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. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
1R01CA131335-01A1
Application #
7527873
Study Section
Epidemiology of Cancer Study Section (EPIC)
Program Officer
Schully, Sheri D
Project Start
2008-07-01
Project End
2012-06-30
Budget Start
2008-07-01
Budget End
2009-06-30
Support Year
1
Fiscal Year
2008
Total Cost
$319,550
Indirect Cost
Name
University of Texas MD Anderson Cancer Center
Department
Type
Schools of Medicine
DUNS #
800772139
City
Houston
State
TX
Country
United States
Zip Code
77030
Ke, Hung-Lung; Lin, Jie; Ye, Yuanqing et al. (2015) 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. Ann Surg Oncol 22:4104-10
Sanchez-Espiridion, Beatriz; Chen, Meng; Chang, Joe Y et al. (2014) Telomere length in peripheral blood leukocytes and lung cancer risk: a large case-control study in Caucasians. Cancer Res 74:2476-86
de Maturana, Evangelina López; Ye, Yuanqing; Calle, M Luz et al. (2013) Application of multi-SNP approaches Bayesian LASSO and AUC-RF to detect main effects of inflammatory-gene variants associated with bladder cancer risk. PLoS One 8:e83745
Xie, Hui; Wu, Xifeng; Wang, Shui et al. (2013) Long telomeres in peripheral blood leukocytes are associated with an increased risk of soft tissue sarcoma. Cancer 119:1885-91
Lee, Eugene K; Ye, Yuanquing; Kamat, Ashish M et al. (2013) Genetic variations in regulator of G-protein signaling (RGS) confer risk of bladder cancer. Cancer 119:1643-51
Andrew, Angeline S; Hu, Ting; Gu, Jian et al. (2012) HSD3B and gene-gene interactions in a pathway-based analysis of genetic susceptibility to bladder cancer. PLoS One 7:e51301
Wei, Hua; Kamat, Ashish; Chen, Meng et al. (2012) Association of polymorphisms in oxidative stress genes with clinical outcomes for bladder cancer treated with Bacillus Calmette-Guérin. PLoS One 7:e38533
Wei, Hua; Kamat, Ashish M; Aldousari, Saad et al. (2012) Genetic variations in the transforming growth factor beta pathway as predictors of bladder cancer risk. PLoS One 7:e51758
Chang, Joshua; Dinney, Colin P; Huang, Maosheng et al. (2012) Genetic variants in telomere-maintenance genes and bladder cancer risk. PLoS One 7:e30665
Xing, Jinliang; Dinney, Colin P; Shete, Sanjay et al. (2012) Comprehensive pathway-based interrogation of genetic variations in the nucleotide excision DNA repair pathway and risk of bladder cancer. Cancer 118:205-15

Showing the most recent 10 out of 16 publications