Grant Number:	5R01CA098683-05 Interpret this number
Primary Investigator:	Casey, Graham
Organization:	Cleveland Clinic Lerner Com-Cwru
Project Title:	Genetics of Prostate Cancer Risk & Agressiveness
Fiscal Year:	2007

DESCRIPTION (provided by applicant): We hypothesize that multiple genes are involved in risk of prostate cancer and tumor aggressiveness and that many of these genetic risk factors will be represented by low penetrance gene mutations, each accounting for a small effect on risk. We propose to build upon two promising areas of our research program concerned with the influence of genes on prostate cancer risk and tumor aggressiveness. We have localized prostate tumor aggressiveness genes to 7q32-q33 and 19q13.1 through whole genome linkage analysis of sib pairs and loss of heterozygosity studies. We have identified a strong candidate, podocalyxin (PODXL), on 7q32-q33 in which in-frame deletions and SNPs independently are associated with markers of tumor aggressiveness. We will also build upon our studies investigating the impact of single nucleotide polymorphisms (SNPs) in candidate genes involved in metabolic pathways involved in prostate growth on prostate cancer risk and tumor aggressiveness. Thus our Specific Aims are: Specific Aim 1: To further characterize candidate prostate tumor aggressiveness loci identified through whole genome linkage analysis. We will determine whether PODXL functions as a prostate tumor aggressiveness gene by developing stable transfectants expressing wild-type or variant-containing PODXL and assessing their effect on in vitro and in vivo growth of prostate cancer cells. We will also determine PODXL expression in prostate tumors by in situ hybridization and immunohistochemical staining using tissue microarrays. We will further pursue the identification of the 19q13.1 aggressiveness gene using complementary approaches, including positional cloning methods and use of the public Human Genome Project (HGP) and Celera databases. The relationship between the 19q13.1 candidate gene(s) and prostate tumor aggressiveness will be evaluated by mutation analyses followed by association studies. Candidates will be further evaluated by in situ hybridization and immunohistochemical staining. Specific Aim 2: To determine the impact of single nucleotide polymorphisms (SNPs) in candidate genes on prostate cancer risk and tumor aggressiveness. We will study SNPs in candidate genes involved in 1) vitamin D metabolism (vitamin D receptor, 1-alpha-hydroxylase (CYP27B1) and 24-hydroxylase (CYP24)), 2) insulin-like growth factor signaling (IGFBP-3), 3) folate metabolism (5,10- Methylene-tetrahydrofolate reductase (MTHFR) and Methionine Synthase (MTR)), and 4) steroid hormone metabolism (CYP3A7). For SNP association studies, we will employ a fully recruited population consisting of 943 men in 431 families with at least one brother affected with prostate cancer. Epidemiologic and clinical data have been collected, as well as biospecimens and banked DNA. The relationship between these genetic factors and prostate cancer risk and aggressiveness will be statistically evaluated.




Identification And Characterization Of Functional Risk Variants For Colorectal Cancer Mapping To Chromosome 11q23.1
Authors: Biancolella M. , Fortini B.K. , Tring S. , Plummer S.J. , Mendoza-Fandino G.A. , Hartiala J. , Hitchler M.J. , Yan C. , Schumacher F.R. , Conti D.V. , et al. .
Source: Human Molecular Genetics, 2014-04-15 00:00:00.0; 23(8), p. 2198-209.
PMID: 24256810
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Copy number alterations in prostate tumors and disease aggressiveness.
Authors: Cheng I. , Levin A.M. , Tai Y.C. , Plummer S. , Chen G.K. , Neslund-Dudas C. , Casey G. , Rybicki B.A. , Witte J.S. .
Source: Genes, Chromosomes & Cancer, 2012 Jan; 51(1), p. 66-76.
PMID: 21965145
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Fine-mapping of prostate cancer aggressiveness loci on chromosome 7q22-35.
Authors: Liu X. , Cheng I. , Plummer S.J. , Suarez B.K. , Casey G. , Catalona W.J. , Witte J.S. .
Source: The Prostate, 2011-05-15 00:00:00.0; 71(7), p. 682-9.
EPub date: 2011-05-15 00:00:00.0.
PMID: 20945404
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Impact Of Consumption Of Vegetable, Fruit, Grain, And High Glycemic Index Foods On Aggressive Prostate Cancer Risk
Authors: Hardin J. , Cheng I. , Witte J.S. .
Source: Nutrition And Cancer, 2011; 63(6), p. 860-72.
PMID: 21774611
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Prostate cancer susceptibility variants confer increased risk of disease progression.
Authors: Cheng I. , Plummer S.J. , Neslund-Dudas C. , Klein E.A. , Casey G. , Rybicki B.A. , Witte J.S. .
Source: Cancer Epidemiology, Biomarkers & Prevention : A Publication Of The American Association For Cancer Research, Cosponsored By The American Society Of Preventive Oncology, 2010 Sep; 19(9), p. 2124-32.
PMID: 20651075
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Dietary omega-3 fatty acids, cyclooxygenase-2 genetic variation, and aggressive prostate cancer risk.
Authors: Fradet V. , Cheng I. , Casey G. , Witte J.S. .
Source: Clinical Cancer Research : An Official Journal Of The American Association For Cancer Research, 2009-04-01 00:00:00.0; 15(7), p. 2559-66.
