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

Grant Number: 5R01CA132996-05 Interpret this number
Primary Investigator: Zheng, Yun-Ling
Organization: Georgetown University
Project Title: Telomere Dysfunction, Chromosome 9 Instability and Bladder Cancer Risk
Fiscal Year: 2013
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Abstract

DESCRIPTION (provided by applicant): Cancer of the urinary bladder continues to present significant health challenges worldwide and its incidence continues to increase. Bladder cancer is the fourth most common malignancy in men from developed countries, whereas it is the most common malignancy in men in the Middle East and sub-Saharan Africa. Previous studies have established that environmental exposures, particularly tobacco smoking, are important risk factors in transitional cell carcinoma (TCC) of the urinary bladder. In contrast, genetic factors that contribute to the risk of TCC are less well understood. Chromosomal instability (CIN) is the dominant form of the genomic alterations seen in bladder tumors and telomere dysfunction may be one of the mechanisms that cause CIN. We propose to conduct a molecular epidemiology study of bladder cancer, using the biological specimens and epidemiological data collected by an ongoing case-control study in Egypt, to test two primary hypotheses: (1) Individuals with short telomeres have an increased susceptibility to bladder cancer; (2) Short telomeres on chromosome 9p or 9q increase the likelihood of chromosome 9 alterations and risk of bladder cancer. The specific aims of proposed study are: (1) to determine the association between bladder cancer risk and overall telomere length of blood lymphocytes and determine if telomere length exerts differential effects on bladder cancer risk in non-smokers and smokers separately; (2) to determine the association between bladder cancer risk and chromosome 9 specific telomere lengths of blood lymphocytes and determine if chromosome 9 telomere lengths exert differential effects on bladder cancer risk in non-smokers and smokers separately; (3) to evaluate effects of interactions between environmental exposures (i.e., tobacco smoking or SH infection) and the telomere lengths on bladder cancer risk; (4) to determine if chromosome 9 telomere lengths are associated with chromosome 9 aberrations in bladder tumors and determine whether the association of chromosome 9 telomere length and bladder cancer risk differs by tumor chromosome 9 aberration status. The study design is case-control. Cases (N = 2,042) are patients who are newly diagnosed with TCC of urinary bladder and recruited from three medical institutions in Egypt. Controls (N = 2,042) are healthy individuals randomly selected from the general population within the same geographic districts as the cases using a multistage, clustered random sampling method, frequency matched to case by age and gender. The proposed study aims to understand how telomere deficiencies (both overall and chromosome 9 specific) contribute to bladder cancer development and whether deficiencies in telomeres interact with environmental factors, i.e., tobacco smoking, to synergistically affect bladder cancer risk. It has the potential to identify new biomarkers for better bladder cancer risk assessment. Better risk assessment will improve current and future public health efforts to reduce the bladder cancer burden. The new knowledge to be generated will provide insights in understanding the etiology of bladder carcinogenesis and pave the way for the development of new and better clinical tools for early detection and diagnosis. PUBLIC HEALTH RELEVANCE: Cancer of the urinary bladder is the fourth most common cancer in men in the United States. About 4 times as many men are diagnosed with bladder cancer compared to women. There are 61,420 estimated new cases (men and women combined) and 13,060 deaths in the United States in 2006, according to American Cancer Society statistics. The proposed study aims to understand how telomere deficiencies (both overall and chromosome 9 specific) contribute to bladder cancer development and whether deficiencies in telomeres interact with environmental factors, i.e., tobacco smoking, to synergistically affect bladder cancer risk. It has the potential to identify new biomarkers for better bladder cancer risk assessment. Better risk assessment will improve current and future public health efforts to reduce the bladder cancer burden. The new knowledge to be generated will provide insights in understanding the etiology of bladder carcinogenesis and pave the way for the development of new and better clinical tools for early detection and diagnosis.

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Publications

Telomere Deficiencies On Chromosomes 9p, 15p, 15q And Xp: Potential Biomarkers For Breast Cancer Risk
Authors: Zheng Y.L. , Zhou X. , Loffredo C.A. , Shields P.G. , Sun B. .
Source: Human Molecular Genetics, 2011-01-15 00:00:00.0; 20(2), p. 378-86.
PMID: 20956286
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Urinary Bladder Cancer Risk Factors In Egypt: A Multicenter Case-control Study
Authors: Zheng Y.L. , Amr S. , Saleh D.A. , Dash C. , Ezzat S. , Mikhail N.N. , Gouda I. , Loay I. , Hifnawy T. , Abdel-Hamid M. , et al. .
Source: Cancer Epidemiology, Biomarkers & Prevention : A Publication Of The American Association For Cancer Research, Cosponsored By The American Society Of Preventive Oncology, 2012 Mar; 21(3), p. 537-46.
PMID: 22147365
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Genetic Polymorphisms In Nqo1 And Sod2: Interactions With Smoking, Schistosoma Infection, And Bladder Cancer Risk In Egypt
Authors: Goerlitz D. , Amr S. , Dash C. , Saleh D.A. , El Daly M. , Abdel-Hamid M. , El Kafrawy S. , Hifnawy T. , Ezzat S. , Abdel-Aziz M.A. , et al. .
Source: Urologic Oncology, 2014 Jan; 32(1), p. 47.e15-20.
PMID: 24035474
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Telomerase Enzymatic Component Htert Shortens Long Telomeres In Human Cells
Authors: Zheng Y.L. , Zhang F. , Sun B. , Du J. , Sun C. , Yuan J. , Wang Y. , Tao L. , Kota K. , Liu X. , et al. .
Source: Cell Cycle (georgetown, Tex.), 2014; 13(11), p. 1765-76.
PMID: 24721976
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Simultaneous Quantification Of Alternatively Spliced Transcripts In A Single Droplet Digital Pcr Reaction
Authors: Sun B. , Tao L. , Zheng Y.L. .
Source: Biotechniques, 2014 Jun; 56(6), p. 319-25.
PMID: 24924392
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Telomere Length Variation: A Potential New Telomere Biomarker For Lung Cancer Risk
Authors: Sun B. , Wang Y. , Kota K. , Shi Y. , Motlak S. , Makambi K. , Loffredo C.A. , Shields P.G. , Yang Q. , Harris C.C. , et al. .
Source: Lung Cancer (amsterdam, Netherlands), 2015 Jun; 88(3), p. 297-303.
PMID: 25840848
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Genomic Instability In Human Cancer: Molecular Insights And Opportunities For Therapeutic Attack And Prevention Through Diet And Nutrition
Authors: Ferguson L.R. , Chen H. , Collins A.R. , Connell M. , Damia G. , Dasgupta S. , Malhotra M. , Meeker A.K. , Amedei A. , Amin A. , et al. .
Source: Seminars In Cancer Biology, 2015 Dec; 35 Suppl, p. S5-24.
PMID: 25869442
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Strong Association Between Long And Heterogeneous Telomere Length In Blood Lymphocytes And Bladder Cancer Risk In Egyptian
Authors: Wang H. , Wang Y. , Kota K.K. , Kallakury B. , Mikhail N.N. , Sayed D. , Mokhtar A. , Maximous D. , Yassin E.H. , Gouda I. , et al. .
Source: Carcinogenesis, 2015 Nov; 36(11), p. 1284-90.
PMID: 26342126
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