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人数加起来还要多。肺癌遗传流行病学联盟（GELCC）的目标是进行以家族为基础的研究，以确定家族性肺癌（FLC）的易感基因，从而制定预防、控制和临床管理该疾病的策略。到目前为止，我们已经开发了92个FLC激酶，包括52个具有完整淋巴细胞和档案基因型的家族，我们已经发表了连锁发现（1）。在38个一级亲属中有4人或4人以上患肺癌的家系中，我们发现染色体6q上的LOD值为3.6。进一步限制到多代中有5个或更多受影响个体的23个家庭，导致LOD评分为5.0。吸烟对肺癌风险影响的其他分析表明，任何水平的烟草暴露都会增加染色体6q上遗传性肺癌易感性的风险，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。该6q连锁区与包括肺在内的多种肿瘤类型的肿瘤发生过程有关。在第一个资助期内，我们提出了一个假设，即有特定的基因型会大大增加患肺癌的风险。我们的连锁分析结果强烈支持这一假设。我们建议进一步测试这一假设，通过确定6q上的易感基因，并通过寻找额外的易感基因座。目标1：利用肺癌家族研究的现有研究资源，识别和开发新的信息丰富的家族性肺癌（FLC）家系进行连锁分析，并扩展已通过随访确定的家族。目标二：在新的FLC家系中，使用整个基因组中均匀分布的标记对信息个体进行基因分型，如果需要，使用更密集的标记来减少连锁分析所确定的候选区域的大小。目的3：对FLC家系进行遗传连锁分析，定位肺癌易感基因。目的4：确定肺癌易感基因位于染色体区域的目标3。由于肺癌的低5年生存率（15%）和切除率（25%）使得难以收集足够的DNA样本，因此只有多学科的合作努力来识别，积累和基因型FLC家族才能成功地表征FLC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.