title: Nutrients in folate-mediated, one-carbon metabolism and the risk of rectal tumors in men and women.
abstract: In an investigation of rectal tumors characterized by CpG island methylator phenotype (CIMP), KRAS2 mutation, and TP53 mutation, we examined associations with dietary and supplemental folate, riboflavin, vitamins B(6) and B(12), and methionine, nutrients involved in folate-mediated 1-carbon metabolism. We also examined folate intake and common MTHFR polymorphisms in relation to CIMP. Data from a population-based study of 951 cases (750 with tumor markers) and 1,205 controls were evaluated using multiple logistic regression models and generalized estimating equations. Reduced risk of methylated tumors was suggested in women with the upper tertile of folate intake (≥0.42 mg/day) vs. the lower tertile: OR = 0.6, 95%CI = 0.3-1.2. In men, a significant 3-fold increased risk of CIMP+ tumor was observed for the upper tertile of folate (≥0.75 mg/day) vs. the lower tertile (<0.44 mg/day): OR = 3.2, 95%CI = 1.5-6.7. These men consumed a greater proportion of folic acid fortified foods relative to natural, primarily plant-based sources (52% vs. 48%) than women with CIMP+ tumors (22% vs. 78%). MTHFR 1298A>C influenced folate in male CIMP+ risk (P interaction < 0.01). Our findings suggest folate supplementation effects may differ between genders, perhaps due to variation in MTHFR and/or endogenous/exogenous hormones, and may be important in the initiation and progression of methylated rectal tumors in men.
authors.affiliation: Department of Internal Medicine, University of Utah Health Sciences Center, Salt Lake City, Utah 84132, USA. karen.curtin@hsc.utah.edu
authors.forename: Karen
authors.initials: K
authors.lastname: Curtin
authors.forename: Wade S
authors.initials: WS
authors.lastname: Samowitz
authors.forename: Cornelia M
authors.initials: CM
authors.lastname: Ulrich
authors.forename: Roger K
authors.initials: RK
authors.lastname: Wolff
authors.forename: Jennifer S
authors.initials: JS
authors.lastname: Herrick
authors.forename: Bette J
authors.initials: BJ
authors.lastname: Caan
authors.forename: Martha L
authors.initials: ML
authors.lastname: Slattery
mesh_terms: D000328:Adult; D000368:Aged; D016022:Case-Control Studies; D018899:CpG Islands; D019175:DNA Methylation; D004032:Diet; D019587:Dietary Supplements; D005260:Female; D005492:Folic Acid / Q000008:administration & dosage* / Q000378:metabolism; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D016015:Logistic Models; D008297:Male; D008715:Methionine / Q000378:metabolism; D042965:Methylenetetrahydrofolate Reductase (NADPH2) / Q000235:genetics / Q000378:metabolism; D008875:Middle Aged; D009154:Mutation; D010641:Phenotype; D011110:Polymorphism, Genetic; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism; D016283:Proto-Oncogene Proteins p21(ras); D012004:Rectal Neoplasms / Q000453:epidemiology* / Q000235:genetics* / Q000378:metabolism; D012256:Riboflavin / Q000378:metabolism; D012307:Risk Factors; D012737:Sex Factors; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism; D014805:Vitamin B 12 / Q000378:metabolism; D025101:Vitamin B 6 / Q000378:metabolism; D018631:ras Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: C117307:KRAS protein, human; D011518:Proto-Oncogene Proteins; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D025101:Vitamin B 6; D005492:Folic Acid; D008715:Methionine; D042965:Methylenetetrahydrofolate Reductase (NADPH2); D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins; D014805:Vitamin B 12; D012256:Riboflavin