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的调制是一个有吸引力的可能的机制，在主机易感性的变化。细胞凋亡缺失是肺癌发生的重要机制。细胞凋亡信号的激活是通过内源性Bcl- 2途径和通过激活死亡受体的外源性或TRAIL（TNF相关的细胞凋亡诱导配体）途径。虽然细胞凋亡在进化上是保守的，但在一般人群中，细胞凋亡的能力可能存在个体间的差异。TRAIL通路基因的多态性改变与细胞凋亡的调控有关。到目前为止，还没有研究的作用，遗传多态性的凋亡途径基因作为诱发因素的LC。在本申请中，我们的目的是研究作为LC易感因素的TRAIL途径中所涉及的基因的多态性。本研究的具体目的是：1）评估1000例病例和1000例对照中TRAIL凋亡途径基因（DR 4、DR 5、FADD、半胱天冬酶-8、-10、-3和-9以及BID）中SNP的频率。我们的工作假设是，TRAIL通路基因上的不良等位基因与改变的凋亡能力相关，可能使个体易患肺癌的风险增加; 2）评估单倍型和双倍型作为易感性的标志物。我们将实施基于单倍型的分析，以识别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识别任何基因-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，涉及多个基因的代谢途径，具有共同的，低多态性，这些多态性相互作用和/或环境因素。此应用程序旨在建立在流行病学系正在进行的受资助肺癌病例对照研究的数据和标本库基础上。由于相关的基因型数据和流行病学概况可从父母补助金，这种应用程序是时间和成本效益。本研究的目的是进一步了解肺癌的发生。肿瘤坏死因子相关凋亡诱导配体通路的多态性改变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.