Telomere dysfunction, chromosome 9 instability and bladder cancer risk

描述（由申请人提供）：膀胱癌继续在世界范围内呈现出重大的健康挑战，其发病率持续增加。膀胱癌是发达国家男性中第四大最常见的恶性肿瘤，而它是中东和撒哈拉以南非洲男性中最常见的恶性肿瘤。先前的研究已经证实，环境暴露，特别是吸烟，是膀胱移行细胞癌（TCC）的重要危险因素。相比之下，导致TCC风险的遗传因素却知之甚少。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CIN的机制之一。我们建议对膀胱癌进行分子流行病学研究，利用在埃及正在进行的病例对照研究中收集的生物标本和流行病学数据，验证两个主要假设：(1)端粒短的个体对膀胱癌的易感性增加；(2) 9p或9q染色体上的短端粒增加了9号染色体改变的可能性和膀胱癌的风险。本研究的具体目的是：(1)确定膀胱癌风险与血液淋巴细胞总端粒长度的关系，确定端粒长度对非吸烟者和吸烟者膀胱癌风险的影响是否存在差异；(2)确定膀胱癌风险与血液淋巴细胞9号染色体特异性端粒长度的关系，确定9号染色体端粒长度对非吸烟者和吸烟者膀胱癌风险的影响是否存在差异；(3)评估环境暴露（如吸烟或SH感染）与端粒长度之间的相互作用对膀胱癌风险的影响；(4)确定膀胱肿瘤中9号染色体端粒长度是否与9号染色体畸变相关，确定9号染色体端粒长度与膀胱癌风险的相关性是否因肿瘤9号染色体畸变状态而异。本研究设计为病例对照。病例（N = 2,042）是从埃及三家医疗机构招募的新诊断为膀胱TCC的患者。对照（N = 2,042）是从与病例相同地理区域的一般人群中随机选择的健康个体，采用多阶段聚类随机抽样方法，频率按年龄和性别与病例相匹配。本研究旨在了解端粒缺陷（包括整体缺陷和9号染色体特异性缺陷）如何促进膀胱癌的发展，以及端粒缺陷是否与环境因素（如吸烟）相互作用，协同影响膀胱癌风险。它有可能为更好的膀胱癌风险评估识别新的生物标志物。更好的风险评估将改善当前和未来的公共卫生工作，以减少膀胱癌的负担。所产生的新知识将为理解膀胱癌的病因学提供见解，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：在美国，膀胱癌是男性第四大常见癌症。被诊断患有膀胱癌的男性是女性的四倍。根据美国癌症协会的统计数据，2006年美国估计有61,420例新病例（男性和女性加起来）和13,060例死亡。本研究旨在了解端粒缺陷（包括整体缺陷和9号染色体特异性缺陷）如何促进膀胱癌的发展，以及端粒缺陷是否与环境因素（如吸烟）相互作用，协同影响膀胱癌风险。它有可能为更好的膀胱癌风险评估识别新的生物标志物。更好的风险评估将改善当前和未来的公共卫生工作，以减少膀胱癌的负担。所产生的新知识将为理解膀胱癌的病因学提供见解，并为开发新的更好的早期检测和诊断临床工具铺平道路。

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.