Grant Number:	5R01CA112517-04 Interpret this number
Primary Investigator:	Isaacs, William
Organization:	Johns Hopkins University
Project Title:	Genetic Susceptibility for Prostate Cancer Progression
Fiscal Year:	2008

DESCRIPTION (provided by applicant): Of the 220,900 men estimated to be diagnosed with prostate cancer in 2004 in the U.S; about one half will undergo radical prostatectomy (RP) for treatment of their disease. As many as 25% or more men who undergo this treatment will experience a re-elevation in their serum Prostate Specific Antigen (PSA) level within months to years later. This rise in PSA after prostatectomy, termed biochemical recurrence or failure, is a clear indication of the proliferation of prostate cancer cells which escaped (metastasized) prior to prostatectomy. Statistically, more than one-third of men with biochemical recurrence develop clinically detectable metastatic disease (Pound 1999). This non-curable, lethal stage of prostate cancer claims over 29,000 lives in the U.S. annually. Clinicians are unable to predict with certainty which men are likely to fail therapy and subsequently develop metastatic disease and which are not. We hypothesize that the likelihood of disease recurrence after treatment of prostate cancer by RP is modified and/or determined by sequence variation in genes that regulate prostate cancer metastasis. Restating this hypothesis, genetic background is a determinant of metastatic potential. The Specific Aims of this application are: 1) Explore the association between genetic variants in metastasis-related genes and disease progression in a case-control population of men who have undergone radical prostatectomy for treatment of clinically localized prostate cancer; cases are men whose disease progressed after surgical therapy, and controls are men whose disease did not progress; 2) For genes demonstrating association with progression in Specific Aim 1, confirm the association in a second, similar case-control population; 3) For genes associated in both populations, perform fine-mapping association tests, and assess association in non-European Americans cases; 4) Assess genotype - phenotype correlation for progression associated genes. We anticipate that this study will provide novel insights into the mechanisms responsible for prostate cancer progression, and provide a basis for the identification of men at elevated risk for this life threatening event.




Variation In Il10 And Other Genes Involved In The Immune Response And In Oxidation And Prostate Cancer Recurrence
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Identification of novel CHD1-associated collaborative alterations of genomic structure and functional assessment of CHD1 in prostate cancer.
Authors: Liu W. , Lindberg J. , Sui G. , Luo J. , Egevad L. , Li T. , Xie C. , Wan M. , Kim S.T. , Wang Z. , et al. .
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EPub date: 2012-08-30 00:00:00.0.
PMID: 22139082
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Inherited Susceptibility For Aggressive Prostate Cancer
Authors: Isaacs W.B. .
Source: Asian Journal Of Andrology, 2012 May; 14(3), p. 415-8.
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Pathway-based Analysis Of Genetic Susceptibility To Cervical Cancer In Situ: Hla-dpb1 Affects Risk In Swedish Women
Authors: Ivansson E.L. , Juko-Pecirep I. , Erlich H.A. , Gyllensten U.B. .
Source: Genes And Immunity, 2011 Dec; 12(8), p. 605-14.
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Genome-wide Association Study Identifies New Prostate Cancer Susceptibility Loci
Authors: Schumacher F.R. , Berndt S.I. , Siddiq A. , Jacobs K.B. , Wang Z. , Lindstrom S. , Stevens V.L. , Chen C. , Mondul A.M. , Travis R.C. , et al. .
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Comparison of two methods for estimating absolute risk of prostate cancer based on single nucleotide polymorphisms and family history.
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PMID: 20332264
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Inherited genetic variant predisposes to aggressive but not indolent prostate cancer.
Authors: Xu J. , Zheng S.L. , Isaacs S.D. , Wiley K.E. , Wiklund F. , Sun J. , Kader A.K. , Li G. , Purcell L.D. , Kim S.T. , et al. .
Source: Proceedings Of The National Academy Of Sciences Of The United States Of America, 2010-02-02 00:00:00.0; 107(5), p. 2136-40.
EPub date: 2010-02-02 00:00:00.0.
PMID: 20080650
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Individual and cumulative effect of prostate cancer risk-associated variants on clinicopathologic variables in 5,895 prostate cancer patients.
Authors: Kader A.K. , Sun J. , Isaacs S.D. , Wiley K.E. , Yan G. , Kim S.T. , Fedor H. , DeMarzo A.M. , Epstein J.I. , Walsh P.C. , et al. .
