DNMT3b -149C/T promoter variants and methylation of colorectal cancer-associated genes.

Abstract

DNMT3B overexpression has been linked with the CpG island methylator phenotype in various cancers. Considering the role of the DNMT3b -149C/T promoter polymorphism on the gene expression, we evaluated the associations of this polymorphism with colorectal cancer (CRC) risk and hypermethylation of six tumor suppressor genes in CRC tumors. The DNMT3b was genotyped by PCR-RFLP in 108 sporadic CRC patients and 185 healthy controls and methylation of genes' promoter was determined by methylation specific PCR. In comparison to controls, the TT genotype was strongly associated with a high risk of cancer incidence (OR = 3.3, 95% CI = 1.6-6.9). The frequency of methylated hMLH1 was significantly higher in patients with the DNMT3bCT genotype (p= 0.03), especially in male subjects. The frequency of hMLH1 methylation was significantly higher in young patients (< 60 years) with the CT/TT genotypes. The combined CT/TT genotypes also showed significant associations with the ECAD methylation in the entire group of patients (p= 0.04), in patients with distal tumors, and in old cases. The DNMT3b genotype was not associated with methylation of other genes examined in this study. Our results suggest that DNMT3b polymorphism is involved in the development of colon cancer and non-random genes promoter methylation among Iranian population.