Nutrition, Metabolism, and Cancer

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FOLATE AND ONE-CARBON METABOLISM Folate is essential for one-carbon (methyl group) metabolism, a biochemical pathway involved in DNA synthesis, repair, and methylation. Efficient one-carbon metabolism also requires vitamins B-6 and B-12, riboflavin, and optimal activity of 10-20 enzymes. In a community-based, case-control study of invasive cervical cancer, we showed that high serum homocysteine was associated with a statistically significant 100-200% increase in risk and low serum or red blood cell folate, with only a 20-60% increase. This pattern suggests that circulating homocysteine may be an integratory measure of insufficient folate in tissues or a biomarker of disruption of one-carbon metabolism. Variant forms of two common polymorphisms in the methylene tetrahydrofolate reductase gene and a common polymorphism in the methionine synthase gene were each associated with elevated cervical cancer risk. Risk generally increased as copies of the variant gene increased. These results suggest that both genetic variability in the one-carbon metabolism pathway and micronutrient inadequacy can contribute to increased risk of cervical cancer. Additional polymorphisms in pathway genes are now being assayed. We are also exploring the role of one-carbon metabolism in the etiology of both colorectal and breast cancer in the Prostate, Lung, Colorectal, and Ovarian Cancer (PLCO) cohort. The large number of advanced colorectal adenomas (1200) identified will allow us to systematically search for main effects of polymorphic variation in key one-carbon metabolism genes, using spaced polymorphisms as biomarkers of genetic change. The relationships among circulating levels of homocysteine and various folate forms and genotype will also be explored.VEGETABLES, FRUITS, AND CAROTENOIDS The protective effect of vegetables and fruits is frequently touted as the most persuasive finding to emerge from epidemiologic studies of diet and cancer, with evidence strongest for lung