether the sample contains cancer cells likely to respond to a chemotherapy, the method comprising:
 determining a normalized expression value for at least one gene from Table 5, or its expression product, in a colorectal cancer tissue sample obtained from the patient;   inputting the normalized expression value of the least one gene from Table 5, or a gene co-expressed with a gene of Table 5, into a computer programmed to execute an algorithm to convert the value to a score indicative of a likelihood of the patient to respond to chemotherapy, wherein
 expression of one or more of the genes selected from the group consisting of AURKB, Axin 2, BIK, BRAF, BRCA2, BUB1, C20 orf1, C20ORF126, CASP9, CCNE2 variant 1, CDC2, CDC4, CENPA, CENPF, CLIC1, CYR61, Cdx2, Chk1, DLC1, DUSP1, E2F1, EGR3, EI24, ESPL1, FBXO5, FGF2, FOS, FUT6, GSK3B, Grb10, HES6, HLA-G, HNRPAB, HOXB13, HSPE1, KIF22, KIFC1, KLRK1, Ki-67, LAT, LMYC, MAD2L1, MSH2, MSH3, NR4A1, PDGFA, PRDX2, RAB32, RAD54L, RANBP2, RCC1, ROCK2, RhoB, S100P, SAT, SOD1, SOS1, STK15, TCF-1, TOP2A, TP53BP1, UBE2C, VCP, and cMYC, or a gene co-expressed with one or more of said genes, is positively correlated with an increased likelihood of a positive clinical response to treatment with chemotherapy; and 
 expression of one or more of the genes selected from the group consisting of ABCB1, AMFR, ANXA1, APC, B-Catenin, BGN, CALD1, CD44E, CD44s, CD44v6, CD68, CDH11, CHFR, CLDN1, CLTC, COL1A1, COL1A2, CREBBP, CTSB, CTSL, CXCL12, EFNB2, ENO1, EPAS1, FGF18, FOXO3A, FPGS, FZD1, GJB2, GPX1, HIF1A, HNRPD, HSD17B2, HoxA5, IGFBP3, IGFBP5, IGFBP7, IL6ST, ITGA5, KLF5, KLK10, KRT8, LEF, LOX, MADH7, MCM3, MCP1, MMP1, MMP2, Maspin, NRP1, PDGFC, PDGFD, PDGFRa, PFN2, PKR2, RUNX1, SEMA4B, SIAT4A, SKP2, SPARC, SPRY1, THBS1, TIMP1, UPP1, and VDAC2, or a gene co-expressed with one or more of said genes, is negatively correlated withan increased likelihood of a positive response to treatment with chemotherapy; 
   and
 generating a report comprising the score. 
   
     
     
         15 . The method of  claim 14 , wherein said tumor sample is obtained from a solid tumor. 
     
     
         16 . The method of  claim 14 , wherein said solid tumor is colorectal cancer. 
     
     
         17 . The method of  claim 14 , wherein the chemotherapy is a a 5-fluorouracil (5-FU)-based treatment.