GENETIC EPIDEMIOLOGY OF LUNG CANCER

肺癌是男性和女性中最常见的癌症死亡形式 在美国，这是医疗保健的一个重大负担。 资源 我们的长期目标是描述肺癌的特征 易感基因，因为它将允许识别个体 特别高的风险（包括前吸烟者）， 针对加强努力，预防吸烟，环境风险 减少，并可能化学预防。 累积的证据表明 肺癌中存在遗传易感性成分， 基因与环境的相互作用很重要。 家族聚集性 肺癌的分离分析研究表明， 表明对肺癌的不同易感性可能是 孟德尔共显性遗传的主要常染色体 与吸烟相关的基因， 肺癌的早期发病年龄。 我们假设 这些基因型会大大增加患上肺癌的风险， 癌症，通过与吸烟和/或其他 环境代理人。 我们的具体目标是1。利用现有的 肺癌家族研究资源，以确定家族性肺癌 (FLC)用于遗传连锁分析的家系。 六个已建立的中心 将收集血液样本，肿瘤组织和风险因素数据， 在85个家系中（包含4个或更多个家系）有可用的相关家系成员 受影响的病例和0.3或更高的预期LOD评分（LOD））。 已完成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名受影响的 同胞/亲属对，除了那些在85 FLC激酶; 2.到 FLC家系中400个基因型信息个体平均 在整个基因组中间隔的标记（大约10厘摩）。 从血液、存档石蜡块中分离的DNA将用于 对受影响和未受影响的家庭进行基因分型 成员 我们已经证明，档案DNA可以基因分型与我们的 全局标记集;以及3.绘制肺癌易感基因图谱 FLC家系的遗传连锁分析。 两个参数（lod- 评分）和非参数相对对方法将用于 遗传连锁分析。 这项研究旨在确定一个 可能处于相对高风险发展的人群亚群 即使是低水平暴露于香烟烟雾和其他 环境代理人。 在高危家庭中使用连锁的策略 已被证明是成功的鉴定易感基因， 乳腺癌结肠癌和前列腺癌虽然重大突破已经 在了解这些其他疾病的遗传易感性基础上， 癌症，确定影响肺癌的特定主要基因座的研究 风险明显不足。 高病死率和低切除率 这使得肺癌家族的研究特别具有挑战性 因为很难收集足够数量的生物样本， DNA法证科学化验结果 我们相信只有多学科的合作努力 识别、积累和基因分型FLC家族将成功地 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.