Telomere length, telomere maintenance gene polymorphisms, and bladder cancer risk

端粒长度、端粒维持基因多态性和膀胱癌风险

• 批准号: 7527873
• 负责人: Jian Gu
• 金额: $ 31.96万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-07-01 至 2012-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7527873
• 关键词: 11q; 12q; 17p; Affect; Age; Biological Assay; Biology; Bladder; Cancer Etiology; Cancer Patient; Case-Control Studies; Chemoprevention; Chromosomes; Clinic; DNA Damage; DNA Repair; Databases; Development; Dietary Factors; Doctor of Medicine; Doctor of Philosophy; Environmental Risk Factor; Epidemiologic Factors; Epidemiologic Studies; Ethnic Origin; Exhibits; Frequencies; Funding; Gender; Genes; Genetic; Genetic Polymorphism; Genetic Predisposition to Disease; Genetic Variation; Genotype; Goals; Haplotypes; Health Benefit; Histologic; Human Chromosomes; Individual; Individual Differences; Inherited; Lead; Length; Lymphocyte; Malignant Neoplasms; Malignant neoplasm of urinary bladder; Measures; Medical Surveillance; Methods; Molecular; Newly Diagnosed; Pathway interactions; Peripheral Blood Lymphocyte; Persons; Phenotype; Physicians; Polymerase Chain Reaction; Predisposing Factor; Predisposition; Public Health; Relative (related person); Research Personnel; Risk; Role; Sample Size; Single Nucleotide Polymorphism; Structure; Subgroup; System; Telomere Length Maintenance; Telomere Maintenance; Telomere Maintenance Gene; Telomere Shortening; Testing; Time; Tissues; base; cancer risk; carcinogenesis; case control; genetic variant; medical specialties; multidisciplinary; novel; parent grant; telomere; trait

DESCRIPTION (provided by applicant): 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.

描述(申请人提供)：这项拟议的研究将建立在广泛的流行病学数据库和生物样本的基础上，该研究来源于一项正在进行的名为“膀胱癌的遗传易感性：分子流行病学方法”的膀胱癌病例对照研究(R01 CA74880，PI：吴喜峰，医学博士，博士，1999年至2009年资助)。家长赠款涉及一个多学科的研究小组，应用分子流行病学方法来确定膀胱癌易感性的个体差异，重点是在代孕组织(淋巴细胞)中进行DNA修复系统的基因和表型分析，并评估基因-表型相关性和代孕-目标组织相关性。当前建议的目标是通过显著增加样本量和测量染色体特定的端粒长度来扩大我们之前的开创性观察，即端粒缩短是癌症的易感因素。此外，我们还建议确定预测端粒长度的流行病学因素和端粒维持基因中的遗传变异。这项建议的四个具体目标是：1)使用高通量实时定量方法测定1000例新诊断的、经组织学证实的膀胱癌患者和1000例频率匹配的对照组的外周血淋巴细胞的端粒总长度；2)使用一种改进的基于实时荧光聚合酶链式反应的单个端粒长度分析(STELA)方法，测定相同1000例患者和1000名对照组的外周血淋巴细胞的染色体特异端粒长度(17p、2p、11q、12q和XpYp)。我们假设，在癌症病因学中，最短的端粒(例如17P)比长的端粒表现出更强的致癌作用；3)确定所有病例和对照的端粒维持途径基因的单核苷酸多态(SNPs)频率，并确定候选基因和单倍型作为膀胱癌的易感性标记；4)评估端粒长度的基因型-表型相关性。这项研究是评估整体端粒缩短在膀胱癌风险中的作用的最大规模的流行病学研究。此外，这是第一次评估染色体特定的端粒长度和癌症风险，并全面评估端粒维持基因在癌症病因学中的遗传变异。大样本量将使我们能够确定环境和饮食因素与端粒长度之间的联系，以及它们在调节膀胱癌风险方面的相互作用。与公共健康相关：癌症发展的标志之一是遗传不稳定。人类有23对染色体，它们不断受到内源性和外源性DNA损伤剂的攻击。端粒是每条染色体上的末端结构，就像鞋带两端的鞋带帽一样，防止花边(染色体)解开。我们假设，遗传的端粒较短的个体比端粒较长的个体更有可能患膀胱癌，某些染色体上的短端粒比其他染色体上的短端粒更有可能致癌。我们还想确定端粒维持基因的遗传变异，这些基因变异可以预测端粒缩短，从而影响一个人患膀胱癌的风险。我们将在1000名膀胱癌患者和1000名健康对照中测试这些假设。识别膀胱癌高危人群的能力将为那些可能受到密切监测和化学预防的高危人群提供巨大的公共健康益处。