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

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。遗传因素在肺癌的病因学中起重要作用。最近的全基因组关联研究（GWAS）已经确定了肺癌的多个遗传易感性位点。然而，这些新发现的遗传因素只能解释肺癌遗传性的一小部分。此外，这些研究主要是在吸烟者中进行的，这增加了所确定的关联可能与烟草使用行为、肺癌发生或两者有关的可能性。在从不吸烟者中进行的遗传研究提供了发现与吸烟无关的肺癌风险的遗传变异的绝佳机会。最近出现的证据有力地表明，癌症和其他复杂疾病的大部分遗传风险可能是由于大量的低频，中度突变基因。在此，我们提出了一个全外显子组测序研究，系统地搜索人类基因组中的整个编码区，以检测肺癌易感基因和变异，不能通过传统的GWAS或基于家庭的连锁分析确定。这项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联盟的基础上，所有这些研究都是在东亚妇女中进行的。研究的具体目的如下：所有病例和对照组均为从不吸烟的女性。目的1是测序600例NSCLC病例和600例对照（第1阶段）的全外显子组。目标2是在2,500例NSCLC病例和2,500例对照中验证目标1中鉴定的约350个有希望基因的变体（第2阶段）。目的3是在另外2,500例NSCLC病例和2,500例对照中验证来自第2阶段的大约15个基因（第3阶段）。据我们所知，这是第一个使用全外显子组测序在从不吸烟者中进行的肺癌大型关联研究。凭借其强大的方法学和使用新技术和研究设计，拟议的研究将通过识别新基因和途径显着提高我们对肺癌遗传学和生物学的理解。新发现的基因和途径可以作为新的癌症治疗的靶点，这些基因的遗传变异可以用于癌症筛查和风险评估，旨在确定针对肺癌预防的高风险个体。 公共卫生相关性：我们建议进行全外显子组测序研究，系统地搜索人类基因组中的肺癌易感基因和变异的整个编码区中的从不吸烟者。在从不吸烟者中进行的遗传研究提供了发现与吸烟无关的肺癌风险的遗传变异的绝佳机会。这项研究不仅具有高度创新性和极高的成本效益，而且具有很大的潜力来识别新的基因和途径，这将显着提高我们对肺癌遗传学和生物学的理解。

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. PUBLIC HEALTH RELEVANCE: We propose to conduct a whole-exome sequencing study to systematically search the entire coding region in the human genome for lung cancer susceptibility genes and variants among never-smokers. Genetic studies conducted among never-smokers provide exceptional opportunities to discover genetic variants that confer risk for lung cancer independent of smoking. The proposed study is not only highly innovative and extremely cost-efficient, but also has great potential to identify novel genes and pathways that will significantly improve our understanding of lung cancer genetics and biology.