GENETIC SUSCEPTIBILITY TO LUNG CANCER

尽管肺癌通常被认为主要是由环境引起的疾病，但越来越多的证据支持这样一种假设，即肺癌在一定程度上是由遗传因素决定的。该项目的主要目标是最终发现基因标记，以确定那些在考虑吸烟暴露后患肺癌风险最高的人。这些发现的翻译应用将被用来寻找用于识别最适合进行化学预防研究的高危个体的标记。该项目的具体目标包括进一步了解可能增加肺癌风险的特定因素或可能是遗传易感性迹象的遗传标记。我们将继续收集不同种族背景的新诊断肺癌患者，以研究肺癌风险的可能生物标志物。作为孢子的一部分，对两种特定化学致癌物的敏感性与对肺癌的敏感性进行了比较研究。首先，我们已经研究并将继续研究博莱霉素诱导肺癌患者淋巴细胞DNA的染色体断裂。我们将进一步研究博莱霉素引起的染色体断裂与肺癌家族聚集性的关系。此外，我们还将研究高加索人和非裔美国人对博莱霉素引起的染色体断裂易感性的种族差异。其次，我们将研究苯并[a]芘二醇环氧化物(BPDE)诱导的染色体3p上遗传物质的丢失，我们观察到肺癌患者与对照组相比频率增加，BPDE诱导的断裂增加的人患肺癌的风险增加14倍。然而，目前尚不清楚3p的丢失是否是因为3p上的一个或多个关键基因的丢失，或者这种丢失是否仅仅反映了3p上的染色体非常脆弱。在这项研究中，我们将比较BPDE在3p21.3和3pl4.2引起的染色体3p缺失率，3pl4.2是已知的脆性部位。我们项目的一个新目标将涉及对异型增生受试者的研究，异型增生是一种与肺癌风险增加相关的组织学前驱病变，以及I期和II期代谢酶的遗传多态。预计对不典型增生个体的额外遗传学研究将导致对肺癌发生中的遗传途径的更全面的了解。

Although lung cancer is often considered primarily an environmentally induced disease, increasing evidence supports the hypothesis that lung cancer is in part determined by genetic factors. The main goal of this project is to ultimately discover genetic markers that identify those persons at highest risk for developing lung cancer after accounting for smoking exposure. The translational application of these findings will be used to find markers used to identify high-risk individuals who would be most suitable for chemoprevention studies. The Specific Aims of this project involve furthering the understanding of specific factors which may increase the risk of lung cancer or genetic markers which may be signs of a genetic susceptibility. We will continue to accrue newly diagnosed lung cancer patients of diverse ethnic backgrounds for the study of possible biomarkers of lung cancer risk. Susceptibility to two specific chemical carcinogens have been studied as part of the SPORE vis a vis susceptibility to lung cancer. First, we have studied and will continue to study bleomycin induced chromosomal breakage of lymphocyte DNA in lung cancer patients. We will further study the association of bleomycin induced chromosomal breaks and familial aggregation of lung cancer. In addition we will study ethnic differences in susceptibility to bleomycin induced chromosomal breaks in Caucasians and African Americans. Secondly, we will study benzo [a] pyrene diol epoxide (BPDE) induced loss of genetic materials on chromosome 3p which we have observed at increased frequency in lung cancer patients compared to controls such that a person with increased BPDE induced breaks has a 14-fold increased risk of developing lung cancer. It is not clear, however, whether loss at 3p is important because of the loss of a critical gene or genes on 3p or whether or not the loss merely reflects a very high degree of chromosome fragility at sites on 3p. In this study we will compare the rate of BPDE induced chromosome 3p loss at 3p2l.3 vs. 3pl4.2, a known fragile site. A new Aim of our Project will involve the study of subjects with dysplasia, a histologic precursor lesion associated with increased risk of lung cancer, and genetic polymorphisms of the Phase I and Phase II metabolic enzymes. It is anticipated that the additional genetic studies of individuals with dysplasia will lead to a more complete understanding of the genetic pathways in lung cancer development.