The effect of folic acid supplementation on dna biomarkers of colorectal cancer risk (uracil misincorporation, global and gene-specific dna hypomethylation) : a randomised intervention study

Abstract

Background - Alterations in folate status are associated with colorectal carcinogenesis. Folate&rsquo;s role has been postulated to be either via prevention of changes in DNA methylation or uracil misincorporation.Objective - To investigate the effect of folic acid supplementation on colonocyte folate status and DNA biomarkers. Design - Twenty individuals harbouring colonic adenomas were randomised to receive folic acid (600 g daily) or placebo for 6 months post polypectomy. Systemic and colonocyte folate status was determined at baseline and following the intervention. Modified Comet assays were used to determine uracil misincorporation and global DNA hypomethylation at the site adjacent to the polyp and a site distal to the polyp. Outcomes - Supplementation resulted in increased colonocyte folate, which approached significance, at the site adjacent to the polyp (P= 0.06) but not distal to the polyp (P= 0.36); correspondingly there was a reduction in uracil misincorporation at the site adjacent to the polyp (P = 0.02) and the distal site showed no such trend (P= 0.39). There were no significant changes in global DNA hypomethylation at either site post-intervention. Conclusions - Folic acid supplementation resulted in increased colonocyte folate and decreased uracil misincorporation at the site of the adenoma but not distal to the adenoma. This supports the hypothesis that localised areas of folate deficiency may exist in human colonic mucosa which respond to folic acid supplementation through increasing colonocyte folate and improving folate-related DNA biomarkers of cancer risk.<br /