Exome Sequencing to identify Novel Genetic Factors for Lung Cancer in Nonsmokers

外显子组测序鉴定非吸烟者肺癌的新遗传因素

• 批准号: 9248773
• 负责人: QIUYIN CAI
• 金额: $ 58.88万
• 依托单位: VANDERBILT UNIVERSITY MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-06-01 至 2017-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9248773
• 关键词: Exome; Sequencing; identify; Novel; Genetic

DESCRIPTION (provided by applicant): Lung cancer is the leading cause of cancer death in the United States and many other countries. Genetic factors play an important role in the etiology of lung cancer. Recent genome-wide association studies (GWAS) have identified multiple genetic susceptibility loci for lung cancer. However, these newly-identified genetic factors explain only a small fraction of the heritability for lung cancer. Moreover, these studies were conducted primarily among smokers, raising the possibility that the identified associations could be related to tobacco use behavior, lung carcinogenesis, or both. Genetic studies conducted among never-smokers provide exceptional opportunities to discover genetic variants that confer risk for lung cancer independent of smoking. Recently evidence has emerged to strongly suggest that most of the heritable risk for cancer and other complex diseases may be due to a large number of low-frequency, moderate-penetrance genes. Herein, we propose a whole-exome sequencing study to systematically search the entire coding region in the human genome to detect lung cancer susceptibility genes and variants that cannot be identified through conventional GWAS or family-based linkage analyses. The proposed study will be built on the resources established in the Shanghai Women's Health Study, Guangzhou Lung Cancer Study, and the Female Lung Cancer Consortium in Asia, all of which are conducted among East-Asian women. The specific aims of the study are as follows; all cases and controls are female never-smokers. Aim 1 is to sequence the whole exome of 600 NSCLC cases and 600 controls (Stage 1). Aim 2 is to validate variants in approximately 350 promising genes identified in Aim 1 in 2,500 NSCLC cases and 2,500 controls (Stage 2). Aim 3 is to validate approximately 15 genes from Stage 2 in an additional 2,500 NSCLC cases and 2,500 controls (Stage 3). To our knowledge, this is the first large association study of lung cancer conducted among never-smokers using whole-exome sequencing. With its strong methodology and use of novel technologies and study design, the proposed study will significantly improve our understanding of lung cancer genetics and biology through the identification of novel genes and pathways. Newly-identified genes and pathways could serve as targets for novel cancer treatments, and genetic variants from these genes could be used for cancer screening and risk assessment aimed at identifying high-risk individuals for targeted lung cancer prevention.

描述（由申请人提供）：肺癌是美国和许多其他国家癌症死亡的主要原因。遗传因素在肺癌病因中起重要作用。最近的全基因组关联研究（GWAS）已经确定了多个遗传易感性基因座对肺癌。但是，这些新鉴定的遗传因素仅解释了肺癌遗传力的一小部分。此外，这些研究主要是在吸烟者中进行的，从而提出了可能与烟草使用行为，肺癌发生或两者兼而有之有关的可能性。从未吸烟的人进行的遗传研究提供了出色的机会，可以发现独立于吸烟的肺癌风险的遗传变异。最近，有证据表明，大多数癌症和其他复杂疾病的可遗传风险可能是由于大量低频，中等原质基因所致。本文中，我们提出了一项全外观测序研究，以系统地搜索人类基因组中的整个编码区域，以检测无法通过常规GWAS或基于家庭的联系分析来鉴定的肺癌敏感性基因和变体。拟议的研究将建立在上海妇女健康研究，广州肺癌研究和亚洲女性肺癌财团中建立的资源，所有这些联盟都是在东亚洲妇女中进行的。该研究的具体目的如下；所有病例和控制都是女性从未吸烟的人。目的1是对600个NSCLC病例和600个对照的整个外显子组进行测序（第1阶段）。 AIM 2是验证在2500个NSCLC病例和2,500个对照中鉴定出的大约350个有希望的基因的变异基因（第2阶段）。 AIM 3是在另外2,500个NSCLC病例和2,500个对照中验证第2阶段的大约15个基因（第3阶段）。据我们所知，这是使用全外观测序在永不吸烟者中进行的首次大型肺癌研究。凭借其强大的方法论和新型技术和研究设计的使用，提出的研究将通过鉴定新基因和途径来显着提高我们对肺癌遗传学和生物学的理解。新鉴定的基因和途径可以用作新型癌症治疗的靶标，这些基因的遗传变异可以用于癌症筛查和风险评估，旨在鉴定有针对性的肺癌预防的高风险个体。