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Grant Details

Grant Number: 5R01CA074880-10 Interpret this number
Primary Investigator: Wu, Xifeng
Organization: Ut Md Anderson Cancer Ctr
Project Title: Markers of Genetic Susceptibility to Bladder Cancer
Fiscal Year: 2008
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Abstract

DESCRIPTION (provided by applicant): This proposal is a competitive renewal for the grant entitled "Genetic Susceptibility to Bladder Cancer: A Molecular Epidemiologic Approach". The purpose of the initial project was to identify interindividual differences in susceptibility to tobacco-induced carcinogenesis, as risk factors for bladder cancer (BC). We now propose to build upon this epidemiologic and specimen resource of 600 cases and 600 controls and to recruit an additional 400 patients with newly diagnosed BC and 400 healthy controls matched to the cases on the basis of sex, age (+/- 5 years), and ethnicity. We intend to apply promising novel phenotypic biomarkers of constitutive genetic instability, such as telomere length and mutagen-induced DNA damage. Specifically, we plan to determine telomere length in peripheral blood lymphocytes (PBLs) of the newly recruited 400 BC patients and 400 controls using quantitative fluorescent in situ hybridization laser scanning cytometry (Q-FISH/LSC). Our hypothesis is that BC cases exhibit shortened telomeres compared with control subjects. To assess latent genetic instability, we plan to quantify mutagen-induced DNA damage using the comet assay in the PBLs of 400 BC patients and 400 controls. Our hypothesis is that BC patients exhibit increased levels of BPDE-induced and or gamma-radiation-induced genetic damage. To evaluate the role of genetic variations, we will use a pathway approach to estimate the frequencies of single-nucleotide polymorphisms (SNPs) in DNA repair genes implicated in the nucleotide excision repair (NER), base excision repair (BER), and double-stranded break (DSB) pathways for all 1000 cases and 1000 controls. Our hypothesis is that individuals with adverse genotypes of the NER, BER, and DBS pathways are at increased risk for BC and that these genotypes predict higher levels of induced DATA damage. To assess whether surrogate (PBL) tissue reflects molecular events in the target tissue, we plan to determine telomere length in paired samples of urine epithelial cells and blood lymphocytes from 75 patients with superficial BC and 75 healthy controls. Our hypothesis is that there will be a positive correlation in telomere length between target and surrogate tissues. Finally, using a multi-color fluorescent in situ hybridization (FISH) assay that includes a mixture of probes for the centromeric regions in chromosomes 3, 7, and 17 and the 91321 region, we will test the hypothesis that individuals with short telomeres, adverse genotypes and or high mutagen-induced DNA damage in PBLs (surrogate tissue) exhibit higher levels of genetic instability in the target tissue. As a secondary aim, we will correlate the predicted functional significance of these SNPs using a computational algorithm approach with risk estimated from this proposal to develop new tools for future candidate SNPs selection. The ability to rapidly screen individuals for risk, using minimally invasive procedures (blood samples), has immense clinical implication, such as intensive screening and chemopreventive interventions.