Source: The Prostate, 2009-08-01 00:00:00.0; 69(11), p. 1195-205.
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Prostate cancer risk associated loci in African Americans.
Authors: Xu J. , Kibel A.S. , Hu J.J. , Turner A.R. , Pruett K. , Zheng S.L. , Sun J. , Isaacs S.D. , Wiley K.E. , Kim S.T. , et al. .
Source: Cancer Epidemiology, Biomarkers & Prevention : A Publication Of The American Association For Cancer Research, Cosponsored By The American Society Of Preventive Oncology, 2009 Jul; 18(7), p. 2145-9.
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Fine-mapping and family-based association analyses of prostate cancer risk variants at Xp11.
Authors: Lu L. , Sun J. , Isaacs S.D. , Wiley K.E. , Smith S. , Pruett K. , Zhu Y. , Zhang Z. , Wiklund F. , Grönberg H. , et al. .
Source: Cancer Epidemiology, Biomarkers & Prevention : A Publication Of The American Association For Cancer Research, Cosponsored By The American Society Of Preventive Oncology, 2009 Jul; 18(7), p. 2132-6.
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Two independent prostate cancer risk-associated Loci at 11q13.
Authors: Zheng S.L. , Stevens V.L. , Wiklund F. , Isaacs S.D. , Sun J. , Smith S. , Pruett K. , Wiley K.E. , Kim S.T. , Zhu Y. , et al. .
Source: Cancer Epidemiology, Biomarkers & Prevention : A Publication Of The American Association For Cancer Research, Cosponsored By The American Society Of Preventive Oncology, 2009 Jun; 18(6), p. 1815-20.
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Fine mapping association study and functional analysis implicate a SNP in MSMB at 10q11 as a causal variant for prostate cancer risk.
Authors: Chang B.L. , Cramer S.D. , Wiklund F. , Isaacs S.D. , Stevens V.L. , Sun J. , Smith S. , Pruett K. , Romero L.M. , Wiley K.E. , et al. .
Source: Human Molecular Genetics, 2009-04-01 00:00:00.0; 18(7), p. 1368-75.
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A novel prostate cancer susceptibility locus at 19q13.
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Source: Cancer Research, 2009-04-01 00:00:00.0; 69(7), p. 2720-3.
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Association of a germ-line copy number variation at 2p24.3 and risk for aggressive prostate cancer.
Authors: Liu W. , Sun J. , Li G. , Zhu Y. , Zhang S. , Kim S.T. , Sun J. , Wiklund F. , Wiley K. , Isaacs S.D. , et al. .
Source: Cancer Research, 2009-03-15 00:00:00.0; 69(6), p. 2176-9.
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Authors: Sun J. , Zheng S.L. , Wiklund F. , Isaacs S.D. , Li G. , Wiley K.E. , Kim S.T. , Zhu Y. , Zhang Z. , Hsu F.C. , et al. .
Source: Cancer Research, 2009-01-01 00:00:00.0; 69(1), p. 10-5.
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Evidence For Two Independent Prostate Cancer Risk-associated Loci In The Hnf1b Gene At 17q12
Authors: Sun J. , Zheng S.L. , Wiklund F. , Isaacs S.D. , Purcell L.D. , Gao Z. , Hsu F.C. , Kim S.T. , Liu W. , Zhu Y. , et al. .
Source: Nature Genetics, 2008 Oct; 40(10), p. 1153-5.
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Association Of Prostate Cancer Risk Variants With Clinicopathologic Characteristics Of The Disease
Authors: Xu J. , Isaacs S.D. , Sun J. , Li G. , Wiley K.E. , Zhu Y. , Hsu F.C. , Wiklund F. , Turner A.R. , Adams T.S. , et al. .
Source: Clinical Cancer Research : An Official Journal Of The American Association For Cancer Research, 2008-09-15 00:00:00.0; 14(18), p. 5819-24.
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Cumulative Effect Of Five Genetic Variants On Prostate Cancer Risk In Multiple Study Populations
Authors: Sun J. , Chang B.L. , Isaacs S.D. , Wiley K.E. , Wiklund F. , Stattin P. , Duggan D. , Carpten J.D. , Trock B.J. , Partin A.W. , et al. .
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Family-based Samples Can Play An Important Role In Genetic Association Studies
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