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

Grant Number: 5R01CA131335-04 Interpret this number
Primary Investigator: Gu, Jian
Organization: University Of Tx Md Anderson Can Ctr
Project Title: Telomere Length, Telomere Maintenance Gene Polymorphisms, and Bladder Cancer Risk
Fiscal Year: 2011
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Abstract

DESCRIPTION (provided by applicant): This proposed study will build upon the extensive epidemiologic database and biospecimens derived from an ongoing bladder cancer case control study entitled "Genetic Susceptibility to Bladder Cancer: A Molecular Epidemiologic Approach" (R01 CA74880, PI: Xifeng Wu, M.D., Ph.D., funded from 1999 to 2009). The parent grant involved a multidisciplinary group of researchers applying a molecular epidemiologic approach to identify inter-individual differences in susceptibility to bladder carcinogenesis, with a focus on performing genotypic and phenotypic assays in DNA repair system in surrogate tissue (lymphocytes) and evaluating genotype-phenotype correlation and surrogate-target tissue correlation. The goal of the current proposal is to expand our previous pioneering observation that telomere shortening is a cancer predisposing factor by significantly increasing sample size and by measuring chromosome specific telomere length. In addition, we also propose to identify epidemiologic factors and genetic variants in telomere maintenance genes that predict telomere length. The four specific aims of this proposal are: 1) To determine the overall telomere length in peripheral blood lymphocyte from 1000 newly diagnosed, histologically confirmed bladder cancer patients and 1000 frequency matched controls, using a high-throughput quantitative real-time method; 2) To determine chromosome specific telomere length (17p, 2p, 11q, 12q, and XpYp), using a modified real-time PCR based single telomere length analysis (STELA) method in peripheral blood lymphocytes from the same 1000 cases and 1000 controls. We hypothesize that the shortest telomeres, 17p being one example, exhibit stronger cancer predisposing effect than long telomeres in cancer etiology; 3) To determine frequencies of single nucleotide polymorphisms (SNPs) in telomere maintenance pathway genes in all cases and controls and to identify candidate genotypes and haplotypes as markers of susceptibility to bladder cancer; 4) To assess genotype-phenotype correlations for telomere length. This study is the largest epidemiologic study to evaluate the role of overall telomere shortening in bladder cancer risk. Moreover, it is the first study to evaluate chromosome specific telomere length and cancer risk and to comprehensively assess genetic variations in telomere maintenance genes in cancer etiology. The large sample size will allow us to determine the association between environmental and dietary factors and telomere length and their interactions in modulating bladder cancer risk. PUBLIC HEALTH RELEVANCE: One of the hallmarks of cancer development is genetic instability. There are 23 pairs of human chromosomes and they are under constant attack from endogenous and exogenous DNA damaging agents. Telomere is the end structure on each chromosome, like the shoelace cap on the ends of a shoelace, keeping the lace (chromosome) from unraveling. We hypothesize that individuals with inherited shorter telomeres are more likely to develop bladder cancer than individuals with longer telomeres, and short telomeres on certain chromosomes are more likely to cause cancer than short telomeres on other chromosomes. We also want to identify genetic variations in telomere maintenance genes than may predict telomere shortening and hence affect a person's bladder cancer risk. We will test these hypotheses in a large group of 1000 bladder cancer patients and 1000 healthy controls. The ability to identify high-risk subgroups of individuals for bladder cancer will provide immense public health benefit for those high-risk people who may be subjected to close surveillance and chemoprevention.

