The Cooperative Family Registry for Colorectal Cancer Studies (Colon CFR) proposes to investigate the role of genetic polymorphisms in the non-steroidal anti-inflammatory drugs/prostaglandin synthase (NSAIDs/PTGS) pathway in preventing colorectal cancer. Risk of colorectal cancer, the second leading cause of cancer-related deaths in the United States, can be reduced by the regular use of aspirin and other NSAIDs by approximately 50%, presumably through inhibition of prostaglandin synthesis. Recurrence of adenomas can also be reduced by up to 40%. The chemopreventive benefit across the population is clear but at the individual level, given some unwanted effects and varying efficacy due to genetic variation in metabolism, the equation is less clear. We showed previously that polymorphisms in NSAIDs metabolism - glucuronidation and oxidation - and prostaglandin synthesis can affect adenoma risk or modify the benefit derived from regular NSAIDs use. Accordingly, in 4310 discordant sib-pairs (affected case/unaffected relative) in the Colon CFR, we now propose to use candidate SNP and haplotype-based approaches to investigate effects of polymorphisms in NSAIDs metabolism and in prostaglandin synthesis on colorectal cancer risk. Haplotypes will be generated for PTGS1, PTGS2, NF-KappaB, and IkappaB in 300 individuals in 5 ethnic groups and genotyping will be undertaken across the 4310 discordant sibpairs. In addition, we will establish in vitro studies, which of the UGTs catalyze the glucuronidation of aspirin and other NSAIDs including ibuprofen, sulindac, sulindac sulfone, and indomethacin, and the effects of polymorphisms on metabolic capacities. Ultimately, such information on the metabolic variation will be useful in optimizing NSAIDs and NSAID regimens and will allow individual tailoring of chemoprevention.
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