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Publications

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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Intake of red meat and heterocyclic amines, metabolic pathway genes and bladder cancer risk.
Authors: Lin J, Forman MR, Wang J, Grossman HB, Chen M, Dinney CP, Hawk ET, Wu X
Source: Int J Cancer, 2012 Oct 15;131(8), p. 1892-903.
EPub date: 2012 Mar 6.
PMID: 22261697
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Association of Aurora-A (STK15) kinase polymorphisms with clinical outcome of esophageal cancer treated with preoperative chemoradiation.
Authors: Pan JY, Ajani JA, Gu J, Gong Y, Quin A, Hung M, Wu X, Izzo JG
Source: Cancer, 2012 Sep 1;118(17), p. 4346-53.
EPub date: 2011 Dec 27.
PMID: 22213102
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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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Gamma-radiation sensitivity and polymorphisms in RAD51L1 modulate glioma risk.
Authors: Liu Y, Shete S, Wang LE, El-Zein R, Etzel CJ, Liang FW, Armstrong G, Tsavachidis S, Gilbert MR, Aldape KD, Xing J, Wu X, Wei Q, Bondy ML
Source: Carcinogenesis, 2010 Oct;31(10), p. 1762-9.
EPub date: 2010 Jul 7.
PMID: 20610542
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Genetic variations of the PI3K-AKT-mTOR pathway and clinical outcome in muscle invasive and metastatic bladder cancer patients.
Authors: Chen M, Gu J, Delclos GL, Killary AM, Fan Z, Hildebrandt MA, Chamberlain RM, Grossman HB, Dinney CP, Wu X
Source: Carcinogenesis, 2010 Aug;31(8), p. 1387-91.
EPub date: 2010 Jun 7.
PMID: 20530239
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Risk of urinary bladder cancer: a case-control analysis of industry and occupation.
Authors: Cassidy A, Wang W, Wu X, Lin J
Source: BMC Cancer, 2009 Dec 15;9, p. 443.
EPub date: 2009 Dec 15.
PMID: 20003537
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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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Polymorphisms in DNA repair genes, smoking, and bladder cancer risk: findings from the international consortium of bladder cancer.
Authors: Stern MC, Lin J, Figueroa JD, Kelsey KT, Kiltie AE, Yuan JM, Matullo G, Fletcher T, Benhamou S, Taylor JA, Placidi D, Zhang ZF, Steineck G, Rothman N, Kogevinas M, Silverman D, Malats N, Chanock S, Wu X, Karagas MR, Andrew AS, Nelson HH, Bishop DT, Sak SC, Choudhury A, Barrett JH, Elliot F, Corral R, Joshi AD, Gago-Dominguez M, Cortessis VK, Xiang YB, Gao YT, Vineis P, Sacerdote C, Guarrera S, Polidoro S, Allione A, Gurzau E, Koppova K, Kumar R, Rudnai P, Porru S, Carta A, Campagna M, Arici C, Park SS, Garcia-Closas M, International Consortium of Bladder Cancer
Source: Cancer Res, 2009 Sep 1;69(17), p. 6857-64.
EPub date: 2009 Aug 25.
PMID: 19706757
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Profiling of genetic variations in inflammation pathway genes in relation to bladder cancer predisposition.
Authors: Yang H, Gu J, Lin X, Grossman HB, Ye Y, Dinney CP, Wu X
Source: Clin Cancer Res, 2008 Apr 1;14(7), p. 2236-44.
PMID: 18381966
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Projecting individualized probabilities of developing bladder cancer in white individuals.
Authors: Wu X, Lin J, Grossman HB, Huang M, Gu J, Etzel CJ, Amos CI, Dinney CP, Spitz MR
Source: J Clin Oncol, 2007 Nov 1;25(31), p. 4974-81.
PMID: 17971596
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Matrix metalloproteinase polymorphisms are associated with bladder cancer invasiveness.
Authors: Kader AK, Liu J, Shao L, Dinney CP, Lin J, Wang Y, Gu J, Grossman HB, Wu X
Source: Clin Cancer Res, 2007 May 1;13(9), p. 2614-20.
PMID: 17473191
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Genotypes, haplotypes and diplotypes of XPC and risk of bladder cancer.
Authors: Zhu Y, Lai M, Yang H, Lin J, Huang M, Grossman HB, Dinney CP, Wu X
Source: Carcinogenesis, 2007 Mar;28(3), p. 698-703.
EPub date: 2006 Oct 19.
PMID: 17052994
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Bladder cancer risk as modified by family history and smoking.
Authors: Lin J, Spitz MR, Dinney CP, Etzel CJ, Grossman HB, Wu X
Source: Cancer, 2006 Aug 15;107(4), p. 705-11.
PMID: 16845665
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Genetic variations in radiation and chemotherapy drug action pathways predict clinical outcomes in esophageal cancer.
Authors: Wu X, Gu J, Wu TT, Swisher SG, Liao Z, Correa AM, Liu J, Etzel CJ, Amos CI, Huang M, Chiang SS, Milas L, Hittelman WN, Ajani JA
Source: J Clin Oncol, 2006 Aug 10;24(23), p. 3789-98.
EPub date: 2006 Jun 19.
PMID: 16785472
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Polymorphisms in inflammation genes and bladder cancer: from initiation to recurrence, progression, and survival.
Authors: Leibovici D, Grossman HB, Dinney CP, Millikan RE, Lerner S, Wang Y, Gu J, Dong Q, Wu X
Source: J Clin Oncol, 2005 Aug 20;23(24), p. 5746-56.
PMID: 16110031
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Serum levels of insulin growth factor (IGF-I) and IGF-binding protein predict risk of second primary tumors in patients with head and neck cancer.
Authors: Wu X, Zhao H, Do KA, Johnson MM, Dong Q, Hong WK, Spitz MR
Source: Clin Cancer Res, 2004 Jun 15;10(12 Pt 1), p. 3988-95.
PMID: 15217929
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An association between NQO1 genetic polymorphism and risk of bladder cancer.
Authors: Park SJ, Zhao H, Spitz MR, Grossman HB, Wu X
Source: Mutat Res, 2003 Apr 20;536(1-2), p. 131-7.
PMID: 12694753
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Genetic instability in bladder cancer assessed by the comet assay.
Authors: Schabath MB, Spitz MR, Grossman HB, Zhang K, Dinney CP, Zheng PJ, Wu X
Source: J Natl Cancer Inst, 2003 Apr 2;95(7), p. 540-7.
PMID: 12671022
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Myeloperoxidase promoter region polymorphism and lung cancer risk.
Authors: Wu X, Schabath MB, Spitz MR
Source: Methods Mol Med, 2003;75, p. 121-33.
PMID: 12407737
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