|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|
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.
Genetic variation in prostaglandin synthesis and related pathways, NSAID use and colorectal cancer risk in the Colon Cancer Family Registry.
Authors: Resler AJ, Makar KW, Heath L, Whitton J, Potter JD, Poole EM, Habermann N, Scherer D, Duggan D, Wang H, Lindor NM, Passarelli MN, Baron JA, Newcomb PA, Le Marchand L, Ulrich CM
Source: Carcinogenesis, 2014 Sep;35(9), p. 2121-6.
EPub date: 2014 Jun 7.
Genetic variation in UGT genes modify the associations of NSAIDs with risk of colorectal cancer: colon cancer family registry.
Authors: Scherer D, Koepl LM, Poole EM, Balavarca Y, Xiao L, Baron JA, Hsu L, Coghill AE, Campbell PT, Kleinstein SE, Figueiredo JC, Lampe JW, Buck K, Potter JD, Kulmacz RJ, Jenkins MA, Hopper JL, Win AK, Newcomb PA, Ulrich CM, Makar KW
Source: Genes Chromosomes Cancer, 2014 Jul;53(7), p. 568-78.
EPub date: 2014 Mar 28.
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.
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.
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.
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.
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.
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.
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.
Polymorphisms in WNT6 and WNT10A and colorectal adenoma risk.
Authors: Galbraith RL, Poole EM, Duggan D, Muehling J, Hsu L, Makar K, Xiao L, Potter JD, Ulrich CM
Source: Nutr Cancer, 2011;63(4), p. 558-64.
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.