Inflammation Pathways and COPD in the Development of Lung Cancer

描述(申请人提供)：吸烟导致多种慢性疾病，包括慢性阻塞性肺疾病(COPD)和肺癌；大约15%的吸烟者会患上这些疾病。流行病学研究和家庭研究已经证明了COPD和肺癌之间的联系，表明这些疾病的共同潜在基因贡献。COPD与肺癌之间的生物学机制尚不清楚，但慢性炎症可能起到一定作用。我们建议评估炎症途径中基因的SNPs和拷贝数变异。这项拟议的研究将在以前工作的基础上扩展，将COPD表型与肺气肿的CT诊断和肺功能测试(PFT)结合起来。它还将扩大已评估的少数几个基因的范围，纳入拷贝数变异以及非同义和功能性SNP，并将包括大量非裔美国人。目前还没有关于非裔美国人这些途径基因的研究，这一群体报告COPD的可能性较小，吸烟较少，但比白人更有可能被诊断为肺癌。具体地说，我们将从两个大型城市卫生系统招募2050名肺癌患者、2050名吸烟者和600名COPD患者。大约46%的受试者将是非裔美国人。每个受试者将完成一份危险因素问卷，接受CT和PFT，提供血样，并在可用时进行组织块。据推测，炎症相关基因的遗传变异有助于肺癌的发展，这种联系因COPD的存在与否和种族而异。我们的目标是开发一种基于SNPs和炎症途径基因拷贝数变化的基因图谱，预测在吸烟暴露下有或没有COPD的肺癌易感性。此外，还将评估250例COPD患者和250例非COPD患者的正常肺组织中一组370个炎症途径基因的基因表达。没有其他大量的病例收集，包括肺癌和COPD的详细表型，并联合评估相同个体的生殖系DNA和靶组织中的炎症基因。这项工作将有助于更好地了解肺癌发生中的炎症过程，为识别高危人群进行干预提供途径，并为可能的治疗方案提供洞察力。

DESCRIPTION (provided by applicant): Smoking contributes to a multitude of chronic diseases, including chronic obstructive lung disease (COPD) and lung cancer; approximately 15% of smokers will develop these diseases. The link between COPD and lung cancer has been demonstrated in epidemiologic studies, as well as family studies suggesting a common underlying genetic contribution to these diseases. The biologic mechanisms linking COPD and lung cancer are unknown, however chronic inflammation is likely to play a role. We propose to evaluate SNPs and copy number variation in genes in inflammatory pathways. The proposed study will expand on previous work by incorporating COPD phenotyping using CT diagnosis of emphysema and pulmonary function testing (PFT). It also will expand on the panel of genes beyond those few already evaluated, will incorporate copy number variation as well as non-synonymous and functional SNPs, and will include a large African American population. There has not been a study of these pathway genes in African Americans, a group that is less likely to report COPD, smokes fewer cigarettes, but is more likely to be diagnosed with lung cancer than whites. Specifically, from two large, urban health systems we will recruit 2050 lung cancer cases, 2050 smokers, and 600 patients with COPD. Approximately 46% of subjects will be African American. Each subject will complete a risk factor questionnaire, undergo CTs and PFTs, provide a blood sample, and when available a tissue block. It is hypothesized that genetic variation in inflammation-related genes contributes to the development of lung cancer and this association varies by the presence or absence of COPD, and by race. The goal is to develop a genetic profile based on SNPs and copy number variation in inflammation pathway genes that predicts susceptibility to lung cancer with and without COPD in response to tobacco exposure. In addition, gene expression of a panel of 370 inflammatory pathway genes will be evaluated in normal lung tissue in a subset of 250 cases with and 250 cases without a COPD diagnosis. No other large collection of cases is available that includes detailed phenotyping of lung cancer and COPD and jointly evaluates inflammatory genes in germline DNA and target tissue in the same individuals. This work will lead to a better understanding of the inflammatory process in lung carcinogenesis, provide avenues for the identification of a high risk group for intervention, and provide insight into possible treatment options.