Abstract
Background: Decreased genomic and increased gene-specific DNA methylation predispose to colorectal cancer. Dietary folate intake and the methylenetetrahydrofolate reductase polymorphism (MTHFR 677C>T) may influence risk by modifying DNA methylation.Objective: We investigated the associations between MTHFR 677C>T genotype, folate status, and DNA methylation in the colon.Design: We conducted a cross-sectional study of 336 men and women (age 19–92 y) in the United Kingdom without colorectal neoplasia. We obtained blood samples for measurement of serum and red blood cell folate, plasma homocysteine, and MTHFR 677C>T genotype and colonic tissue biopsies for measurement of colonic tissue folate and DNA methylation (genomic- and gene-specific, estrogen receptor 1, ESR1; myoblast determination protein 1, MYOD1; insulin-like growth factor II, IGF2; tumor suppressor candidate 33, N33; adenomatous polyposis coli, APC; mut-L homolog 1, MLH1; and O6-methylguanine-DNA methyltransferase, MGMT) by liquid chromatography/electrospray ionization mass spectrometry and pyrosequencing, respectively.Results: Of the 336 subjects recruited, 185 (55%) carried the CC, 119 (35%) the CT, and 32 (10%) the TT alleles. No significant differences in systemic markers of folate status and colonic tissue folate between genotypes were found. The MTHFR TT genotype was not associated with genomic or gene-specific DNA methylation. Biomarkers of folate status were not associated with genomic DNA methylation. Relations between biomarkers of folate status and gene-specific methylation were inconsistent. However, low serum folate was associated with high MGMT methylation (P = 0.001).Conclusion: MTHFR 677C>T genotype and folate status were generally not associated with DNA methylation in the colon of a folate-replete population without neoplasia. This trial was registered at clinicaltrials.gov as ISRCTN43577261.
Highlights
There is conflicting evidence regarding the role of folate in colorectal cancer
Results from randomized controlled trials investigating whether folic acid supplementation decreases the risk of colorectal adenoma are largely negative [7,8,9,10], the follow up of these trials has been probably too short to result in changes in risk of colorectal cancer, which develops over decades
We investigated gene-specific DNA methylation in 7 tumor suppressor genes: estrogen receptor 1 (ESR1), myoblast determination protein 1 (MYOD1), insulin-like growth factor II (IGF2), tumor suppressor candidate 33 (N33), adenomatous polyposis coli (APC), mut-L homolog 1 (MLH1), and O6-methylguanine-DNA methyltransferase (MGMT)
Summary
There is conflicting evidence regarding the role of folate in colorectal cancer. Meta-analyses of cohort studies generally point to a negative association between folate intake and risk [1,2,3]. Decreased genomic and increased gene-specific DNA methylation predispose to colorectal cancer. Dietary folate intake and the methylenetetrahydrofolate reductase polymorphism (MTHFR 677C.T) may influence risk by modifying DNA methylation. Objective: We investigated the associations between MTHFR 677C.T genotype, folate status, and DNA methylation in the colon. The MTHFR TT genotype was not associated with genomic or gene-specific DNA methylation. Biomarkers of folate status were not associated with genomic DNA methylation. Relations between biomarkers of folate status and gene-specific methylation were inconsistent. Conclusion: MTHFR 677C.T genotype and folate status were generally not associated with DNA methylation in the colon of a folate-replete population without neoplasia. This trial was registered at clinicaltrials.gov as ISRCTN43577261.
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