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Grant Details

Grant Number: 5R01CA089445-03 Interpret this number
Primary Investigator: Ulrich, Cornelia
Organization: Fred Hutchinson Can Res Ctr
Project Title: Polymorphisms in Pg/Cox Pathway and Colorectal Polyps
Fiscal Year: 2003
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Abstract

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.

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Publications

Gene-diet-interactions in folate-mediated one-carbon metabolism modify colon cancer risk.
Authors: Liu A.Y. , Scherer D. , Poole E. , Potter J.D. , Curtin K. , Makar K. , Slattery M.L. , Caan B.J. , Ulrich C.M. .
Source: Molecular nutrition & food research, 2013 Apr; 57(4), p. 721-34.
EPub date: 2012-09-07.
PMID: 22961839
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PTGS1, PTGS2, ALOX5, ALOX12, ALOX15, and FLAP SNPs: interaction with fatty acids in colon cancer and rectal cancer.
Authors: Habermann N. , Ulrich C.M. , Lundgreen A. , Makar K.W. , Poole E.M. , Caan B. , Kulmacz R. , Whitton J. , Galbraith R. , Potter J.D. , et al. .
Source: Genes & nutrition, 2013 Jan; 8(1), p. 115-26.
EPub date: 2012-06-08.
PMID: 22678777
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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.
EPub date: 2011-12-06.
PMID: 22154103
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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 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.
EPub date: 2010-01-19.
PMID: 20086108
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C-reactive protein genotypes and haplotypes, polymorphisms in NSAID-metabolizing enzymes, and risk of colorectal polyps.
Authors: Poole 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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Polymorphisms predicted to alter function in prostaglandin E2 synthase and prostaglandin E2 receptors.
Authors: Bigler J. , Sibert J.G. , Poole E.M. , Carlson C.S. , Potter J.D. , Ulrich C.M. .
Source: Pharmacogenetics and genomics, 2007 Mar; 17(3), p. 221-7.
PMID: 17460551
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Prostacyclin synthase and arachidonate 5-lipoxygenase polymorphisms and risk of colorectal polyps.
Authors: Poole E.M. , Bigler J. , Whitton J. , Sibert J.G. , 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, 2006 Mar; 15(3), p. 502-8.
PMID: 16537708
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Thromboxane synthase (TBXAS1) polymorphisms in African-American and Caucasian populations: evidence for selective pressure.
Authors: Ulrich C.M. , Carlson C.S. , Sibert J. , Poole E.M. , Yu J.H. , Wang L.H. , Sparks R. , Potter J.D. , Bigler J. .
Source: Human mutation, 2005 Oct; 26(4), p. 394-5.
PMID: 16134166
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A Michaelis-Menten-style model for the autocatalytic enzyme prostaglandin H synthase.
Authors: Tien J.H. , Hazelton W.D. , Sparks R. , Ulrich C.M. .
Source: Bulletin of mathematical biology, 2005 Jul; 67(4), p. 683-700.
PMID: 15893548
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PTGS2 (COX-2) -765G > C promoter variant reduces risk of colorectal adenoma among nonusers of nonsteroidal anti-inflammatory drugs.
Authors: Ulrich C.M. , Whitton J. , Yu J.H. , Sibert J. , Sparks R. , Potter J.D. , Bigler J. .
Source: Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology, 2005 Mar; 14(3), p. 616-9.
PMID: 15767339
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TGFbeta1 polymorphism (L10P) and risk of colorectal adenomatous and hyperplastic polyps.
Authors: Sparks R. , Bigler J. , Sibert J.G. , Potter J.D. , Yasui Y. , Ulrich C.M. .
Source: International journal of epidemiology, 2004 Oct; 33(5), p. 955-61.
EPub date: 2004-03-11.
PMID: 15020570
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Prostaglandin H synthases: members of a class of quasi-linear threshold switches.
Authors: Hazelton W.D. , Tien J.H. , Donato V.W. , Sparks R. , Ulrich C.M. .
Source: Biochemical pharmacology, 2004-08-01; 68(3), p. 423-32.
PMID: 15242809
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Polymorphisms in PTGS1 (=COX-1) and risk of colorectal polyps.
Authors: Ulrich C.M. , Bigler J. , Sparks R. , Whitton J. , Sibert J.G. , Goode E.L. , Yasui Y. , Potter J.D. .
Source: Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology, 2004 May; 13(5), p. 889-93.
PMID: 15159324
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Rescreening for gonorrhea and chlamydial infection through the mail: a randomized trial.
Authors: Sparks R. , Helmers J.R. , Handsfield H.H. , Totten P.A. , Holmes K.K. , Wroblewski J.K. , Malinski C. , Golden M.R. .
Source: Sexually transmitted diseases, 2004 Feb; 31(2), p. 113-6.
PMID: 14743074
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Cyclooxygenase 1 (COX1) polymorphisms in African-American and Caucasian populations.
Authors: Ulrich C.M. , Bigler J. , Sibert J. , Greene E.A. , Sparks R. , Carlson C.S. , Potter J.D. .
Source: Human mutation, 2002 Nov; 20(5), p. 409-10.
PMID: 12402351
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