Genetic Epidemiology of Lung Cancer

对家族聚集和暴露后风险差异的研究表明，基因在肺癌易感性中起作用。包括这项研究在内的两项研究已经发现了肺癌中一种罕见常染色体基因的孟德尔共显性遗传的证据，一项连锁研究正在进行中。肺癌的连锁研究受到发病年龄较晚和疾病迅速致命性质的限制。候选易感基因的研究集中在I期和II期酶多态性和DNA修复酶多态性上，结果不一致。总的来说，这些研究有一些局限性，包括只关注少量的多态性，样本量小，由于群体分层造成的偏差，以及群体间的差异。发现复杂疾病基因的另一种方法是通过混合作图。最近的混血儿群体，如非裔美国人，为这类分析提供了最大的力量。为了进一步表征肺癌的遗传风险，该研究将使用新的方法和最近验证的单核苷酸多态性，在一项仅病例研究设计中确定非裔美国人肺癌的遗传标记。该研究的具体目的是：1)收集800例非裔美国人肺癌病例进行混合制图；2)使用混合作图方法在800例病例和200例对照（用于检查模型假设）中确定显示与肺癌易感性相关的证据区域，使用3011个snp，已知非洲人和欧裔美国人之间的频率差异为0.5 >.5，并且整个基因组间隔为1.2cM；3)继续扩大有三个或更多肺癌患者的家庭成员，以进行未来的关联研究。这将是第一个使用混合作图来鉴定肺癌易感基因的研究。通过将重点放在非裔美国人人群上，并证明了这种方法可以成功地使用，并且是本研究的下一个合乎逻辑的步骤。

Studies of familial aggregation and differences in risk after exposure suggest that genetics plays a role in lung cancer susceptibility. Two studies, including this one, have found evidence consistent with Mendelian codominant inheritance of a rare autosomal gene in lung cancer and one linkage study is underway. Linkage studies in lung cancer are limited by the late age of onset and the rapidly fatal nature of the disease. Inconsistent findings have been reported in studies of candidate susceptibility genes focused on phase I and phase II enzyme polymorphisms and DNA repair enzyme polymorphisms. Overall, these studies have several limitations including a focus on only a small number of polymorphisms, small sample sizes, bias due to population stratification, and variations across populations. An alternative approach to the discovery of genes for complex diseases is through admixture mapping. Recently admixed populations, such as African Americans, provide the most power for this type of analysis. To further characterize genetic risk of lung cancer, the proposed study will use new methodology and a recently validated panel of SNPs in a case-only study design to identify genetic markers for lung cancer in African Americans. The specific aims of the proposed study are: 1) to accrue 800 African American lung cancer cases for admixture mapping; 2) to identify regions showing evidence of linkage to lung cancer susceptibility using admixture mapping methods in 800 cases and 200 controls (used to check model assumptions) using 3,011 SNPs known to differ in frequency by > 0.5 between Africans and European Americans and spaced 1.2cM across the genome; and 3) to continue to extend families with three or more lung cancer affected family members for future linkage studies. This will be the first study to use admixture mapping to identify susceptibility genes for lung cancer. By focusing on the African American population, with demonstrated admixture, this approach can be used successfully and is the next logical step in this research.