Promoter Methylation of Specific Genes is Associated with the Phenotype and Progression of Colorectal Adenocarcinomas

Background

Promoter methylation of colorectal cancer-related genes were examined with respect to phenotype and tumor progression.

Materials and Methods

We assayed promoter methylation of 11 genes including established CpG island methylator phenotype (CIMP) markers (MLH1, MINT1, MINT2, MINT31, p16 ^INK4a , p14 ^ARF , and CACNA1G) and four genes (COX2, DAPK, MGMT, and APC) frequently methylated in colorectal cancer in 285 patients with sporadic colorectal cancer.

Results

CIMP+ tumors were more than two times more frequent among high-frequency microsatellite instability tumors (MSI-H) than in tumors without MSI (P ≤ .0001–.002). COX2 and DAPK methylation were significantly associated with CIMP+ and MSI. KRAS showed tendency toward more frequent codon 12-13 mutations identified in tumors with APC and p16 ^INK4a methylation than in those with unmethylation (P = .033 and .05, respectively). Additionally, tumors with synchronous adenoma were associated with p16 ^INK4a methylation (P = .004). The p16 ^INK4a methylation was significantly associated with poor overall and disease-free survival in 131 rectal cancer patients who underwent curative operation, according to multivariate analyses (relative risk [RR] = 0.317 and 0.349; P = .033 and .024, respectively). Specifically, in 175 stage II and III patients receiving adjuvant-based fluoropyrimidine chemotherapy, p16 ^INK4a methylation and MINT31 unmethylation showed a significant or tendency toward an association with recurrence and DFS (P = .007–.032).

Conclusions

The study suggests that specific CIMP markers, such as p16 ^INK4a and MINT31, should be further verified as potential epigenetic targets for the design of efficient chemotherapy regimens. We also identified a subset of colorectal cancer, possibly comprising APC methylation-KRAS mutation-p16 ^INK4a methylation.