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Grant Details

Grant Number: 5R03CA123577-02 Interpret this number
Primary Investigator: Ulrich, Cornelia
Organization: Fred Hutchinson Cancer Research Center
Project Title: Genetic Study of Prostaglandin Synthesis/Egfr and Risk of Colorectal Neoplasia
Fiscal Year: 2007
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Abstract

DESCRIPTION (provided by applicant): Aspirin and other non-steroidal anti-inflammatory drugs (NSAIDs) are effective chemopreventive agents against colorectal adenomas, precursors of colorectal cancer. NSAIDs exert their chemopreventive effects through the inhibition of the cyclooxygenases (COX)1 and 2, key enzymes in the prostaglandin synthesis pathway. Initial studies suggest that genetic variation in prostaglandin synthesis can affect colorectal carcinogenesis. One of the main downstream products of the COX enzymes is prostaglandin E2 (PGE2). PGE2 is the most upregulated prostaglandin in colorectal cancer, and experimental studies directly implicate PGE2 in the development of colorectal neoplasia. Recent studies have shown that PGE2 signaling can activate epidermal growth factor receptor (EGFR) signaling, a second pathway of key importance in olorectal carcinogenesis. This study will evaluate the association between colorectal adenomas and genetic variability in enzymes, receptors, and signaling molecules in the prostaglandin/EGFR pathways. We will focus on proteins that: a) regulate PGE2 levels (prostaglandin E synthase (PGES) and 15- hydroxyprostaglandin dehydrogenase (PGDN); b) bind to PGE2 at the cell surface (receptors EP1, EP2, and EP4); or c) are involved in PGE2 cross-talk with EGFR signaling (Src and EGFR). We will genotype individuals in an existing case-control study of 540 adenoma cases and 640 polyp-free controls. Participants were recruited through gastroenterology practices in Minnesota and information on health status, family history, dietary intake, physical activity, and NSAID use has been obtained. All patients underwent a full colonoscopy and completed questionnaires prior to diagnosis. Several of the target genes have been resequenced for polymorphism discovery (PGES, EP1, 2, and 4, EGFR) and resequencing of the other target genes (PGDN, Src) is underway. We propose a study design that maximizes available information regarding genetic variability in the prostaglandin/EGFR pathways by examining common haplotypes with tag SNPs, as well as specific candidate polymorphisms. As a secondary aim, interactions with NSAID use will be investigated to determine responses of genetically-defined subgroups. Gene-gene interactions will also be evaluated, providing a comprehensive analysis of the role of genetic variation in this pathway. This study uses a cost-effective approach to address the research question of genetic variability in the prostaglandin/EGFR pathways and risk of colorectal neoplasia. It builds on past successful collaborations, as well as promising preliminary data, and provides training for a new investigator. This study of genetic variation in the prostaglandin/EGFR pathway will provide insights into the complex process of colorectal carcinogenesis, and increase understanding of the pharmacogenetics of NSAID chemoprevention.

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Publications

Genetic variation in the lipoxygenase pathway and risk of colorectal neoplasia.
Authors: Kleinstein SE, Heath L, Makar KW, Poole EM, Seufert BL, Slattery ML, Xiao L, Duggan DJ, Hsu L, Curtin K, Koepl L, Muehling J, Taverna D, Caan BJ, Carlson CS, Potter JD, Ulrich CM
Source: Genes Chromosomes Cancer, 2013 May;52(5), p. 437-49.
EPub date: 2013 Feb 12.
PMID: 23404351
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Glutathione peroxidase tagSNPs: associations with rectal cancer but not with colon cancer.
Authors: Haug U, Poole EM, Xiao L, Curtin K, Duggan D, Hsu L, Makar KW, Peters U, Kulmacz RJ, Potter JD, Koepl L, Caan BJ, Slattery ML, Ulrich CM
Source: Genes Chromosomes Cancer, 2012 Jun;51(6), p. 598-605.
EPub date: 2012 Feb 27.
PMID: 22371331
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Genetic variation in prostaglandin E2 synthesis and signaling, prostaglandin dehydrogenase, and the risk of colorectal adenoma.
Authors: Poole EM, Hsu L, Xiao L, Kulmacz RJ, Carlson CS, Rabinovitch PS, Makar KW, Potter JD, Ulrich CM
Source: Cancer Epidemiol Biomarkers Prev, 2010 Feb;19(2), p. 547-57.
EPub date: 2010 Jan 19.
PMID: 20086108
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A review of gene-drug interactions for nonsteroidal anti-inflammatory drug use in preventing colorectal neoplasia.
Authors: Cross JT, Poole EM, Ulrich CM
Source: Pharmacogenomics J, 2008 Aug;8(4), p. 237-47.
EPub date: 2008 Jan 15.
PMID: 18195728
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