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 B₆ and B₁₂, 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.

ACKNOWLEDGMENTS

We would like to acknowledge the contributions of Sandra Edwards, Leslie Palmer, and Judy Morse to the data collection and management efforts of this study; to Michael Hoffman for genotyping and MSI assessment; and to Michael Hoffman and Erica Wolff for CIMP analysis. The contents of this article are solely the responsibility of the authors and do not necessarily represent the official view of the National Cancer Institute. We declare that there are no conflicts of interest.

This study was funded by NIH grants R01 CA48998 and CA61757 (to M.L.S.). This research was also supported by the Utah Cancer Registry, which is funded by Contract N01-PC-35141 from the National Cancer Institute's SEER program, with additional support from the State of Utah Department of Health and the University of Utah, the Northern California Cancer Registry, and the Sacramento Tumor Registry.