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: 7491066
• 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 2010-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7491066
• 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）： 百分之八十七的肺癌 (LC) 归因于接触烟草。然而，只有一小部分吸烟者会患上癌症。基因决定的环境暴露调节是宿主易感性变化的一种有吸引力的可能机制。细胞凋亡的丧失已被证明是肺癌发生的重要机制。细胞凋亡信号传导的激活是通过内在的 Bcl-2 途径和通过死亡受体的激活的外在或 TRAIL（TNF 相关细胞凋亡诱导配体）途径进行的。尽管细胞凋亡在进化上是保守的，但一般人群中细胞凋亡能力可能存在个体间差异。据报道，TRAIL 通路基因的多态性变化与细胞凋亡的调节有关。迄今为止，尚无关于凋亡途径基因中的遗传多态性作为LC诱发因素的作用的研究。在此应用中，我们旨在检查 TRAIL 通路相关基因的多态性作为 LC 的易感因素。本研究的具体目的是： 1) 评估 1000 例 TRAIL 凋亡途径基因（DR4、DR5、FADD、半胱天冬酶 -8、-10、-3、-9 和 BID）中 SNP 的频率和 1000 个控件。我们的工作假设是，与细胞凋亡能力改变相关的 TRAIL 通路基因上的不良等位基因可能会增加个体患肺癌的风险； 2) 评估作为易感性标记的单倍型和双倍型。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，涉及细胞凋亡途径中的多个基因，这些基因具有共同的、低外显率的多态性，并且这些多态性彼此和/或环境因素相互作用。该应用程序旨在建立流行病学系正在进行的资助的肺癌病例对照研究的数据和样本存储库。由于相关基因型数据和流行病学概况可从父资助中获得，因此该申请既节省时间又节省成本。这项研究的目的是加深我们对肺癌发生的了解。 TRAIL 通路的多态性变化可能是识别高危人群的有用风险生物标志物。