Abstract:
The CpG island methylator phenotype (CIMP), together with extensive promoter methylation, is regarded as one of the mechanisms involved in colorectal carcinogenesis (CRC). The mechanisms underlying the presence of CIMP in sporadic colorectal cancer are poorly understood. Genes involved in methyl-group metabolism are likely to affect DNA methylation and thereby influence an individual's susceptibility to CIMP. To test this hypothesis, we examined the potential association between the polymorphisms of MTHFR 677C>T, TS 5’UTR 2R/3RG>C, TS 3’UTR 1494del6, MTHFD1 401G>A, DNMT3B -149C>T and DNMT3B -283T>C and the presence of CIMP in a group of 186 sporadic CRC cases and 100 controls. The CIMP status of the tumors was determined by a panel of five markers (CACNA1G, IGF2, NEUROG1, RUNX3 and SOCS1), which was also followed by analysing hMLH1 methylation and BRAF V600E mutation. Individuals with TS 3R/3R had an increased risk of CIMP- colorectal cancer (OR = 2.38, 95% CI = 1.0-5.7; P = 0.042, Fisher's exact test) when compared with 2R/2R homozygotes. Individuals with DNMT3B -283 CC reduced risk of CIMP+ colorectal cancer (OR = 0.220, 95% CI = 0.0226-1.07; P = 0.046, Fisher's exact test) when compared to -283 TT carriers. This study provides some support to the hypothesis that methyl-group metabolism plays a role in the etiology of both CIMP+ and CIMP - colorectal cancers.