Selenium is one of the most promising agents under consideration for use in the reduction of colon cancer risk. In animal models, providing low, non-toxic doses of selenium can attenuate tumor development and human studies have provided support for a chemopreventive role for selenium at both dietary and pharmacological doses. The study of colon cancer prevention in humans would benefit from biological endpoints other than tumor incidence that would serve as a surrogate for cancer, but would permit the evaluation and examination of potential chemopreventives, such as selenium. One such marker of particular promise is aberrant crypt focus (ACF), preneoplastic lesions of the colon which have long served as a biomarker for colon carcinogenesis studies in rodents. Preliminary data is provided in this application indicating an inverse association between dietary intake of selenium and ACF number in humans, and a supplementation study is proposed to investigate whether providing individuals 200 g/day of selenium as selenized yeast for 6 months can reduce the number of these lesions in patients, as compared to those receiving placebo. It will be determined whether the efficacy of selenium in reducing ACF numbers is influenced by allelic identity at the GPx-1 and MnSOD loci. In order to mechanistically evaluate the mode of action of selenium, lymphocytes from study participants and non-transformed human colonic epithelial cells will be examined for susceptibility to DNA damage and for expression of potential downstream targets of selenium. Collectively, these studies will establish the usefulness of ACFs as a useful biomarker for colon cancer prevention studies with selenium and generate new evidence on the mechanism of action, focusing on the GPx-1 selenoprotein as the candidate target of selenium action.