EPub date: 2009-04-01 00:00:00.0.
PMID: 19318492
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Carboxypeptidase 4 gene variants and early-onset intermediate-to-high risk prostate cancer.
Authors: Ross P.L. , Cheng I. , Liu X. , Cicek M.S. , Carroll P.R. , Casey G. , Witte J.S. .
Source: Bmc Cancer, 2009-02-26 00:00:00.0; 9, p. 69.
EPub date: 2009-02-26 00:00:00.0.
PMID: 19245716
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8q24 and prostate cancer: association with advanced disease and meta-analysis.
Authors: Cheng I. , Plummer S.J. , Jorgenson E. , Liu X. , Rybicki B.A. , Casey G. , Witte J.S. .
Source: European Journal Of Human Genetics : Ejhg, 2008 Apr; 16(4), p. 496-505.
PMID: 18231127
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Pathological Aggressiveness Of Prostatic Carcinomas Related To Rnasel R462q Allelic Variants
Authors: Larson B.T. , Magi-Galluzzi C. , Casey G. , Plummer S.J. , Silverman R. , Klein E.A. .
Source: The Journal Of Urology, 2008 Apr; 179(4), p. 1344-8.
PMID: 18289577
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COX2 genetic variation, NSAIDs, and advanced prostate cancer risk.
Authors: Cheng I. , Liu X. , Plummer S.J. , Krumroy L.M. , Casey G. , Witte J.S. .
Source: British Journal Of Cancer, 2007-08-20 00:00:00.0; 97(4), p. 557-61.
EPub date: 2007-08-20 00:00:00.0.
PMID: 17609663
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Podocalyxin Increases The Aggressive Phenotype Of Breast And Prostate Cancer Cells In Vitro Through Its Interaction With Ezrin
Authors: Sizemore S. , Cicek M. , Sizemore N. , Ng K.P. , Casey G. .
Source: Cancer Research, 2007-07-01 00:00:00.0; 67(13), p. 6183-91.
PMID: 17616675
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Trans-fatty acid intake and increased risk of advanced prostate cancer: modification by RNASEL R462Q variant.
Authors: Liu X. , Schumacher F.R. , Plummer S.J. , Jorgenson E. , Casey G. , Witte J.S. .
Source: Carcinogenesis, 2007 Jun; 28(6), p. 1232-6.
PMID: 17234723
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MIC1 and IL1RN genetic variation and advanced prostate cancer risk.
Authors: Cheng I. , Krumroy L.M. , Plummer S.J. , Casey G. , Witte J.S. .
Source: Cancer Epidemiology, Biomarkers & Prevention : A Publication Of The American Association For Cancer Research, Cosponsored By The American Society Of Preventive Oncology, 2007 Jun; 16(6), p. 1309-11.
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Association of testis derived transcript gene variants and prostate cancer risk.
Authors: Liu X. , Cicek M.S. , Plummer S.J. , Jorgenson E. , Casey G. , Witte J.S. .
Source: The Journal Of Urology, 2007 Mar; 177(3), p. 894-8.
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Toll-like receptor 4 genetic variation and advanced prostate cancer risk.
Authors: Cheng I. , Plummer S.J. , Casey G. , Witte J.S. .
Source: Cancer Epidemiology, Biomarkers & Prevention : A Publication Of The American Association For Cancer Research, Cosponsored By The American Society Of Preventive Oncology, 2007 Feb; 16(2), p. 352-5.
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Vitamin D receptor genotypes/haplotypes and prostate cancer risk.
Authors: Cicek M.S. , Liu X. , Schumacher F.R. , Casey G. , Witte J.S. .
Source: Cancer Epidemiology, Biomarkers & Prevention : A Publication Of The American Association For Cancer Research, Cosponsored By The American Society Of Preventive Oncology, 2006 Dec; 15(12), p. 2549-52.
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Nonsteroidal antiinflammatory drugs and decreased risk of advanced prostate cancer: modification by lymphotoxin alpha.
Authors: Liu X. , Plummer S.J. , Nock N.L. , Casey G. , Witte J.S. .
Source: American Journal Of Epidemiology, 2006-11-15 00:00:00.0; 164(10), p. 984-9.
EPub date: 2006-11-15 00:00:00.0.
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Polymorphisms In Estrogen Bioactivation, Detoxification And Oxidative Dna Base Excision Repair Genes And Prostate Cancer Risk
Authors: Nock N.L. , Cicek M.S. , Li L. , Liu X. , Rybicki B.A. , Moreira A. , Plummer S.J. , Casey G. , Witte J.S. .
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Polymorphisms In Polycyclic Aromatic Hydrocarbon Metabolism And Conjugation Genes, Interactions With Smoking And Prostate Cancer Risk
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Source: Cancer Epidemiology, Biomarkers & Prevention : A Publication Of The American Association For Cancer Research, Cosponsored By The American Society Of Preventive Oncology, 2006 Apr; 15(4), p. 756-61.
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Relationship between methylenetetrahydrofolate reductase C677T and A1298C genotypes and haplotypes and prostate cancer risk and aggressiveness.
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Source: Cancer Epidemiology, Biomarkers & Prevention : A Publication Of The American Association For Cancer Research, Cosponsored By The American Society Of Preventive Oncology, 2004 Aug; 13(8), p. 1331-6.
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