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

描述(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中起着重要作用。最近的全基因组关联研究已经确定了肺癌的多个遗传易感基因。然而，这些新发现的遗传因素只解释了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，这增加了已确定的关联可能与吸烟行为、肺癌发生或两者都有关的可能性。在从不吸烟的人中进行的基因研究为发现与吸烟无关的肺癌风险的基因变异提供了特殊的机会。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可遗传风险可能是由于大量低频、中等外显性基因造成的。在这里，我们提出了一个完整的外显子组测序研究，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体，这些基因和变异体无法通过传统的GWAS或基于家族的连锁分析来识别。这项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联合会建立的资源基础上，所有这些研究都是在东亚妇女中进行的。这项研究的具体目标如下：所有病例和对照均为从不吸烟的女性。目的1是对600例非小细胞肺癌患者和600例对照的外显子全序列进行测序(阶段1)。目标2是在2,500例非小细胞肺癌患者和2,500名对照(阶段2)中验证在目标1中确定的大约350个有希望的基因的变异。目标3是在另外2,500例非小细胞肺癌患者和2,500名对照(阶段3)中验证大约15个来自阶段2的基因。据我们所知，这是第一次使用全外显子组测序在从不吸烟的人中进行的与肺癌的大型关联研究。凭借其强大的方法学以及新技术和研究设计的使用，拟议的研究将通过识别新的基因和途径显著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，这些基因的基因变异可以用于癌症筛查和风险评估，目的是识别高危个体，进行有针对性的肺癌预防。

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.