GENETIC VARIABILITY AS PROGNOSTIC OR PREDICTIVE FACTORS IN COLORECTAL INTRAEPITHE

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The translational goal of this project is to identify host characteristics that can be used to individually tailor colon cancer prevention therapy in order to reduce the development of clinically significant colorectal intraepithelial neoplasia (IEN) in humans with elevated risk for colon cancer. The hypothesis to be tested in this proposal is that individual responses to certain colon cancer preventive agents, including specific non-steroidal anti-inflammatory drugs (NSAIDS) and agents that target features of polyamine metabolism, are influenced by host factors, including genetic background, and diet. Three specific aims are proposed to test this hypothesis. First, we will determine if genetic variability in the host gene encoding ornithine decarboxylase (ODC) can explain individual variability in colorectal mucosal polyamine contents. We will also determine if variability in the ODC and/or the flavin monooxygenase 3 (FM03) genes modulate the action and/or bioavailability of the chemopreventive agents sulindac and difluoromethylornithine (DFMO) when given in combination for the reduction of colon polyp recurrence. Second, we will determine if the association between the ODC G316A promoter variant alleles and adenoma recurrence in aspirin users involves other genes, which affect polyamine metabolism. This aim will focus on the spermidine/spermine N1-acetyltransferase (SSAT), and determine if acetylated polyamines, which are substrates for polyamine export, may be a useful biomarker of NSAID action. Third, we will assess the independent and joint effects of aspirin use,dietary sources of polyamines, and gene modifiers of polyamine synthesis (ODC) on risk of colorectal adenoma recurrence. We will pool data from three adenoma recurrence studies, including the Polyp Prevention Trial (PPT), Wheat Bran Fiber (WBF) and Ursodeoxycholic Acid (UDCA) colon polyp prevention trials to assess these effects on overall adenoma recurrence and recurrence of advanced lesions. The long-term goal of this project is to determine the influence of host and adenoma factors as predictors of efficacy for the chemoprevention of colorectal adenomas, particularly advanced, clinically significant lesions, and to use this information to reduce the incidence of colorectal cancer in individuals with high risk of developing this disease.