Genetic Epidemiology of Lung Cancer

描述(由申请人提供)： 死于肺癌的人数比死于乳腺癌、结肠癌和前列腺癌的总和还要多。肺癌遗传流行病学联合会(GELCC)的目标是进行以家庭为基础的研究，以确定家族性肺癌(FLC)的易感基因，从而为预防、控制和临床治疗提供策略。到目前为止，我们已经建立了92个FLC家系，包括52个具有完整淋巴细胞和档案基因型的家系，我们已经发表了关于这些家系的连锁发现(1)。在38个有4个或4个以上一级亲属患有肺癌的家庭中，我们在染色体6q上发现了3.6的LOD分数。进一步限制到在多代中有5个或更多受影响个体的23个家庭导致LOD评分为5.0。对吸烟对肺癌风险影响的进一步分析表明，任何程度的烟草暴露都会增加染色体6q上遗传性肺癌易感性人群的风险，这表明这些人应该成为预防吸烟的目标，并通过早期检测程序进行监测。这个6q连接区域与多种肿瘤类型的发生过程有关，包括肺癌。在第一个资助阶段，我们提出了一项假设，即存在特定的基因类型，极大地增加了患肺癌的风险。我们的连锁分析结果有力地支持了这一假说。我们建议通过鉴定6q上的易感基因和寻找额外的易感基因来进一步检验这一假说。目的1：利用已有的肺癌家系研究资源，确定和发展新的信息丰富的家族性肺癌(FLC)家系，用于连锁分析，并扩大已被追踪确定的家系。目的2：在新的FLC家系中用均匀分布的标记对新的FLC家系中的信息丰富的个体进行基因分型，如果需要，还可以用更密集的标记来减少连锁分析确定的候选区域的大小。目的：对肺癌家系进行遗传连锁分析，定位肺癌易感基因S。目的4：确定位于AIM 3染色体区域的肺癌易感基因。由于肺癌的5年生存率(15%)和切除率(25%)较低，很难收集到足够的DNA样本，只有多学科的合作努力才能确定FLC家系的遗传基础。

DESCRIPTION (provided by applicant): There are more persons who die from lung cancer than from breast, colon, and prostate cancer combined. The objective of the Genetic Epidemiology of Lung Cancer Consortium (GELCC) is to conduct family-based studies to identify susceptibility genes in familial lung cancer (FLC) that can lead to strategies for the prevention, control, and clinical management of the disease. To date, we have developed 92 FLC kindreds, including 52 families with complete lymphocyte and archival genotypes on whom we have published linkage findings (1). In 38 families having 4 or more first-degree relatives with lung cancer, we found a LOD score of 3.6 on chromosome 6q. Further restricting to the 23 families with 5 or more affected individuals in multiple generations led to a LOD score of 5.0. Additional analysis of the impact of smoking on risk of lung cancer suggested that any level of tobacco exposure increases risk among those with inherited lung cancer susceptibility on chromosome 6q, suggesting that these individuals should be targeted for smoking prevention and monitored by early detection procedures. This 6q linkage region has been implicated in the tumorigenic process of numerous tumor types, including lung. In the first funding period, we proposed to test the hypothesis that there are specific genotypes that greatly increase the risk of developing lung cancer. Our linkage analysis findings strongly support this hypothesis. We propose to further test this hypothesis by identifying the susceptibility gene on 6q and by searching for additional susceptibility loci. Aim 1: To utilize established research resources for lung cancer family studies to identify and develop new informative familial lung cancer (FLC) pedigrees for linkage analyses and extend families already identified by follow-up. Aim 2: To genotype informative individuals in the new FLC pedigrees with evenly spaced markers throughout the genome and, if required, denser markers to reduce the size of candidate regions identified by linkage analyses. Aim 3: To map lung cancer susceptibility gene(s) by genetic linkage analysis of the FLC pedigrees. Aim 4: To identify lung cancer susceptibility genes located in chromosomal regions identified in Aim 3. Because the low 5-year survival (15%) and resection rate (25%) of lung cancer makes it difficult to collect adequate DNA samples, only a multidisciplinary, collaborative effort to identify, accrue and genotype FLC families will be successful in characterizing the genetic basis of FLC.