Genome-Wide Association Studies of Inherited Predisposition to Lung Cancer

描述（由申请人提供）：本提案的长期目标是确定肺癌诱导的基因修饰剂。虽然肺癌很大程度上是由吸烟引起的，但有强有力的证据表明，遗传易感性和基因-环境相互作用在肺癌的发展中起作用。然而，由于人类群体中有限的遗传变异和在人类中进行遗传分析的局限性，确定人类肺癌诱发的遗传因素受到阻碍。通过控制交配和控制烟草暴露，近交小鼠模型提供了识别候选肺癌易感位点的有效手段。通过绘制几个肺腺瘤易感性（Pas）和肺腺瘤抗性（Par）位点，对各种自交系小鼠进行遗传连锁研究，证明了自交系小鼠模型的有效性。随着可用的小鼠多态性遗传标记数量的增加，全基因组关联分析已成为鉴定新的数量性状位点（QTL）和对已鉴定的QTL进行精细定位的重要遗传方法。我们假设，肺肿瘤发生的遗传修饰因子可以通过大量相关个体（小鼠或人类）和每个受试者的全基因组单核苷酸多态性（snp）来确定。为了实现我们的目标，提出了三个目标。在aim 1中，我们将使用超过190,000个SNP标记进行GWA分析，绘制44株小鼠对烟草烟雾的小鼠肺肿瘤易感性QTL。在目标2中，我们将研究高风险肺癌家族和散发性肺癌人群中小鼠易感位点的人类同源物。最后，在Aim 2中发现的这些候选基因将在Aim 3中使用功能分析进一步检查。这些研究的重要意义在于，它们将确定导致肺癌风险增加的人类肺癌基因修饰因子，并将有助于开发与这些基因座相关的小鼠模型。这项提议的创新之处在于，我们将研究人类和小鼠易感位点之间的相关性。公共卫生相关性：肺癌是美国男性和女性癌症死亡的主要原因。尽管近年来取得了重大进展，但大多数肺癌在发病时已播散，死亡率约为90%。对肺癌家族聚集性的研究表明，遗传因素参与了人类肺癌的发展。本提案将使用比较基因组学方法确定肺癌诱导的遗传修饰因子。我们期望通过提出的人类和小鼠易感位点之间的跨物种研究来鉴定人类肺癌基因修饰因子，这些基因修饰因子会增加肺癌的风险。

DESCRIPTION (provided by applicant): The long-term goal of this proposal is to identify genetic modifiers of lung cancer induction. Although lung cancer is largely induced by smoking, there is strong evidence for genetic susceptibility and gene-environment interactions in the development of lung cancer. However, the identification of genetic factors underlying lung cancer induction in humans is impeded by limited genetic variation in human populations and by limitations in conducting genetic analysis in humans. Inbred mouse models offer an effective means of identifying candidate lung cancer susceptibility loci by using controlled mating as well as controlled tobacco exposure. The effectiveness of the inbred mouse model was demonstrated by genetic linkage studies using various strains of inbred mice by having mapped several pulmonary adenoma susceptibility (Pas) and pulmonary adenoma resistance (Par) loci. With the increasing number of available mouse polymorphic genetic markers, genome- wide association (GWA) analysis has become an important genetic method to identify novel quantitative trait loci (QTL) and to fine-map previously identified QTL. We hypothesize that genetic modifiers for lung tumorigenesis can be identified using large populations of relevant individuals (mice or humans) and genome-wide set of single nucleotide polymorphisms (SNPs) for each subject. Three aims are proposed to accomplish our goal. In aim 1, we will conduct GWA analysis to map mouse lung tumor susceptibility QTL in response to tobacco smoke in 44 strains of mice using more than 190,000 SNP markers. In aim 2, we will examine human homologues of mouse susceptibility loci in high risk lung cancer families and sporadic lung cancer populations. Finally, these candidate genes indentified in Aim 2 will be further examined using funcational analyses in Aim 3. The significance of these studies is that they will identify human lung cancer genetic modifiers which confer increased risk of lung cancer and will help in developing mouse models relevant to these loci. The innovative aspect of this proposal is that we will examine the correlation between human and mouse susceptibility loci. PUBLIC HEALTH RELEVANCE: Lung cancer is the leading cause of cancer death in men and women in the United States. Despite major advances in recent years, most lung cancers are disseminated at the time of presentation and have a mortality rate of about 90%. Studies of familial aggregation of lung cancer suggest that genetic factors are involved in human lung tumor development. This proposal will identify genetic modifiers of lung cancer induction using comparative genomic approaches. We anticipate the identification of human lung cancer genetic modifiers which confer increased risk of lung cancer through the proposed cross-species studies between human and mouse susceptibility loci.