Polymorphisms in the PG/COX Pathway and Colorectal Polyps (ProGEN)(R01 CA 89445)

PI: Cornelia (Neli) Ulrich PhD

Aspirin and other non-steroidal inflammatory drugs (NSAIDs) reduce the recurrence of colorectal polyps among patients with familial adenomatous polyposis (FAP) and are associated with a lower risk of both adenoma and colorectal cancer. Primary targets for these drugs are cyclooxygenases (COX1 and COX2) in the prostaglandin (PG) pathway. The goals of this study were to evaluate the association between colorectal polyps and polymorphisms in enzymes, growth factors, and receptors linked to prostaglandin synthesis or COX activity. At the onset of this study, very few polymorphisms in this pathway had been reported, and, of those, the population allele frequency was not known. Thus, several steps in this study aimed to systematically identify new genetic polymorphisms in this pathway, and to establish allele frequency and potential impact on enzyme function. Methods included screening of enzymes in the COX/PG pathway for new polymorphisms by DNA sequencing. Genotyping of a population of 48 Caucasians and 47 African Americans for candidate polymorphisms was used to establish allele frequency. We have published results for the screening of COX1 (Ulrich et al, Human Mutation, 2002), and thromboxane synthase (Ulrich et al, Human Mutation, 2005) and have submitted results for prostaglandin E2 synthase and three prostaglandin E2 receptors.

Subsequently, selected genetic polymorphisms in enzymes or growth factors related to prostaglandin synthesis were investigated to determine their association with colorectal polyps. We genotyped >500 cases with adenomatous polyps, >190 cases with hyperplastic polyps only, and >600 polyp-free controls. Study participants were recruited as part of the Minnesota case-control study in 1991-4 in which comprehensive questionnaire information on health status, family history, diet, physical activity, and use of aspirin and other NSAIDs had been obtained. We have published associations between polymorphisms in COX-1 or prostacyclin synthase with risk of colorectal polyps (Ulrich et al, Cancer Epidemiol Biomarkers Prev, 2004; Ulrich et al, Cancer Epidemiol Biomarkers Prev, 2005; Poole et al, Cancer Epidemiol Biomarkers Prev, 2006)and found evidence that certain polymorphisms in COX1 (P17L), COX2 (-765G>C), and prostacyclin synthase (promoter repeat polymorphism) modify the protective associations for NSAID use (Ulrich et al, Cancer Epidemiol Biomarkers Prev, 2004; Ulrich et al, Cancer Epidemiol Biomarkers Prev, 2005; Poole et al, Cancer Epidemiol Biomarkers Prev, 2006). Finally, we have also published results of work on developing a mathematical model of COX enzyme functioning (Hazelton et al, Biochemical Pharmacology, 2004; Tien et al, Bulletin of Mathematical Biology, 2005).