[unreadable] The search for modifiable risk factors for prostate cancer has focused on a number of dietary components, including fat, meats, and micronutrients. However, one nutrient that has been shown to influence risk for a number of other cancers for which there has been little investigation of in prostate cancer is folate. This vitamin plays an essential role in DNA synthesis, repair and methylation, and imbalances in folate metabolism increase genetic instability and facilitate carcinogenesis. Perturbations in folate metabolism can result from genetic polymorphisms in folate-metabolizing enzymes or inadequate dietary consumption of nutrients required for this process. [unreadable] [unreadable] In this study, we will determine whether altered folate metabolism, resulting from either genetic or dietary factors, is associated with prostate cancer risk. A case-control study, nested in the ongoing American Cancer Society CPS-II cohort, will be conducted to do this. DNA samples from 1209 men with prostate cancer and 1209 matched controls will be analyzed to determine the genotype of nine polymorphisms in seven genes encoding folate-metabolizing proteins. Dietary information collected prior to the cancer diagnosis will be analyzed to determine levels of five nutrients that influence folate metabolism. Logistic regression models will be applied to determine the main effects of each of the genetic and dietary variables. Stratification according to quartiles of folate and high or low alcohol intake will be used to measure the influence of interacting nutrients on the various polymorphisms. Finally, gene-gene interactions will be studied using newly developed techniques to classify men into high- and low-risk genotypes depending on the number of variant alleles they have. The results of this study are expected to indicate the importance of folate for prostate cancer and whether changing folate consumption can modify the risk associated with genetic variants in the pathway for folate metabolism. [unreadable] [unreadable]