Long-Chain Fatty Acids, Oxidative Stress and Colorectal Neoplasm Risk

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DESCRIPTION (provided by applicant):Colorectal cancer is the third most common cancer and the second leading cause of cancer related mortality in the United States. Chronic inflammation and genotoxic free radicals are contributors to colorectal carcinogenesis. As such, our long-term goals are to identify and evaluate lifestyle and dietary factors that can reduce the risk of colorectal cancer through direct modulation of oxidative stress and chronic inflammation. Eicosapentanoic acid is an omega-3 polyunsaturated fatty acid found predominately in marine fish and has consistently demonstrated cancer inhibitory activity in animal models. Eicosapentanoic acid exhibits anti- inflammatory actions while arachidonic acid, an omega-6 polyunsaturated fatty acid, appears pro- inflammatory. Our overarching hypothesis is that individuals with increased dietary ratios of arachidonic acid to eicosapentanoic acid will have an increased risk of colorectal adenoma and that this increased risk is mediated through pro-inflammatory eicosanoids and increased oxidative stress. The specific aims of this research proposal are: 1) To test the hypothesis that a greater erythrocyte phospholipid membrane arachidonic acid to eicosapentanoic acid ratio is associated with an increased risk of colorectal adenomas; 2) To test the hypothesis that an increase in urinary levels of F2-isoprostanes is associated with an increase risk of colorectal adenomas while an increase in urinary levels of F3-isoprostanes is associated with a decreased risk of colorectal adenomas and; 3) To test the hypothesis that a greater arachidonic acid to eicosapentanoic acid ratio is associated with increased levels of prostaglandin E2 and urinary F2-isoprostanes and decreased levels of urinary F3-isoprostanes. To complete these aims we will perform a case-control study of 700, non-advanced colorectal adenomas, 350 advanced colorectal adenoma cases and 1050 polyp-free controls using data collected as part of the Tennessee Colorectal Polyp Study. Our research team is uniquely qualified to complete these aims as all samples and clinical data needed for the study have been collected as part of the on-going Tennessee Colorectal Polyp Study, the largest colonoscopy-based adenoma case-control study in the United States. In addition, our colleagues at Vanderbilt University are global leaders in eicosanoid research. The results from these experiments will contribute to our understanding of the colorectal cancer protective ability of eicosapentanoic acid in humans as well as potential mechanisms underlying this effect. PUBLIC HEALTH RELEVANCE: Colorectal cancer is the second leading cause of cancer related mortality in the United States. Omega-3 fatty acids, as found in fish and fish oil supplements, are being increasingly consumed because of their reported anti-inflammatory properties. The purpose of this study is to determine if omega-3 fatty acids reduce the risk of colorectal adenomas and diminishes the production of inflammatory and oxidative stress biomarkers.