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Association between DNA Methylation and Shortened Survival in Patients with Advanced Colorectal Cancer Treated with 5-Fluorouracil–Based Chemotherapy

Authors' Affiliation: ¹ The University of Texas M. D. Anderson Cancer Center, Houston, Texas; ² Eastern Cooperative Oncology Group Statistical Center, Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, Massachusetts; ³ Northwestern University Feinberg School of Medicine, Chicago, Illinois; and ⁴ University of Pennsylvania Cancer Center, Philadelphia, Pennsylvania

Requests for reprints: Jean-Pierre Issa, Department of Leukemia, M. D. Anderson Cancer Center, Unit 428, 1515 Holcombe Blvd., Houston, TX 77030. Phone: 713-745-2260; Fax: 713-794-4297; E-mail: jpissa{at}mdanderson.org.

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-2a 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 hMLH1, 11% for p14^ARF, and 17% for p16^INK4a. 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 p14^ARF, and 1.51 (P = 0.05) for p16^INK4a. Concurrent methylation of two or more genes of the CIMP-associated subset (MINT1, MINT31, p14^ARF 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.

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