Telomere dysfunction, chromosome 9 instability and bladder cancer risk

端粒功能障碍、9号染色体不稳定和膀胱癌风险

• 批准号: 8324699
• 负责人: YUN-LING ZHENG
• 金额: $ 58.89万
• 依托单位: GEORGETOWN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-21 至 2014-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8324699
• 关键词: 9p21; Affect; Africa South of the Sahara; Age; American Cancer Society; Aneuploidy; Arsenic; Biological; Biological Markers; Bladder; Bladder Neoplasm; Blood; CDKN2A gene; Cancer Burden; Cancer Patient; Carcinogens; Case-Control Studies; Cell Aging; Cell Proliferation; Cessation of life; Characteristics; Chromosomal Gain; Chromosomal Instability; Chromosomal Rearrangement; Chromosome abnormality; Chromosomes; Chromosomes, Human, Pair 9; Clinical; Cyclin-Dependent Kinase Inhibitor 2A; DNA Damage; Data; Developed Countries; Development; Diagnosis; Early Diagnosis; Egypt; Employee Strikes; Environment; Environmental Exposure; Environmental Risk Factor; Environmental Tobacco Smoke; Epidemiologic Studies; Epidemiology; Etiology; Exposure to; FGFR3 gene; Frequencies; Functional disorder; Funding; Future; Gender; General Population; Genes; Genetic; Genetic Predisposition to Disease; Genome Stability; Genomics; HRAS gene; Health; Human; Incidence; Individual; Infection; Institution; Knowledge; Length; Link; Lymphocyte; Malignant Neoplasms; Malignant neoplasm of urinary bladder; Medical; Methods; Middle East; Molecular; Molecular Epidemiology; Molecular Genetics; Mutagens; Mutation; National Cancer Institute; Newly Diagnosed; Occupational; Pathogenesis; Pathway interactions; Patients; Point Mutation; Predisposition; Principal Investigator; Public Health; Recruitment Activity; Research; Research Design; Risk; Risk Assessment; Risk Factors; Role; Sampling; Schistosomiasis; Series; Smoker; Somatic Cell; Specimen; TP53 gene; Telomere Maintenance; Telomere Pathway; Testing; Time; Tobacco smoking; Transitional Cell Carcinoma; United States; Urinary tract infection; Woman; base; bladder cancer prevention; bladder transitional cell carcinoma; cancer risk; carcinogenesis; case control; drinking water; epidemiology study; gene environment interaction; improved; insight; men; non-smoker; patient population; population based; prevent; regional difference; role model; statistics; telomere; tool; tumor

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.

描述（由申请人提供）：膀胱癌继续在全世界范围内带来重大的健康挑战，并且其发病率持续增加。膀胱癌是发达国家男性第四大常见恶性肿瘤，也是中东和撒哈拉以南非洲男性最常见恶性肿瘤。先前的研究已经证实，环境暴露，尤其是吸烟，是膀胱移行细胞癌（TCC）的重要危险因素。相比之下，人们对导致 TCC 风险的遗传因素知之甚少。染色体不稳定性 (CIN) 是膀胱肿瘤中基因组改变的主要形式，端粒功能障碍可能是导致 CI​​N 的机制之一。我们建议利用埃及正在进行的病例对照研究收集的生物标本和流行病学数据进行膀胱癌的分子流行病学研究，以检验两个主要假设：（1）端粒短的个体对膀胱癌的易感性增加; (2) 9p 或 9q 染色体上的短端粒会增加 9 号染色体改变的可能性和膀胱癌的风险。拟议研究的具体目的是：（1）确定膀胱癌风险与血液淋巴细胞端粒总长度之间的关联，并确定端粒长度是否对非吸烟者和吸烟者的膀胱癌风险分别产生不同的影响； (2) 确定膀胱癌风险与血液淋巴细胞的 9 号染色体特定端粒长度之间的关联，并确定 9 号染色体端粒长度是否分别对非吸烟者和吸烟者的膀胱癌风险产生不同的影响； (3) 评估环境暴露（即吸烟或 SH 感染）和端粒长度之间的相互作用对膀胱癌风险的影响； (4) 确定 9 号染色体端粒长度是否与膀胱肿瘤中的 9 号染色体畸变相关，并确定 9 号染色体端粒长度与膀胱癌风险的关联是否因肿瘤 9 号染色体畸变状态而异。研究设计为病例对照。病例（N = 2,042）是从埃及三个医疗机构招募的新诊断膀胱TCC患者。对照（N = 2,042）是使用多阶段、整群随机抽样方法从与病例相同地理区域内的一般人群中随机选出的健康个体，频率与病例年龄和性别相匹配。拟议的研究旨在了解端粒缺陷（整体缺陷和 9 号染色体特异性缺陷）如何导致膀胱癌的发展，以及端粒缺陷是否与环境因素（即吸烟）相互作用，从而协同影响膀胱癌风险。它有潜力识别新的生物标志物，以更好地评估膀胱癌风险。更好的风险评估将改善当前和未来的公共卫生工作，以减轻膀胱癌负担。将产生的新知识将为理解膀胱癌发生的病因提供见解，并为开发新的、更好的早期检测和诊断临床工具铺平道路。公共卫生相关性：膀胱癌是美国男性第四大常见癌症。被诊断患有膀胱癌的男性人数大约是女性的四倍。据美国癌​​症协会统计，2006 年美国估计有 61,420 例新发病例（男性和女性合计），死亡人数为 13,060 人。拟议的研究旨在了解端粒缺陷（整体缺陷和 9 号染色体特异性缺陷）如何导致膀胱癌的发展，以及端粒缺陷是否与环境因素（即吸烟）相互作用，从而协同影响膀胱癌风险。它有潜力识别新的生物标志物，以更好地评估膀胱癌风险。更好的风险评估将改善当前和未来的公共卫生工作，以减轻膀胱癌负担。将产生的新知识将为理解膀胱癌发生的病因提供见解，并为开发新的、更好的早期检测和诊断临床工具铺平道路。