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: 7860618
• 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/7860618
• 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; Epidemiology; 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; Methods; Molecular; Newly Diagnosed; Pathway interactions; Peripheral Blood Lymphocyte; Persons; Phenotype; Physicians; 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; high risk; medical specialties; multidisciplinary; novel; parent grant; public health relevance; 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（由申请方提供）：本拟定研究将建立在广泛的流行病学数据库和来自一项正在进行的膀胱癌病例对照研究的生物标本基础上，该研究题为“膀胱癌的遗传易感性：分子流行病学方法”（R 01 CA 74880，PI：Xifeng Wu，M.D.，哲学博士、1999年至2009年）。母基金涉及一个多学科研究小组，应用分子流行病学方法来确定膀胱癌发生易感性的个体间差异，重点是在替代组织（淋巴细胞）中进行DNA修复系统的基因型和表型检测，并评估基因型-表型相关性和替代靶组织相关性。当前提案的目标是通过显著增加样本量和测量染色体特异性端粒长度来扩展我们先前的开创性观察，即端粒缩短是癌症易感因素。此外，我们还建议确定流行病学因素和端粒维持基因的遗传变异预测端粒长度。该提案的四个具体目标是：1）使用高通量定量实时方法测定1000名新诊断、组织学确诊的膀胱癌患者和1000名频率匹配的对照者外周血淋巴细胞的总体端粒长度; 2）确定染色体特异性端粒长度（17 p、2p、11 q、12 q和XpYp），采用改良的基于实时PCR的单端粒长度分析（STELA）方法，对来自相同1000例病例和1000例对照的外周血淋巴细胞进行分析。我们假设，最短的端粒，17 p是一个例子，表现出更强的癌症易感性比长端粒的癌症病因的影响; 3）确定在所有的情况下和对照组中的端粒维持途径基因的单核苷酸多态性（SNP）的频率，并确定候选基因型和单倍型作为膀胱癌易感性的标志物; 4）评估端粒长度的基因型-表型相关性。这项研究是最大的流行病学研究，以评估整体端粒缩短在膀胱癌风险中的作用。此外，这是第一项评估染色体特异性端粒长度和癌症风险的研究，并全面评估癌症病因学中端粒维持基因的遗传变异。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关联及其在调节膀胱癌风险中的相互作用。公共卫生相关性：癌症发展的标志之一是遗传不稳定性。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。端粒是每个染色体上的末端结构，就像鞋带两端的鞋带帽，防止鞋带（染色体）解开。我们假设，遗传端粒较短的个体比端粒较长的个体更容易患膀胱癌，某些染色体上的短端粒比其他染色体上的短端粒更容易导致癌症。我们还想确定端粒维持基因的遗传变异，而不是预测端粒缩短，从而影响一个人的膀胱癌风险。我们将在一个由1000名膀胱癌患者和1000名健康对照组成的大组中测试这些假设。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卫生益处。