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鉴定肺癌诱导的遗传修饰剂。虽然肺癌主要是由吸烟引起的，但有强有力的证据表明肺癌的发生与遗传易感性和基因-环境相互作用有关。然而，人类肺癌诱导的遗传因素的鉴定受到人类群体中有限的遗传变异和在人类中进行遗传分析的限制的阻碍。近交系小鼠模型提供了一种有效的方法，通过使用控制交配以及控制烟草暴露来鉴定候选肺癌易感基因座。近交系小鼠模型的有效性通过使用不同品系的近交系小鼠的遗传连锁研究证明，所述遗传连锁研究通过绘制几个肺腺瘤易感性（Pas）和肺腺瘤抗性（Par）基因座。随着可用的小鼠多态性遗传标记数量的不断增加，全基因组关联（genome-wide association，GWA）分析已成为鉴定新的数量性状基因座（quantitative trait loci，QTL）和精细定位先前鉴定的QTL的重要遗传学方法。我们假设，肺肿瘤发生的遗传修饰可以使用大量的相关个体（小鼠或人类）和每个受试者的全基因组单核苷酸多态性（SNP）来识别。为实现我们的目标，提出了三个目标。在目标1中，我们将使用超过190，000个SNP标记在44个品系的小鼠中进行GWA分析以定位响应烟草烟雾的小鼠肺肿瘤易感性QTL。在目标2中，我们将在高风险肺癌家族和散发性肺癌人群中检测小鼠易感基因座的人类同源物。最后，将在目标3中使用功能分析进一步检查目标2中鉴定的这些候选基因。这些研究的重要性在于，它们将确定增加肺癌风险的人类肺癌遗传修饰物，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基因座之间的相关性。

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.