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 goal of this study is to evaluate the association between colorectal polyps and polymorphisms in enzymes, growth factors, and receptors linked to prostaglandin synthesis or COX activity. Currently, very few polymorphisms in this pathway have been reported, and, of those, the population allele frequency is not known. Thus, several steps in this proposal (Projects 1-3) aim to systematically identify new genetic polymorphisms in this pathway, and to establish allele frequency and potential impact on enzyme function. Methods include screening of enzymes in the COX/PG pathway for new polymorphisms both by searching genetic databases and by using other techniques (dHPLC, enzyme mismatch cleavage, DNA sequencing). Genotyping of a population of 75 Caucasians and 75 African Americans for candidate polymorphisms will be used to establish allele frequency. Subsequently (Project 4) we propose to investigate a selected 5 to 10 genetic polymorphisms in COX1,COX2, and other enzymes in the PG/COX pathway, or growth factors and receptors related to it, and their association with colorectal polyps. We propose to genotype 550 cases with adenomatous polyps, 200 cases with hyperplastic polyps only, and 700 polyp-free controls. Study participants were recruited as part of the Minnesota case-control study in 1991-4 and comprehensive questionnaire information on health status, family history, diet, physical activity, and use of aspirin and other NSAIDs has been obtained. We will 1) investigate the main effects of the genetic polymorphisms, and 2) investigate whether these polymorphisms modify the association between environmental factors (in particular aspirin and NSAID use) and colorectal polyps. Finally, we plan to develop a model for integrating information on genetic variability at multiple points in this metabolic pathway.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
1R01CA089445-01
Application #
6232381
Study Section
Epidemiology and Disease Control Subcommittee 2 (EDC)
Program Officer
Verma, Mukesh
Project Start
2001-06-05
Project End
2004-05-31
Budget Start
2001-06-05
Budget End
2002-05-31
Support Year
1
Fiscal Year
2001
Total Cost
$414,814
Indirect Cost
Name
Fred Hutchinson Cancer Research Center
Department
Type
DUNS #
075524595
City
Seattle
State
WA
Country
United States
Zip Code
98109
Liu, Amy Y; Scherer, Dominique; Poole, Elizabeth et al. (2013) Gene-diet-interactions in folate-mediated one-carbon metabolism modify colon cancer risk. Mol Nutr Food Res 57:721-34
Poole, Elizabeth M; Curtin, Karen; Hsu, Li et al. (2012) Genetic variability in IL23R and risk of colorectal adenoma and colorectal cancer. Cancer Epidemiol 36:e104-10
Galbraith, Rachel L; Poole, Elizabeth M; Duggan, David et al. (2011) Polymorphisms in WNT6 and WNT10A and colorectal adenoma risk. Nutr Cancer 63:558-64
Poole, Elizabeth M; Hsu, Li; Xiao, Liren et al. (2010) Genetic variation in prostaglandin E2 synthesis and signaling, prostaglandin dehydrogenase, and the risk of colorectal adenoma. Cancer Epidemiol Biomarkers Prev 19:547-57
Poole, Elizabeth M; Bigler, Jeannette; Whitton, John et al. (2009) C-reactive protein genotypes and haplotypes, polymorphisms in NSAID-metabolizing enzymes, and risk of colorectal polyps. Pharmacogenet Genomics 19:113-20
Bigler, Jeannette; Sibert, Justin G; Poole, Elizabeth M et al. (2007) Polymorphisms predicted to alter function in prostaglandin E2 synthase and prostaglandin E2 receptors. Pharmacogenet Genomics 17:221-7
Poole, Elizabeth M; Bigler, Jeannette; Whitton, John et al. (2006) Prostacyclin synthase and arachidonate 5-lipoxygenase polymorphisms and risk of colorectal polyps. Cancer Epidemiol Biomarkers Prev 15:502-8
Tien, Joseph H; Hazelton, William D; Sparks, Rachel et al. (2005) A Michaelis-Menten-style model for the autocatalytic enzyme prostaglandin H synthase. Bull Math Biol 67:683-700
Ulrich, Cornelia M; Whitton, John; Yu, Joon-Ho et al. (2005) PTGS2 (COX-2) -765G > C promoter variant reduces risk of colorectal adenoma among nonusers of nonsteroidal anti-inflammatory drugs. Cancer Epidemiol Biomarkers Prev 14:616-9
Ulrich, Cornelia M; Carlson, Christopher S; Sibert, Justin et al. (2005) Thromboxane synthase (TBXAS1) polymorphisms in African-American and Caucasian populations: evidence for selective pressure. Hum Mutat 26:394-5

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