Genetic Polymorphisms in TRAIL Pathway as Susceptibility Markers for Lung Cancer

描述(由申请人提供)： 87%的肺癌(LC)归因于烟草暴露。然而，只有一小部分吸烟者会患上癌症。遗传决定的环境暴露调节是寄主敏感性变化的一种有吸引力的可能机制。细胞凋亡的缺失已被证明是肺癌发生的重要机制。细胞凋亡信号的激活通过内源性的Bcl2途径和通过激活死亡受体的外源性或TRAIL(肿瘤坏死因子相关的凋亡诱导配体)途径实现。尽管细胞凋亡在进化上是保守的，但在一般人群中，细胞凋亡能力可能存在个体间的差异。TRAIL通路基因的多态变化已被报道与细胞凋亡的调控有关。到目前为止，还没有关于凋亡途径基因的遗传多态作为LC的易感因素的研究。在这项应用中，我们旨在检测TRAIL通路中涉及的基因的多态性，作为LC的易感因素。本研究的具体目的是：1)检测1000例乳腺癌和1000例正常对照中TRAIL凋亡途径基因(DR4、DR5、FADD、caspase-8、-10、-3、-9和Bid)的SNPs频率。我们的工作假设是TRAIL途径基因上的不利等位基因与修饰的凋亡能力相关，可能使个体更容易患肺癌；2)评估单倍型和双倍型作为易感性标记。我们将实施基于单倍型的分析，以确定任何额外的遗传因素；3)应用分层模型来完善风险评估，并应用新型机器学习工具来确定任何基因-环境和基因-基因相互作用。我们的假设是，LC是一种复杂的疾病，涉及到凋亡通路中的多个基因，这些基因具有共同的低外显性多态，并且这些多态相互作用和/或环境因素。这一应用程序旨在建立流行病学系正在进行的肺癌病例对照研究的数据和标本库。由于相关的基因数据和流行病学资料可以从父母的赠款中获得，因此这种应用既省时又省钱。这项研究的目的是加深我们对肺癌发生的了解。TRAIL通路的多态变化可能是识别高危人群的有用的危险生物标志物。

DESCRIPTION (provided by applicant): Eighty-seven percent of lung cancers (LC) are attributed to tobacco exposure. However, only a fraction of smokers develop cancer. Genetically determined modulation of environmental exposures is an attractive possible mechanism for the variation in host susceptibility. Loss of apoptosis has been demonstrated to be an important mechanism for lung carcinogenesis. The activation of apoptosis signaling is through an intrinsic Bcl- 2 pathway and an extrinsic or TRAIL (TNF-related Apoptosis Inducing Ligand) pathway by activation of the death receptor. Although apoptosis is evolutionarily conserved, there may be interindividual variation in apoptotic capacity in general population. Polymorphic changes on genes of TRAIL pathway have been reported to be associated with modulated apoptosis. To date, there have been no studies on the role of genetic polymorphisms in the apoptotic pathway genes as predisposing factors for LC. In this application, we aim at examining polymorphisms in genes involved in the TRAIL pathway as predisposition factor for LC. The specific aims of this proposed study are: 1) To assess frequencies of SNPs in genes in the TRAIL apoptotic pathway (DR4, DR5, FADD, caspases -8, -10, -3, and -9, and BID) in 1000 cases and 1000 controls. Our working hypothesis is that adverse alleles on TRAIL pathway genes which are associated with modified apoptosis capacity may predispose individuals to increased lung cancer risk; 2) To Assess haplotypes and diplotypes as markers of susceptibility. We will implement haplotype-based analyses to identify any additional genetic factors; 3) To apply hierarchical model to refine the risk assessment and to apply novel machine- learning tools to identify any gene-environment and gene-gene interactions. Our hypothesis is that LC is a complex disease involving multiple genes in the apoptic pathway that have common, low penetrance polymorphisms, and that these polymorphisms interacting with each other and/or environmental factors. This application is designed to build upon a data and specimen repository from on ongoing funded lung-cancer case- control study in the Department of Epidemiology. Because relevant genotype data and epidemiologic profiles are available from the parent grant, this application is both time and cost effective. The goal of this study is to further our understanding of lung carcinogenesis. Polymorphic changes on TRAIL pathway may be useful risk biomarkers to identify high-risk populations.