科研之友
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摘要
Purpose: There are no good genomic markers of survival in patients with advanced colorectal cancer. The CpG island methylator phenotype (CIMP) marks a distinctive pathway in colorectal cancer. We sought to determine the prognostic significance of CIMP in advanced colorectal cancer patients treated with 5-fluorouracil (5-FU) in an Eastern Cooperative Oncology Group clinical trial. Experimental Design: We studied 188 patients enrolled on protocol E2290, a five-arm trial comparing 5-FU, 5-FU in combination with N-phosphonoacetyl-L-aspartic acid, oral leucovorin, i.v.. leucovorin, or IFN alpha-2 alpha in patients with advanced colorectal cancer. Methylation of MINT1, MINT31, hMLH1, p14(ARF) and p16(INK4a) in DNA extracted from formalin-fixed paraffin-embedded specimens was evaluated by combined bisulfite restriction analysis, and methylation of MINT2 was studied by methylation-specific PCR. Results: Methylation frequencies were 21% for MINT1, 23%for MINT2, 24% for MINT31,4% for WK4, R hMLH1, 11% for p14ARF, and 17% for p16. Methylation of MINT1, MINT31, p14(ARF), and p16(INK4a) were correlated, as expected. There was no association between methylation and clinicopathologic factors or response to therapy. Methylation of MINT1, MINT31, p14(ARF) or p16(INK4a) was associated individually with shortened overall survival. Hazard ratios were 1.51 (P = 0.05) for MINT1, 1.70 (P = 0.006) for MINT31, 2.22 (P = 0.001) for p144RF, and 1.51 (P = 0.05) for p16(INK4a). Concurrent methylation of two or more genes of the CIMP-associated subset (MINT1, MINT31, p144RF and p16(INK4a)) defined a group of cases with markedly reduced overall survival and hazard ratio was 3.22 (P < 0.0001 in multivariate analyses). Conclusions: CIMP is associated with poor survival in advanced colorectal cancer patients.
- 出版日期2007-10-15
- 单位西北大学