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Publications

Genetic Variation In The Prostate Stem Cell Antigen Gene Psca Confers Susceptibility To Urinary Bladder Cancer
Authors: Wu X. , Ye Y. , Kiemeney L.A. , Sulem P. , Rafnar T. , Matullo G. , Seminara D. , Yoshida T. , Saeki N. , Andrew A.S. , et al. .
Source: Nature Genetics, 2009 Sep; 41(9), p. 991-5.
PMID: 19648920
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Genetic Variations In Pi3k-akt-mtor Pathway And Bladder Cancer Risk
Authors: Chen M. , Cassidy A. , Gu J. , Delclos G.L. , Zhen F. , Yang H. , Hildebrandt M.A. , Lin J. , Ye Y. , Chamberlain R.M. , et al. .
Source: Carcinogenesis, 2009 Dec; 30(12), p. 2047-52.
PMID: 19875696
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Prostate Stem Cell Antigen: A Jekyll And Hyde Molecule?
Authors: Saeki N. , Gu J. , Yoshida T. , Wu X. .
Source: Clinical Cancer Research : An Official Journal Of The American Association For Cancer Research, 2010-07-15 00:00:00.0; 16(14), p. 3533-8.
PMID: 20501618
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Genetic Variations In The Sonic Hedgehog Pathway Affect Clinical Outcomes In Non-muscle-invasive Bladder Cancer
Authors: Chen M. , Hildebrandt M.A. , Clague J. , Kamat A.M. , Picornell A. , Chang J. , Zhang X. , Izzo J. , Yang H. , Lin J. , et al. .
Source: Cancer Prevention Research (philadelphia, Pa.), 2010 Oct; 3(10), p. 1235-45.
PMID: 20858759
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A Genome-wide Association Study Identifies A Locus On Chromosome 14q21 As A Predictor Of Leukocyte Telomere Length And As A Marker Of Susceptibility For Bladder Cancer
Authors: Gu J. , Chen M. , Shete S. , Amos C.I. , Kamat A. , Ye Y. , Lin J. , Dinney C.P. , Wu X. .
Source: Cancer Prevention Research (philadelphia, Pa.), 2011 Apr; 4(4), p. 514-21.
PMID: 21460395
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Comprehensive Pathway-based Interrogation Of Genetic Variations In The Nucleotide Excision Dna Repair Pathway And Risk Of Bladder Cancer
Authors: Xing J. , Dinney C.P. , Shete S. , Huang M. , Hildebrandt M.A. , Chen Z. , Gu J. .
Source: Cancer, 2012-01-01 00:00:00.0; 118(1), p. 205-15.
PMID: 21692063
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Genetic Susceptibility To Bladder Cancer Risk And Outcome
Authors: Gu J. , Wu X. .
Source: Personalized Medicine, 2011 May; 8(3), p. 365-374.
PMID: 21927616
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Genetic Variants In Telomere-maintenance Genes And Bladder Cancer Risk
Authors: Chang J. , Dinney C.P. , Huang M. , Wu X. , Gu J. .
Source: Plos One, 2012; 7(2), p. e30665.
PMID: 22363464
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Association Of Polymorphisms In Oxidative Stress Genes With Clinical Outcomes For Bladder Cancer Treated With Bacillus Calmette-guérin
Authors: Wei H. , Kamat A. , Chen M. , Ke H.L. , Chang D.W. , Yin J. , Grossman H.B. , Dinney C.P. , Wu X. .
Source: Plos One, 2012; 7(6), p. e38533.
PMID: 22701660
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Genetic Variations In The Transforming Growth Factor Beta Pathway As Predictors Of Bladder Cancer Risk
Authors: Wei H. , Kamat A.M. , Aldousari S. , Ye Y. , Huang M. , Dinney C.P. , Wu X. .
Source: Plos One, 2012; 7(12), p. e51758.
PMID: 23251617
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Hsd3b And Gene-gene Interactions In A Pathway-based Analysis Of Genetic Susceptibility To Bladder Cancer
Authors: Andrew A.S. , Hu T. , Gu J. , Gui J. , Ye Y. , Marsit C.J. , Kelsey K.T. , Schned A.R. , Tanyos S.A. , Pendleton E.M. , et al. .
Source: Plos One, 2012; 7(12), p. e51301.
PMID: 23284679
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Genetic Variations In Regulator Of G-protein Signaling (rgs) Confer Risk Of Bladder Cancer
Authors: Lee E.K. , Ye Y. , Kamat A.M. , Wu X. .
Source: Cancer, 2013-05-01 00:00:00.0; 119(9), p. 1643-51.
PMID: 23529717
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Application Of Multi-snp Approaches Bayesian Lasso And Auc-rf To Detect Main Effects Of Inflammatory-gene Variants Associated With Bladder Cancer Risk
Authors: de Maturana E.L. , Ye Y. , Calle M.L. , Rothman N. , Urrea V. , Kogevinas M. , Petrus S. , Chanock S.J. , Tardón A. , García-Closas M. , et al. .
Source: Plos One, 2013; 8(12), p. e83745.
PMID: 24391818
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Genetic Variations In Glutathione Pathway Genes Predict Cancer Recurrence In Patients Treated With Transurethral Resection And Bacillus Calmette-guerin Instillation For Non-muscle Invasive Bladder Cancer
Authors: Ke H.L. , Lin J. , Ye Y. , Wu W.J. , Lin H.H. , Wei H. , Huang M. , Chang D.W. , Dinney C.P. , Wu X. .
Source: Annals Of Surgical Oncology, 2015 Nov; 22(12), p. 4104-10.
PMID: 25851338
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Telomere length in peripheral blood leukocytes and lung cancer risk: a large case-control study in Caucasians.
Authors: Sanchez-Espiridion B. , Chen M. , Chang J.Y. , Lu C. , Chang D.W. , Roth J.A. , Wu X. , Gu J. .
Source: Cancer research, 2014-05-01; 74(9), p. 2476-86.
EPub date: 2014-03-11.
PMID: 24618342
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Long telomeres in peripheral blood leukocytes are associated with an increased risk of soft tissue sarcoma.
Authors: Xie H. , Wu X. , Wang S. , Chang D. , Pollock R.E. , Lev D. , Gu J. .
Source: Cancer, 2013-05-15; 119(10), p. 1885-91.
EPub date: 2013-02-13.
PMID: 23408253
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