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Grant Details

Grant Number: 5R01CA114467-05 Interpret this number
Primary Investigator: Ulrich, Cornelia
Organization: Fred Hutchinson Can Res Ctr
Project Title: Prostaglandin Synthesis, Genetics and Colorectal Cancer
Fiscal Year: 2010
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Abstract

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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Publications

COX-1 (PTGS1) and COX-2 (PTGS2) polymorphisms, NSAID interactions, and risk of colon and rectal cancers in two independent populations.
Authors: Makar KW, Poole EM, Resler AJ, Seufert B, Curtin K, Kleinstein SE, Duggan D, Kulmacz RJ, Hsu L, Whitton J, Carlson CS, Rimorin CF, Caan BJ, Baron JA, Potter JD, Slattery ML, Ulrich CM
Source: Cancer Causes Control, 2013 Dec;24(12), p. 2059-75.
PMID: 24022467
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Impact of genetic polymorphisms on adenoma recurrence and toxicity in a COX2 inhibitor (celecoxib) trial: results from a pilot study.
Authors: Kraus S, Hummler S, Toriola AT, Poole EM, Scherer D, Kotzmann J, Makar KW, Kazanov D, Galazan L, Naumov I, Coghill AE, Duggan D, Gigic B, Arber N, Ulrich CM
Source: Pharmacogenet Genomics, 2013 Aug;23(8), p. 428-37.
PMID: 23778325
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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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Functional analysis of human thromboxane synthase polymorphic variants.
Authors: Chen CY, Poole EM, Ulrich CM, Kulmacz RJ, Wang LH
Source: Pharmacogenet Genomics, 2012 Sep;22(9), p. 653-8.
PMID: 22735388
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Decreased cyclooxygenase inhibition by aspirin in polymorphic variants of human prostaglandin H synthase-1.
Authors: Liu W, Poole EM, Ulrich CM, Kulmacz RJ
Source: Pharmacogenet Genomics, 2012 Jul;22(7), p. 525-37.
PMID: 22513397
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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 variability in IL23R and risk of colorectal adenoma and colorectal cancer.
Authors: Poole EM, Curtin K, Hsu L, Duggan DJ, Makar KW, Xiao L, Carlson CS, Caan BJ, Potter JD, Slattery ML, Ulrich CM
Source: Cancer Epidemiol, 2012 Apr;36(2), p. e104-10.
EPub date: 2011 Dec 6.
PMID: 22154103
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Linking epidemiology to epigenomics--where are we today?
Authors: Ulrich CM, Grady WM
Source: Cancer Prev Res (Phila), 2010 Dec;3(12), p. 1505-8.
PMID: 21149325
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Genetic variation in C-reactive protein in relation to colon and rectal cancer risk and survival.
Authors: Slattery ML, Curtin K, Poole EM, Duggan DJ, Samowitz WS, Peters U, Caan BJ, Potter JD, Ulrich CM
Source: Int J Cancer, 2011 Jun 1;128(11), p. 2726-34.
EPub date: 2010 Nov 28.
PMID: 20949557
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Polymorphic human prostaglandin H synthase-2 proteins and their interactions with cyclooxygenase substrates and inhibitors.
Authors: Liu W, Poole EM, Ulrich CM, Kulmacz RJ
Source: Pharmacogenomics J, 2011 Oct;11(5), p. 337-47.
EPub date: 2010 Jun 15.
PMID: 20548327
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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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C-reactive protein genotypes and haplotypes, polymorphisms in NSAID-metabolizing enzymes, and risk of colorectal polyps.
Authors: Poole EM, Bigler J, Whitton J, Sibert JG, Potter JD, Ulrich CM
Source: Pharmacogenet Genomics, 2009 Feb;19(2), p. 113-20.
PMID: 19077918
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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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DNA alkylation and DNA methylation: cooperating mechanisms driving the formation of colorectal adenomas and adenocarcinomas?
Authors: Grady WM, Ulrich CM
Source: Gut, 2007 Mar;56(3), p. 318-20.
PMID: 17339242
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