Folate status, genomic DNA hypomethylation, and risk of colorectal adenoma and cancer: A case control study

Background & Aims: Low folate intake may increase risk for colorectal cancer by inducing DNA hypomethylation. This study reports the influence of folate status, DNA methylation, and polymorphisms of methylenetetrahydrofolate reductase (MTHFR 677C-->T and 1298A-->C), methionine synthase (MS 2756A-->G), and cystathionine-beta-synthase (CBS 844ins68) on risk for developing colorectal neoplasia. Methods: Thirty-five patients with adenoma, 28 patients with cancer and 76 controls were recruited for a case control study. Recruitment consent rate was 98%. Blood samples were obtained for determination of blood folates, vitamin B-12, homocysteine, DNA methylation, and genotypes. Tissue biopsy samples were obtained at colonoscopy for determination of DNA methylation in colonic mucosa. Folate status was assessed by constructing a score from estimates of dietary intake and serum and erythrocyte folate. Results: Cancer patients had 26% lower folate status (95% confidence interval [CI]: 6% to 44%, P = 0.01) and 21% lower serum vitamin B-12 concentration (95% CI: -38% to 1%, P = 0.06) compared with controls. [H-3] methyl incorporation into colonic DNA was 26% higher in patients with adenoma (95% CI: 8% to 56%, P = 0.009) and 30% higher in patients with cancer (95% CI: -3% to 48%, P = 0.08) compared with controls. High folate status was associated with decreased risk for cancer (P = 0.01 for trend). Colonic and leukocyte DNA hypomethylation were associated with increased risk for adenoma (P = 0.02 and P = 0.01 for trend, respectively) and a nonsignificantly increased risk for cancer (P = 0.09 and P = 0.08 for trend, respectively). Conclusions: Low folate status and DNA hypomethylation are associated with colorectal neoplasia.