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Nutritional Epidemiology

Folic Acid and Vitamin B-12 Supplementation Does Not Favorably Influence Uracil Incorporation and Promoter Methylation in Rectal Mucosa DNA of Subjects with Previous Colorectal Adenomas^1,2

³ Division of Human Nutrition, Wageningen University, 6700 EV Wageningen, The Netherlands; ⁴ Food Bioactives Group, RIKILT-Institute of Food Safety, 6700 AE Wageningen, The Netherlands; ⁵ Vitamins and Carcinogenesis Laboratory, Jean Mayer USDA Human Nutrition Research Center on Aging, Tufts University, Boston, MA 02478; ⁶ The Research Institute GROW, Department of Pathology, University Maastricht, 6200 MD Maastricht, The Netherlands; ⁷ Department of Gastroenterology and Hepatology, Radboud University Nijmegen Medical Centre, 6500 HB Nijmegen, The Netherlands; ⁸ Department of Gastroenterology, Gelderse Vallei Hospital, 6710 HN Ede, The Netherlands; and ⁹ Department of Gastroenterology, Slingeland Hospital, 7000 AD Doetinchem, The Netherlands

^* To whom correspondence should be addressed. E-mail: ellen.kampman{at}wur.nl.

Adequate folate availability is necessary to sustain normal DNA synthesis and normal patterns of DNA methylation and these features of DNA can be modified by methylenetetrahydrofolate reductase (MTHFR) C677T genotype. This study investigated the effect of MTHFR C677T genotype and daily supplementation with 5 mg folic acid and 1.25 mg vitamin B-12 on uracil misincorporation into DNA and promoter methylation. Subjects (n = 86) with a history of colorectal adenoma and MTHFR CC or TT genotype were randomly assigned to receive folic acid plus vitamin B-12 or placebo for 6 mo. Uracil misincorporation and promoter methylation of 6 tumor suppressor and DNA repair genes were assessed in DNA from rectal biopsies at baseline and after the intervention. The biomarkers did not differ between the treated group and the placebo group after 6 mo compared with baseline. The uracil concentration of DNA increased in the treated group (5.37 fmol/µg DNA, P = 0.02), whereas it did not change in the placebo group (P = 0.42). The change from baseline of 4.01 fmol uracil/µg DNA tended to differ between the groups (P = 0.16). An increase in promoter methylation tended to occur more often in the intervention group than in the placebo group (OR = 1.67; P = 0.08). This study suggests that supplementation with high doses of folic acid and vitamin B-12 may not favorably influence uracil incorporation and promoter methylation in subjects with previous colorectal adenomas. Because such alterations may potentially increase the risk of neoplastic transformation, more research is needed to fully define the consequences of these molecular alterations.