Genome-Wide Association Studies of Inherited Predisposition to Lung Cancer

描述(由申请人提供)：这项提案的长期目标是确定肺癌诱发的遗传修饰因素。虽然肺癌在很大程度上是由吸烟引起的，但有强有力的证据表明，肺癌的发生发展中存在遗传易感性和基因-环境相互作用。然而，人类人群中有限的遗传变异和在人类中进行遗传分析的局限性阻碍了对人类肺癌诱因的遗传因素的识别。近交系小鼠模型提供了一种通过控制交配和控制烟草暴露来识别候选肺癌易感基因的有效手段。通过对不同品系近交系小鼠的遗传连锁研究，定位了几个肺腺瘤易感性(PAS)和肺腺瘤抗性(PAR)基因座，证明了近交系小鼠模型的有效性。随着可利用的小鼠多态遗传标记数量的增加，基因组关联分析已成为识别新的数量性状基因座(QTL)和精细定位已发现的QTL的重要遗传方法。我们假设，肺肿瘤发生的遗传修饰物可以使用相关个体(小鼠或人)的大量群体和每个受试者的全基因组单核苷酸多态(SNPs)来识别。为了实现我们的目标，我们提出了三个目标。在目标1中，我们将利用19万多个SNP标记对44个品系的小鼠进行GWA分析，以定位吸烟对小鼠肺癌易感性的QTL。在目标2中，我们将在高危肺癌家系和散发性肺癌人群中检测小鼠易感基因的人类同源物。最后，目标2中确定的这些候选基因将在目标3中使用功能分析进行进一步检查。这些研究的意义在于，它们将识别导致肺癌风险增加的人类肺癌基因修饰物，并将有助于建立与这些基因座相关的小鼠模型。这项建议的创新之处在于，我们将研究人类和老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.