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Grant Details

Grant Number: 5R01CA131335-04 Interpret this number
Primary Investigator: Gu, Jian
Organization: Ut Md Anderson Cancer 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

Telomere length in peripheral blood leukocytes and lung cancer risk: a large case-control study in Caucasians.
Authors: Sanchez-Espiridion B, Chen M, Chang JY, Lu C, Chang DW, Roth JA, Wu X, Gu J
Source: Cancer Res, 2014 May 1;74(9), p. 2476-86.
EPub date: 2014 Mar 11.
PMID: 24618342
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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 EL, Ye Y, Calle ML, Rothman N, Urrea V, Kogevinas M, Petrus S, Chanock SJ, Tardón A, García-Closas M, González-Neira A, Vellalta G, Carrato A, Navarro A, Lorente-Galdós B, Silverman DT, Real FX, Wu X, Malats N
Source: PLoS One, 2013;8(12), p. e83745.
EPub date: 2013 Dec 31.
PMID: 24391818
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Genetic variations in regulator of G-protein signaling (RGS) confer risk of bladder cancer.
Authors: Lee EK, Ye Y, Kamat AM, Wu X
Source: Cancer, 2013 May 1;119(9), p. 1643-51.
EPub date: 2013 Mar 25.
PMID: 23529717
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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 RE, Lev D, Gu J
Source: Cancer, 2013 May 15;119(10), p. 1885-91.
EPub date: 2013 Feb 13.
PMID: 23408253
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HSD3B and gene-gene interactions in a pathway-based analysis of genetic susceptibility to bladder cancer.
Authors: Andrew AS, Hu T, Gu J, Gui J, Ye Y, Marsit CJ, Kelsey KT, Schned AR, Tanyos SA, Pendleton EM, Mason RA, Morlock EV, Zens MS, Li Z, Moore JH, Wu X, Karagas MR
Source: PLoS One, 2012;7(12), p. e51301.
EPub date: 2012 Dec 19.
PMID: 23284679
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Genetic variations in the transforming growth factor beta pathway as predictors of bladder cancer risk.
Authors: Wei H, Kamat AM, Aldousari S, Ye Y, Huang M, Dinney CP, Wu X
Source: PLoS One, 2012;7(12), p. e51758.
EPub date: 2012 Dec 12.
PMID: 23251617
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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 HL, Chang DW, Yin J, Grossman HB, Dinney CP, Wu X
Source: PLoS One, 2012;7(6), p. e38533.
EPub date: 2012 Jun 12.
PMID: 22701660
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Genetic variants in telomere-maintenance genes and bladder cancer risk.
Authors: Chang J, Dinney CP, Huang M, Wu X, Gu J
Source: PLoS One, 2012;7(2), p. e30665.
EPub date: 2012 Feb 17.
PMID: 22363464
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Genetic susceptibility to bladder cancer risk and outcome.
Authors: Gu J, Wu X
Source: Per Med, 2011 May;8(3), p. 365-374.
PMID: 21927616
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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 CP, Shete S, Huang M, Hildebrandt MA, Chen Z, Gu J
Source: Cancer, 2012 Jan 1;118(1), p. 205-15.
EPub date: 2011 Jun 20.
PMID: 21692063
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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 CI, Kamat A, Ye Y, Lin J, Dinney CP, Wu X
Source: Cancer Prev Res (Phila), 2011 Apr;4(4), p. 514-21.
EPub date: 2011 Apr 2.
PMID: 21460395
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Genetic variations in the sonic hedgehog pathway affect clinical outcomes in non-muscle-invasive bladder cancer.
Authors: Chen M, Hildebrandt MA, Clague J, Kamat AM, Picornell A, Chang J, Zhang X, Izzo J, Yang H, Lin J, Gu J, Chanock S, Kogevinas M, Rothman N, Silverman DT, Garcia-Closas M, Grossman HB, Dinney CP, Malats N, Wu X
Source: Cancer Prev Res (Phila), 2010 Oct;3(10), p. 1235-45.
EPub date: 2010 Sep 21.
PMID: 20858759
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Prostate stem cell antigen: a Jekyll and Hyde molecule?
Authors: Saeki N, Gu J, Yoshida T, Wu X
Source: Clin Cancer Res, 2010 Jul 15;16(14), p. 3533-8.
EPub date: 2010 May 25.
PMID: 20501618
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Genetic variations in PI3K-AKT-mTOR pathway and bladder cancer risk.
Authors: Chen M, Cassidy A, Gu J, Delclos GL, Zhen F, Yang H, Hildebrandt MA, Lin J, Ye Y, Chamberlain RM, Dinney CP, Wu X
Source: Carcinogenesis, 2009 Dec;30(12), p. 2047-52.
PMID: 19875696
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Genetic variation in the prostate stem cell antigen gene PSCA confers susceptibility to urinary bladder cancer.
Authors: Wu X, Ye Y, Kiemeney LA, Sulem P, Rafnar T, Matullo G, Seminara D, Yoshida T, Saeki N, Andrew AS, Dinney CP, Czerniak B, Zhang ZF, Kiltie AE, Bishop DT, Vineis P, Porru S, Buntinx F, Kellen E, Zeegers MP, Kumar R, Rudnai P, Gurzau E, Koppova K, Mayordomo JI, Sanchez M, Saez B, Lindblom A, de Verdier P, Steineck G, Mills GB, Schned A, Guarrera S, Polidoro S, Chang SC, Lin J, Chang DW, Hale KS, Majewski T, Grossman HB, Thorlacius S, Thorsteinsdottir U, Aben KK, Witjes JA, Stefansson K, Amos CI, Karagas MR, Gu J
Source: Nat Genet, 2009 Sep;41(9), p. 991-5.
EPub date: 2009 Aug 2.
PMID: 19648920
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