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

描述（由申请人提供）：本研究将建立在广泛的流行病学数据库和来自正在进行的膀胱癌病例对照研究的生物标本基础上，该研究名为“膀胱癌的遗传易感性：分子流行病学方法”（R01 CA74880, PI: Xifeng Wu， M.D, Ph.D.， 1999 - 2009年资助）。父母资助涉及一个多学科研究小组，应用分子流行病学方法确定膀胱癌易感性的个体差异，重点是在替代组织（淋巴细胞）的DNA修复系统中进行基因型和表型分析，并评估基因型-表型相关性和替代靶组织相关性。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，我们还建议确定预测端粒长度的端粒维持基因的流行病学因素和遗传变异。本提案的四个具体目的是：1)使用高通量定量实时方法确定1000名新诊断，组织学证实的膀胱癌患者和1000名频率匹配的对照组外周血淋巴细胞的总端粒长度；2)采用改进的基于实时荧光定量PCR的单端粒长度分析（STELA）方法测定相同1000例患者外周血淋巴细胞的染色体特异性端粒长度（17p、2p、11q、12q和XpYp）。我们假设最短的端粒，17p是一个例子，在癌症病因学上比长端粒表现出更强的癌症易感性；3)测定所有病例和对照组端粒维持通路基因的单核苷酸多态性（snp）频率，并确定候选基因型和单倍型作为膀胱癌易感性的标记；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的流行病学研究。此外，这是第一个评估染色体特异性端粒长度与癌症风险的研究，也是第一个全面评估端粒维持基因遗传变异在癌症病因学中的研究。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系以及它们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。端粒是每条染色体上的末端结构，就像鞋带末端的鞋带帽一样，防止鞋带（染色体）散开。我们假设遗传的端粒较短的个体比端粒较长的个体更容易患膀胱癌，而某些染色体上的短端粒比其他染色体上的短端粒更容易致癌。我们还想确定端粒维持基因的遗传变异，这些基因可能预测端粒缩短，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名健康对照者中测试这些假设。识别膀胱癌高危亚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利益。

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.