Genetic Polymorphisms in TRAIL Pathway as Susceptibility Markers for Lung Cancer

TRAIL 通路的基因多态性作为肺癌的易感性标记

• 批准号: 7264915
• 负责人: Jie Lin
• 金额: $ 7.7万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-01 至 2009-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7264915
• 关键词: Algorithms; Alleles; Apoptosis; Apoptotic; Applications Grants; Asbestos; Asthma; Biological Markers; Build-it; CD95 Antigens; Cancer Patient; Case-Control Studies; Caspase; Caucasians; Caucasoid Race; Cell Cycle Checkpoint; Cessation of life; Characteristics; Complex; DNA Repair; Data; Death Domain; Disease; Dust; Environment; Environmental Exposure; Environmental Risk Factor; Enzymes; Epidemiology; Etiology; Family Cancer History; Frequencies; Funding; General Population; Genes; Genetic; Genetic Polymorphism; Genetic Risk; Genotype; Goals; Haplotypes; Hay fever; Individual; Inflammation; Length; Machine Learning; Malignant Neoplasms; Malignant neoplasm of lung; Malignant neoplasm of urinary bladder; Metabolic; Micronutrients; Modeling; Molecular; Non-Small-Cell Lung Carcinoma; Pathway interactions; Pattern; Penetrance; Population; Predisposing Factor; Predisposition; Pulmonary Emphysema; Recording of previous events; Reporting; Risk; Risk Assessment; Role; Signal Transduction; Smoker; Smoking; Specimen; Stratification; TNF-related apoptosis-inducing ligand; TNFRSF10B gene; Time; Tobacco; Variant; Work; base; cancer risk; case control; caspase-8; cost effective; death receptor-4; design; gene environment interaction; gene interaction; genetic association; human TNFRSF10A protein; lung carcinogenesis; lung small cell carcinoma; novel; parent grant; programs; receptor; repository; smoking cessation; telomere; tobacco exposure; tool

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.

描述（由申请人提供）： 87％的肺癌（LC）归因于烟草暴露。但是，只有一小部分吸烟者患癌症。遗传确定的环境暴露调节是宿主易感性变化的有吸引力的可能机制。凋亡的丧失已被证明是肺癌发生的重要机制。凋亡信号的激活是通过固有的BCl-2途径和外部或TRAIL（与TNF相关的凋亡诱导配体）途径通过激活死亡受体的途径。尽管凋亡在进化上是保守的，但普通人群的凋亡能力可能存在个体差异。据报道，途径的多态性变化与调节凋亡有关。迄今为止，尚无关于遗传多态性在凋亡途径基因中作为LC诱发因素的作用的研究。在此应用中，我们旨在检查涉及跟踪途径的基因中的多态性，作为LC的易感因子。这项拟议的研究的具体目的是：1）评估在1000例和1000个对照中，评估TRAR凋亡途径（DR4，DR5，FADD，CASPASE，-8，-10，-3和-9和BID）基因中SNP的频率。我们的工作假设是，与修改的凋亡能力相关的步道途径基因上的不良等位基因可能会使个体倾向于增加肺癌的风险。 2）评估单倍型和外交型作为易感性的标志。我们将实施基于单倍型的分析，以确定任何其他遗传因素； 3）应用层次模型来完善风险评估并应用新颖的机器学习工具以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，涉及凋亡途径中的多个基因，具有常见的，低渗透性多态性，并且这些多态性相互相互作用和/或环境因素。该应用程序旨在基于流行病学系正在进行的肺癌病例控制研究的数据和标本存储库。由于可从父母赠款获得相关的基因型数据和流行病学概况，因此此应用程序既是时间又是成本效益。这项研究的目的是进一步了解肺癌发生。步道途径上的多态性变化可能是有用的风险生物标志物来识别高风险人群。