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 and colorectal cancer. Individual carotenoids, measured in diet or blood, are reliable measures of intake of a variety of vegetables and fruits. In a nested case-control study of lung cancer in a cohort of Hawaiian Japanese men, individual carotenoids were measured in prediagnostic sera. Low serum levels of beta-cryptoxanthin, lycopene, and alpha-carotene, but not beta-carotene, were each modestly associated with elevated lung cancer risk (smoking-adjusted RRs = 1.3-1.5). There was no evidence of combined or synergistic effects for individual carotenoids. Thus, carotenoids, at physiologic levels, may not contribute substantially to lung cancer prevention. In the PLCO screening trial, we are investigating the relationship of vegetable and fruit intake, with quantity and variety assessed in several ways, to risk of colorectal adenoma. Greater intake of fruits and some vegetables, particularly deep yellow and dark green vegetables, is modestly, but significantly, associated with decreased risk for colorectal adenoma. Pyramid servings, a more comprehensive and quantitative approach to estimating food group intake, did not produce substantially different results than the more traditional number of servings/day.BREAST CANCER AND PROSTATE CANCER IN ASIAN-AMERICAN POPULATIONS International variation in breast cancer incidence and migrant studies indicate that modifiable factors play a major role in breast cancer etiology although the specific lifestyles and environmental exposures remain elusive. We designed a large, population-based case-control study of breast cancer in Asian-American women to take advantage of their diversity in lifestyle and breast cancer risk. Childhood, adolescent, and adult exposures were assessed by interviewing both study participants and their mothers. We observed a six-fold gradient in breast cancer incidence by migration patterns, comparable to the international differences in breast cancer incidence rates
