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Grant Details

Grant Number: 5U01CA127615-05 Interpret this number
Primary Investigator: Wu, Xifeng
Organization: Ut Md Anderson Cancer Ctr
Project Title: Genome-Wide Association Analysis of Bladder Cancer
Fiscal Year: 2012
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Abstract

DESCRIPTION (provided by applicant): This proposal builds on a rich resource of bladder cancer (BC) cases and controls derived from two ongoing BC studies at the University of Texas M.D. Anderson Cancer Center, and from two large independent U.S. BC studies - the New England BC Study and the New Hampshire BC Study. The goal is to identify genetic loci that predispose individuals to BC through a genome-wide scanning approach. There are five specific aims. Aim 1 is to first perform genome-wide, high-density SNP genotyping using the Illumina HumanHap550 SNP platform on 800 cases and 800 controls from M.D. Anderson, with a target of candidate SNPs of about 28,000; followed by an internal validation to narrow down candidate SNPs to about 1,536 using additional 800 pairs of cases and controls. Illumina's Custom Infinium array will be the genotyping format. In this aim, in addition to individual SNP analysis, we will also implement haplotype-based analyses and pathway aggregation analysis to identify additional genetic loci that might have been overlooked using individual SNP analysis. Aim 2 is the first external validation of the 1,536 SNPs from Aim 1 using 1,000 pairs of cases and controls from the New England BC Study. Illumina's GoldenGate assay will be the genotyping format. After this stage, the candidate SNPs will be narrowed down to about 100. Aim 3 is the second independent external validation using 750 pairs of cases and controls form the New Hampshire BC Study. In this aim, the 100 top candidate SNPs passed from Aims 1 and 2 plus additional functional SNPs in genes containing these SNPs will be genotyped. GoldenGate assay will be used for this aim. Aim 4 is to perform fine mapping studies in the flanking regions of each of the top 25 SNP loci confirmed in Aim 3 to identify causative loci. This will utilize all 6,700 cases and controls. An average of 15 additional SNPs (tagging SNPs and functional SNPs) per gene is expected. Aim 5 is to apply novel machine-learning tools to identify any gene-environment and gene-gene interactions greatly influencing risk for BC in all the 6700 subjects. These analyses will be utilized to examine SNP main effect and develop and validate algorithms that will identify individuals at highest risk for BC, given their personal exposure patterns and their genetic risk profiles. This proposal applies state of art technology to perform a multistage, genome-wide SNP analysis in three largest, well-characterized U.S. population of BC cases and controls, and incorporates complete epidemiologic data and rich and unique functional data. In addition, results from this study will be provided to the International Consortium of BC Case Control Studies for future validation. The ability to identify genetically susceptible, high-risk subgroups that would benefit from intensive screening and/or chemopreventive interventions is of immense clinical and public health benefit. PUBLIC HEALTH RELEVANCE Bladder cancer (BC) is a disease mainly caused by smoking and occupational exposure. However, only a small percentage of exposed individuals develop BC. Inherited host genetic factors may play an important role in determining an individual's susceptibility to BC. This proposal builds on three largest well-characterized U.S. populations of BC cases and controls - the M. D. Anderson BC study, the New England BC Study and the New Hampshire BC Study. A total of 6700 cases and controls will be used. The goal is to identify genetic loci that predispose individuals to BC through a non-biased, discovery- driven, genome-wide scanning approach and to incorporate complete epidemiologic data and rich and unique functional data. About 550,000 genetic variations of human genome will be initially screened in an M.D. Anderson population consisting of an equal number of BC cases and normal controls. About 28,000 top candidate variations that are potentially associated with increased BC risk will be first narrowed down and internally replicated in a second M.D. Anderson population, and then be validated in the other two independent U.S. BC populations. Finally, the causative genetic loci that predispose individuals to BC will be mapped. This study is significant because by identifying BC susceptibility loci, it will shed light into the biological mechanisms of BC etiology. Furthermore, it may facilitate identifying high-risk subgroups of individuals for BC, given their genetic makeup and environmental exposures. The ability to identify high-risk subgroups of individuals for BC 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

