Aspirin and other non-steroidal inflammatory drugs (NSAIDs) appear to be effective chemopreventive agents against colorectal carcinogenesis. The recognized NSAID targets are cyclooxygenase-1 and -2 (COX1 and 2, or PTGS1 and 2), key enzymes in conversion of arachidonate to prostaglandin (PG) signaling molecules. This interdisciplinary study will evaluate the association between colon and rectal cancer and genetic variability in enzymes and receptors linked to the synthesis of prostaglandins and related arachidonate metabolites. We have identified polymorphisms and haplotypes in key proteins in these pathways. Target proteins include PTGS1 and 2, the thromboxane, prostacyclin, PGD2 and PGE2 synthases, the 5, 12- and 15- lipoxygenases (ALOX5, ALOX12 and ALOX15), PGE2 receptors, and glutathione peroxidases. We will genotype two existing case-control study populations comprising 1676 colon cancer cases with 2004 controls and 827 rectal cancer cases with 1031 controls. Participants were recruited as part of two multi-center, population-based case-control studies in which information on health status, family history, dietary factors (including intakes of n-6 and n-3 fatty acids), physical activity, and NSAID use has been obtained. We propose to use a study design that maximizes available information regarding genetic variability in these key pathways by examining gene-wide haplotypes for sequenced genes (e.g., PTGS1, PTGS2, ALOX12, ALOX15, PGE2 synthase and PGE2 receptors), and a candidate-polymorphism approach for variants with supporting evidence for functional impact. Interactions with NSAID use and dietary fatty acid intakes will be investigated to determine responses of genetically defined subgroups. Using biochemical assays, we will also establish the enzymatic and pharmacological impact of polymorphisms in several key proteins. This biochemical information will be used to inform the genotyping results and the statistical analysis. Results from this collaborative study will provide a powerful test of the role of genetic variability in prostaglandin or eicosanoid synthesis in colorectal carcinogenesis and chemoprevention. They will also advance tailoring of chemoprevention in a way that maximizes benefit and minimizes toxicity.
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