GENETIC EPIDEMIOLOGY OF LUNG CANCER

肺癌是男性和女性最常见的癌症死亡形式。 在美国，这是医疗保健的重大负担 资源。我们的长期目标是确定肺癌的特征 易感基因(S)，因为它将允许识别个体 处于特别高风险(包括曾经吸烟者)的人群中 针对吸烟预防、环境风险的密集努力 减少，可能还有化学预防。累积的证据表明 肺癌中存在遗传易感性成分，以及 基因与环境的相互作用是重要的。家族聚集性 已经观察到肺癌的可能性，分离分析研究已经 提示肺癌的不同易感性可能是 一个主要常染色体的孟德尔共显性遗传解释 基因(S)，与吸烟共同作用产生 肺癌发病年龄较早。我们假设有 极大地增加发生肺部疾病的风险的特定基因类型 癌症，通过与吸烟和/或其他疾病的相互作用 环保人员。我们的具体目标是1.利用既定的 识别家族性肺癌的肺癌家族研究资源 (FLC)家系用于遗传连锁分析。六个成熟的中心 将收集血液样本、肿瘤组织和危险因素数据 85个家系(包含4个或4个以上)的相关家庭成员 受影响的病例和预期的LOD评分(EROD)为0.3或更高)。 已经完成了7个扩展家系的采样，并进行了基因分型 从这些家庭开始。我们还将累积至少125个受影响的人 除了85个FLC家族中的SIB/亲属对外；2.至 平均400人的FLC家系中的基因信息个体 遍布基因组的间隔标记(大约10个厘米器官)。 从血液中提取的DNA，档案石蜡块将用于 活着和已故的患病和未患病家庭的基因分型 会员。我们已经证明档案DNA可以用我们的 全球标记集；3.定位肺癌易感基因(S) 对FLC家系进行遗传连锁分析。两个参数(LOD- Score)和非参数相对配对方法。 遗传连锁分析。这项研究建议确定一个 患病风险相对较高的人群 即使是低水平暴露在香烟烟雾和其他环境中也会导致肺癌 环保人员。在高危家庭中使用连锁的策略 已被证明成功地鉴定了猪的易感基因 乳腺癌、结肠癌和前列腺癌。虽然取得了重大突破， 在理解这些其他疾病的遗传易感性基础上取得的进展 癌症，识别影响肺癌的特定主要基因的研究 风险明显不足。高病死率、低切除率 Rate使得肺癌家族的研究特别具有挑战性 因为很难收集到足够数量的生物素来 DNA分析。我们相信，只有多学科、协作的努力 对FLC家系进行识别、积累和分型将在 描述了FLC的遗传基础。

Lung cancer is the most common form of cancer mortality in men and women in the United States, and represents a significant burden on health care resources. Our long-term objective is to characterize lung cancer susceptibility gene(s), as it will allow identification of individuals at especially high risk (including former smokers) who can then be targeted for intensive efforts at smoking prevention, environmental risk reduction, and possibly chemoprevention. Accumulated evidence suggests that there are genetic susceptibility components in lung cancer, and that gene-environment interactions are important. Familial aggregation of lung cancer has been observed and segregation analysis studies have suggested that differential susceptibility to lung cancer may be explained by Mendelian codominant inheritance of a major autosomal gene(s) that acts in conjunction with cigarette smoking to produce earlier age of onset of lung cancer. We hypothesize that there are specific genotypes that greatly increase the risk of developing lung cancer, through interaction with cigarette smoking and/or other environmental agents. Our specific aims are 1. To utilize established lung cancer family research resources to identify familial lung cancer (FLC) pedigrees for genetic linkage analysis. Six established centers will accrue blood samples, tumor tissue, and risk factor data from available relevant family members in 85 pedigrees (containing 4 or more affected cases and an expected lod score (ELOD) of 0.3 or higher). Sampling has been completed for 7 extended pedigrees, and genotyping has begun on these families. We will also accrue a minimum of 125 affected sib/relative pairs, in addition to those in the 85 FLC kindreds; 2. To genotype informative individuals in the FLC pedigrees with 400 evenly spaced markers (approximately 10 centimorgans) throughout the genome. DNA isolated from blood, archival paraffin blocks will be used for genotyping both living and deceased affected and unaffected family members. We have shown that archival DNA can be genotyped with our global marker set; and 3. To map a lung cancer susceptibility gene(s) by genetic linkage analysis of the FLC pedigrees. Both parametric (lod- score) and non-parametric relative-pair methods will be utilized in the genetic linkage analyses. This research proposes to identify a subpopulation of persons who may be at a relatively high risk to develop lung cancer from even low level exposure to cigarette smoke and other environmental agents. The strategy to use linkage in high risk families has proven successful for the identification of susceptibility genes in breast, colon, and prostate cancers. While major breakthroughs have been made in understanding the genetic susceptibility basis of these other cancers, studies to identify specific major loci affecting lung cancer risk are notably lacking. The high case-fatality rate and low resection rate makes the study of lung cancer families particularly challenging because it is difficult to collect adequate numbers of biospecimens for DNA analysis. We believe only a multidisciplinary, collaborative effort to identify, accrue, and genotype FLC families will be successful in characterizing the genetic basis of FLC.