Inflammation-Related Genetic Variants Predict Toxicity Following Definitive Radiotherapy for Lung Cancer.
Authors: Pu X, Wang L, Chang JY, Hildebrandt MA, Ye Y, Lu C, Skinner HD, Niu N, Jenkins GD, Komaki R, Minna JD, Roth JA, Weinshilboum RM, Wu X
Source: Clin Pharmacol Ther, 2014 Jul 23;null, p. null.
EPub date: 2014 Jul 23.
PMID: 25054431
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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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Genome-wide association study identifies multiple loci associated with bladder cancer risk.
Authors: Figueroa JD, Ye Y, Siddiq A, Garcia-Closas M, Chatterjee N, Prokunina-Olsson L, Cortessis VK, Kooperberg C, Cussenot O, Benhamou S, Prescott J, Porru S, Dinney CP, Malats N, Baris D, Purdue M, Jacobs EJ, Albanes D, Wang Z, Deng X, Chung CC, Tang W, Bas Bueno-de-Mesquita H, Trichopoulos D, Ljungberg B, Clavel-Chapelon F, Weiderpass E, Krogh V, Dorronsoro M, Travis R, Tjønneland A, Brenan P, Chang-Claude J, Riboli E, Conti D, Gago-Dominguez M, Stern MC, Pike MC, Van Den Berg D, Yuan JM, Hohensee C, Rodabough R, Cancel-Tassin G, Roupret M, Comperat E, Chen C, De Vivo I, Giovannucci E, Hunter DJ, Kraft P, Lindstrom S, Carta A, Pavanello S, Arici C, Mastrangelo G, Kamat AM, Lerner SP, Barton Grossman H, Lin J, Gu J, Pu X, Hutchinson A, Burdette L, Wheeler W, Kogevinas M, Tardón A, Serra C, Carrato A, García-Closas R, Lloreta J, Schwenn M, Karagas MR, Johnson A, Schned A, Armenti KR, Hosain GM, Andriole G Jr, Grubb R 3rd, Black A, Ryan Diver W, Gapstur SM, Weinstein SJ, Virtamo J, Haiman CA, Landi MT, Caporaso N, Fraumeni JF Jr, Vineis P, Wu X, Silverman DT, Chanock S, Rothman N
Source: Hum Mol Genet, 2014 Mar 1;23(5), p. 1387-98.
EPub date: 2013 Oct 24.
PMID: 24163127
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?-H2AX level in peripheral blood lymphocytes as a risk predictor for bladder cancer.
Authors: Fernández MI, Gong Y, Ye Y, Lin J, Chang DW, Kamat AM, Wu X
Source: Carcinogenesis, 2013 Nov;34(11), p. 2543-7.
EPub date: 2013 Aug 14.
PMID: 23946494
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Genome-wide association study of genetic predictors of overall survival for non-small cell lung cancer in never smokers.
Authors: Wu X, Wang L, Ye Y, Aakre JA, Pu X, Chang GC, Yang PC, Roth JA, Marks RS, Lippman SM, Chang JY, Lu C, Deschamps C, Su WC, Wang WC, Huang MS, Chang DW, Li Y, Pankratz VS, Minna JD, Hong WK, Hildebrandt MA, Hsiung CA, Yang P
Source: Cancer Res, 2013 Jul 1;73(13), p. 4028-38.
EPub date: 2013 May 23.
PMID: 23704207
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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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Genetic variations in micro-RNA biogenesis genes and clinical outcomes in non-muscle-invasive bladder cancer.
Authors: Ke HL, Chen M, Ye Y, Hildebrandt MA, Wu WJ, Wei H, Huang M, Chang DW, Dinney CP, Wu X
Source: Carcinogenesis, 2013 May;34(5), p. 1006-11.
EPub date: 2013 Jan 14.
PMID: 23322153
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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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Germline prognostic markers for urinary bladder cancer: obstacles and opportunities.
Authors: Chang DW, Gu J, Wu X
Source: Urol Oncol, 2012 Jul-Aug;30(4), p. 524-32.
PMID: 22742565
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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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Systematic evaluation of apoptotic pathway gene polymorphisms and lung cancer risk.
Authors: Lin J, Lu C, Stewart DJ, Gu J, Huang M, Chang DW, Lippman SM, Wu X
Source: Carcinogenesis, 2012 Sep;33(9), p. 1699-706.
EPub date: 2012 Jun 4.
PMID: 22665367
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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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A genome-wide association study of bladder cancer identifies a new susceptibility locus within SLC14A1, a urea transporter gene on chromosome 18q12.3.
Authors: Garcia-Closas M, Ye Y, Rothman N, Figueroa JD, Malats N, Dinney CP, Chatterjee N, Prokunina-Olsson L, Wang Z, Lin J, Real FX, Jacobs KB, Baris D, Thun M, De Vivo I, Albanes D, Purdue MP, Kogevinas M, Kamat AM, Lerner SP, Grossman HB, Gu J, Pu X, Hutchinson A, Fu YP, Burdett L, Yeager M, Tang W, Tardón A, Serra C, Carrato A, García-Closas R, Lloreta J, Johnson A, Schwenn M, Karagas MR, Schned A, Andriole G Jr, Grubb R 3rd, Black A, Jacobs EJ, Diver WR, Gapstur SM, Weinstein SJ, Virtamo J, Hunter DJ, Caporaso N, Landi MT, Fraumeni JF Jr, Silverman DT, Chanock SJ, Wu X
Source: Hum Mol Genet, 2011 Nov 1;20(21), p. 4282-9.
EPub date: 2011 Aug 8.
PMID: 21824976
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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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A genetic variant near the PMAIP1/Noxa gene is associated with increased bleomycin sensitivity.
Authors: Gu J, Ye Y, Spitz MR, Lin J, Kiemeney LA, Xing J, Hildebrandt MA, Ki Hong W, Amos CI, Wu X
Source: Hum Mol Genet, 2011 Feb 15;20(4), p. 820-6.
EPub date: 2010 Nov 24.
PMID: 21106707
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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 variants and risk of lung cancer in never smokers: a genome-wide association study.
Authors: Li Y, Sheu CC, Ye Y, de Andrade M, Wang L, Chang SC, Aubry MC, Aakre JA, Allen MS, Chen F, Cunningham JM, Deschamps C, Jiang R, Lin J, Marks RS, Pankratz VS, Su L, Li Y, Sun Z, Tang H, Vasmatzis G, Harris CC, Spitz MR, Jen J, Wang R, Zhang ZF, Christiani DC, Wu X, Yang P
Source: Lancet Oncol, 2010 Apr;11(4), p. 321-30.
EPub date: 2010 Mar 19.
PMID: 20304703
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Genome-wide association studies of bladder cancer risk: a field synopsis of progress and potential applications.
Authors: Wu X, Hildebrandt MA, Chang DW
Source: Cancer Metastasis Rev, 2009 Dec;28(3-4), p. 269-80.
PMID: 20016998
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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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