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National Institutes of Health: National Cancer Institute: Division of Cancer Control and Population Sciences
Grant Details

Grant Number: 5R01CA114467-05 Interpret this number
Primary Investigator: Ulrich, Cornelia
Organization: Fred Hutchinson Cancer Research Center
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

Dna Alkylation And Dna Methylation: Cooperating Mechanisms Driving The Formation Of Colorectal Adenomas And Adenocarcinomas?
Authors: Grady W.M. , Ulrich C.M. .
Source: Gut, 2007 Mar; 56(3), p. 318-20.
PMID: 17339242
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A Review Of Gene-drug Interactions For Nonsteroidal Anti-inflammatory Drug Use In Preventing Colorectal Neoplasia
Authors: Cross J.T. , Poole E.M. , Ulrich C.M. .
Source: The Pharmacogenomics Journal, 2008 Aug; 8(4), p. 237-47.
PMID: 18195728
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C-reactive Protein Genotypes And Haplotypes, Polymorphisms In Nsaid-metabolizing Enzymes, And Risk Of Colorectal Polyps
Authors: Poole E.M. , Bigler J. , Whitton J. , Sibert J.G. , Potter J.D. , Ulrich C.M. .
Source: Pharmacogenetics And Genomics, 2009 Feb; 19(2), p. 113-20.
PMID: 19077918
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Genetic Variation In Prostaglandin E2 Synthesis And Signaling, Prostaglandin Dehydrogenase, And The Risk Of Colorectal Adenoma
Authors: Poole E.M. , Hsu L. , Xiao L. , Kulmacz R.J. , Carlson C.S. , Rabinovitch P.S. , Makar K.W. , Potter J.D. , Ulrich C.M. .
Source: Cancer Epidemiology, Biomarkers & Prevention : A Publication Of The American Association For Cancer Research, Cosponsored By The American Society Of Preventive Oncology, 2010 Feb; 19(2), p. 547-57.
PMID: 20086108
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Polymorphic Human Prostaglandin H Synthase-2 Proteins And Their Interactions With Cyclooxygenase Substrates And Inhibitors
Authors: Liu W. , Poole E.M. , Ulrich C.M. , Kulmacz R.J. .
Source: The Pharmacogenomics Journal, 2011 Oct; 11(5), p. 337-47.
PMID: 20548327
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Genetic Variation In C-reactive Protein In Relation To Colon And Rectal Cancer Risk And Survival
Authors: Slattery M.L. , Curtin K. , Poole E.M. , Duggan D.J. , Samowitz W.S. , Peters U. , Caan B.J. , Potter J.D. , Ulrich C.M. .
Source: International Journal Of Cancer, 2011-06-01 00:00:00.0; 128(11), p. 2726-34.
PMID: 20949557
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Linking Epidemiology To Epigenomics--where Are We Today?
Authors: Ulrich C.M. , Grady W.M. .
Source: Cancer Prevention Research (philadelphia, Pa.), 2010 Dec; 3(12), p. 1505-8.
PMID: 21149325
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Polymorphisms In Wnt6 And Wnt10a And Colorectal Adenoma Risk
Authors: Galbraith R.L. , Poole E.M. , Duggan D. , Muehling J. , Hsu L. , Makar K. , Xiao L. , Potter J.D. , Ulrich C.M. .
Source: Nutrition And Cancer, 2011; 63(4), p. 558-64.
PMID: 21547848
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Genetic Variability In Il23r And Risk Of Colorectal Adenoma And Colorectal Cancer
Authors: Poole E.M. , Curtin K. , Hsu L. , Duggan D.J. , Makar K.W. , Xiao L. , Carlson C.S. , Caan B.J. , Potter J.D. , Slattery M.L. , et al. .
Source: Cancer Epidemiology, 2012 Apr; 36(2), p. e104-10.
PMID: 22154103
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Glutathione Peroxidase Tagsnps: Associations With Rectal Cancer But Not With Colon Cancer
Authors: Haug U. , Poole E.M. , Xiao L. , Curtin K. , Duggan D. , Hsu L. , Makar K.W. , Peters U. , Kulmacz R.J. , Potter J.D. , et al. .
Source: Genes, Chromosomes & Cancer, 2012 Jun; 51(6), p. 598-605.
PMID: 22371331
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Decreased Cyclooxygenase Inhibition By Aspirin In Polymorphic Variants Of Human Prostaglandin H Synthase-1
Authors: Liu W. , Poole E.M. , Ulrich C.M. , Kulmacz R.J. .
Source: Pharmacogenetics And Genomics, 2012 Jul; 22(7), p. 525-37.
PMID: 22513397
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Functional Analysis Of Human Thromboxane Synthase Polymorphic Variants
Authors: Chen C.Y. , Poole E.M. , Ulrich C.M. , Kulmacz R.J. , Wang L.H. .
Source: Pharmacogenetics And Genomics, 2012 Sep; 22(9), p. 653-8.
PMID: 22735388
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Genetic Variation In The Lipoxygenase Pathway And Risk Of Colorectal Neoplasia
Authors: Kleinstein S.E. , Heath L. , Makar K.W. , Poole E.M. , Seufert B.L. , Slattery M.L. , Xiao L. , Duggan D.J. , Hsu L. , Curtin K. , et al. .
Source: Genes, Chromosomes & Cancer, 2013 May; 52(5), p. 437-49.
PMID: 23404351
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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 A.T. , Poole E.M. , Scherer D. , Kotzmann J. , Makar K.W. , Kazanov D. , Galazan L. , Naumov I. , et al. .
Source: Pharmacogenetics And Genomics, 2013 Aug; 23(8), p. 428-37.
PMID: 23778325
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Cox-1 (ptgs1) And Cox-2 (ptgs2) Polymorphisms, Nsaid Interactions, And Risk Of Colon And Rectal Cancers In Two Independent Populations
Authors: Makar K.W. , Poole E.M. , Resler A.J. , Seufert B. , Curtin K. , Kleinstein S.E. , Duggan D. , Kulmacz R.J. , Hsu L. , Whitton J. , et al. .
Source: Cancer Causes & Control : Ccc, 2013 Dec; 24(12), p. 2059-75.
PMID: 24022467
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Genetic Variation In Ugt Genes Modify The Associations Of Nsaids With Risk Of Colorectal Cancer: Colon Cancer Family Registry
Authors: Scherer D. , Koepl L.M. , Poole E.M. , Balavarca Y. , Xiao L. , Baron J.A. , Hsu L. , Coghill A.E. , Campbell P.T. , Kleinstein S.E. , et al. .
Source: Genes, Chromosomes & Cancer, 2014 Jul; 53(7), p. 568-78.
PMID: 24677636
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Genetic Variation In Prostaglandin Synthesis And Related Pathways, Nsaid Use And Colorectal Cancer Risk In The Colon Cancer Family Registry
Authors: Resler A.J. , Makar K.W. , Heath L. , Whitton J. , Potter J.D. , Poole E.M. , Habermann N. , Scherer D. , Duggan D. , Wang H. , et al. .
Source: Carcinogenesis, 2014 Sep; 35(9), p. 2121-6.
PMID: 24908683
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