Effect of Folic Acid Supplementation on Genomic DNA Methylation in Patients with Colorectal Adenoma

Overview

Journal Gut

Specialty Gastroenterology

Date 2005 Apr 16

PMID 15831910

Citations 80

Authors

M Pufulete

R Al-Ghnaniem

A Khushal

P Appleby

N Harris

S Gout

P W Emery

T A B Sanders

Affiliations

Soon will be listed here.

Abstract

Background And Aims: A low dietary folate intake can cause genomic DNA hypomethylation and may increase the risk of colorectal neoplasia. The hypothesis that folic acid supplementation increases DNA methylation in leucocytes and colorectal mucosa was tested in 31 patients with histologically confirmed colorectal adenoma using a randomised, double blind, placebo controlled, parallel design.

Methods: Subjects were randomised to receive either 400 microg/day folic acid supplement (n = 15) or placebo (n = 16) for 10 weeks. Genomic DNA methylation, serum and erythrocyte folate, and plasma homocysteine concentrations were measured at baseline and post intervention.

Results: Folic acid supplementation increased serum and erythrocyte folate concentrations by 81% (95% confidence interval (CI) 57-104%; p<0.001 v placebo) and 57% (95% CI 40-74%; p<0.001 v placebo), respectively, and decreased plasma homocysteine concentration by 12% (95% CI 4-20%; p = 0.01 v placebo). Folic acid supplementation resulted in increases in DNA methylation of 31% (95% CI 16-47%; p = 0.05 v placebo) in leucocytes and 25% (95% CI 11-39%; p = 0.09 v placebo) in colonic mucosa.

Conclusions: These results suggest that DNA hypomethylation can be reversed by physiological intakes of folic acid.

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References

Ahuja N, Li Q, Mohan A, Baylin S, Issa J . Aging and DNA methylation in colorectal mucosa and cancer. Cancer Res. 1998; 58(23):5489-94. View

Keku T, Millikan R, Worley K, Winkel S, Eaton A, Biscocho L . 5,10-Methylenetetrahydrofolate reductase codon 677 and 1298 polymorphisms and colon cancer in African Americans and whites. Cancer Epidemiol Biomarkers Prev. 2002; 11(12):1611-21. View

Bird C, SWENDSEID M, Witte J, Shikany J, Hunt I, FRANKL H . Red cell and plasma folate, folate consumption, and the risk of colorectal adenomatous polyps. Cancer Epidemiol Biomarkers Prev. 1995; 4(7):709-14. View

Nagothu K, Jaszewski R, Moragoda L, Rishi A, Finkenauer R, Tobi M . Folic acid mediated attenuation of loss of heterozygosity of DCC tumor suppressor gene in the colonic mucosa of patients with colorectal adenomas. Cancer Detect Prev. 2003; 27(4):297-304. DOI: 10.1016/s0361-090x(03)00100-4. View

Paspatis G, Karamanolis D . Folate supplementation and adenomatous colonic polyps. Dis Colon Rectum. 1994; 37(12):1340-1. DOI: 10.1007/BF02257810. View

Ulrich C, Kampman E, Bigler J, Schwartz S, Chen C, Bostick R . Colorectal adenomas and the C677T MTHFR polymorphism: evidence for gene-environment interaction?. Cancer Epidemiol Biomarkers Prev. 2000; 8(8):659-68. View

Pufulete M, Al-Ghnaniem R, Leather A, Appleby P, Gout S, Terry C . Folate status, genomic DNA hypomethylation, and risk of colorectal adenoma and cancer: a case control study. Gastroenterology. 2003; 124(5):1240-8. DOI: 10.1016/s0016-5085(03)00279-8. View

Friso S, Choi S, Girelli D, Mason J, Dolnikowski G, Bagley P . A common mutation in the 5,10-methylenetetrahydrofolate reductase gene affects genomic DNA methylation through an interaction with folate status. Proc Natl Acad Sci U S A. 2002; 99(8):5606-11. PMC: 122817. DOI: 10.1073/pnas.062066299. View

Ma J, Stampfer M, Christensen B, Giovannucci E, Hunter D, Chen J . A polymorphism of the methionine synthase gene: association with plasma folate, vitamin B12, homocyst(e)ine, and colorectal cancer risk. Cancer Epidemiol Biomarkers Prev. 1999; 8(9):825-9. View

10.

Harmon D, Shields D, Woodside J, McMaster D, Yarnell J, Young I . Methionine synthase D919G polymorphism is a significant but modest determinant of circulating homocysteine concentrations. Genet Epidemiol. 1999; 17(4):298-309. DOI: 10.1002/(SICI)1098-2272(199911)17:4<298::AID-GEPI5>3.0.CO;2-V. View

11.

Shelnutt K, Kauwell G, Gregory 3rd J, Maneval D, Quinlivan E, Theriaque D . Methylenetetrahydrofolate reductase 677C-->T polymorphism affects DNA methylation in response to controlled folate intake in young women. J Nutr Biochem. 2004; 15(9):554-60. DOI: 10.1016/j.jnutbio.2004.04.003. View

12.

Lashner B . Red blood cell folate is associated with the development of dysplasia and cancer in ulcerative colitis. J Cancer Res Clin Oncol. 1993; 119(9):549-54. DOI: 10.1007/BF01686465. View

13.

Cui H, Onyango P, Brandenburg S, Wu Y, Hsieh C, Feinberg A . Loss of imprinting in colorectal cancer linked to hypomethylation of H19 and IGF2. Cancer Res. 2002; 62(22):6442-6. View

14.

Shannon B, Gnanasampanthan S, Beilby J, Iacopetta B . A polymorphism in the methylenetetrahydrofolate reductase gene predisposes to colorectal cancers with microsatellite instability. Gut. 2002; 50(4):520-4. PMC: 1773174. DOI: 10.1136/gut.50.4.520. View

15.

Ma J, Stampfer M, Giovannucci E, Artigas C, Hunter D, Fuchs C . Methylenetetrahydrofolate reductase polymorphism, dietary interactions, and risk of colorectal cancer. Cancer Res. 1997; 57(6):1098-102. View

16.

Balaghi M, Wagner C . DNA methylation in folate deficiency: use of CpG methylase. Biochem Biophys Res Commun. 1993; 193(3):1184-90. DOI: 10.1006/bbrc.1993.1750. View

17.

Levine A, Siegmund K, Ervin C, Diep A, Lee E, FRANKL H . The methylenetetrahydrofolate reductase 677C-->T polymorphism and distal colorectal adenoma risk. Cancer Epidemiol Biomarkers Prev. 2000; 9(7):657-63. View

18.

Issa J, Ottaviano Y, Celano P, Hamilton S, Davidson N, Baylin S . Methylation of the oestrogen receptor CpG island links ageing and neoplasia in human colon. Nat Genet. 1994; 7(4):536-40. DOI: 10.1038/ng0894-536. View

19.

Selhub J, Jacques P, Rosenberg I, Rogers G, Bowman B, Gunter E . Serum total homocysteine concentrations in the third National Health and Nutrition Examination Survey (1991-1994): population reference ranges and contribution of vitamin status to high serum concentrations. Ann Intern Med. 1999; 131(5):331-9. DOI: 10.7326/0003-4819-131-5-199909070-00003. View

20.

van Engeland M, Weijenberg M, Roemen G, Brink M, de Bruine A, Goldbohm R . Effects of dietary folate and alcohol intake on promoter methylation in sporadic colorectal cancer: the Netherlands cohort study on diet and cancer. Cancer Res. 2003; 63(12):3133-7. View