Inflammation Pathways and COPD in the Development of Lung Cancer

肺癌发生过程中的炎症途径和慢性阻塞性肺病

• 批准号: 8717598
• 负责人: Ann G. Schwartz
• 金额: $ 186.64万
• 依托单位: WAYNE STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-01 至 2017-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8717598
• 关键词: Accounting; Address; Adult; African American; Blood specimen; Cancer Etiology; Cancer Patient; Cause of Death; Cessation of life; Chronic; Chronic Bronchitis; Chronic Disease; Chronic Obstructive Airway Disease; Cigarette; Collection; Copy Number Polymorphism; Custom; DNA; Development; Diagnosis; Disease; Disease Association; Enrollment; Epidemiologic Studies; Epidemiology; Evaluation; Family Study; Family history of; Future; Gene Expression; Gene Expression Profile; Genes; Genetic; Genetic Variation; Genomics; Genotype; Goals; Health system; Individual; Inflammation; Inflammatory; Joints; Lead; Link; Malignant neoplasm of lung; Measures; Methods; Molecular; Molecular Profiling; Morbidity - disease rate; Obstruction; Participant; Pathogenesis; Pathway Analysis; Pathway interactions; Patients; Phenotype; Play; Population; Population Intervention; Predisposition; Process; Publishing; Pulmonary Emphysema; Pulmonary function tests; Questionnaires; Race; Recording of previous events; Recruitment Activity; Reporting; Research; Risk; Risk Factors; Role; Severities; Single Nucleotide Polymorphism; Smoke; Smoker; Smoking; Structure of parenchyma of lung; Target Populations; Tissues; Tobacco smoke; Urban Health; Work; X-Ray Computed Tomography; base; cancer risk; cytokine; design; disease diagnosis; disease phenotype; disorder control; genetic profiling; genetic risk factor; group intervention; high risk; improved; inflammatory marker; insight; lung carcinogenesis; mortality; never smoker; response; screening; tobacco exposure

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.

描述（由申请人提供）：吸烟会导致多种慢性疾病，包括慢性阻塞性肺病（COPD）和肺癌；大约15％的吸烟者会发展这些疾病。在流行病学研究中已经证明了COPD和肺癌之间的联系，以及表明对这些疾病的基本遗传贡献的家庭研究。连接COPD和肺癌的生物学机制尚不清楚，但是慢性炎症可能起作用。我们建议评估炎症途径中基因中的SNP和拷贝数变化。拟议的研究将通过使用CT诊断肺气肿和肺功能测试（PFT）纳入COPD表型来扩展先前的工作。它还将扩展到已经评估过的少数人之外的基因面板上，将结合拷贝数变化以及非同义词和功能性SNP，并将包括大量的非裔美国人人群。在非洲裔美国人中，没有对这些途径基因进行的研究，非裔美国人的群体不太可能报告COPD，吸烟较少，但比白人更有可能被诊断出患有肺癌。具体来说，我们将从两个大型城市卫生系统中招募2050例肺癌病例，2050名吸烟者和600例COPD患者。大约46％的受试者将是非裔美国人。每个受试者将填写一份危险因素问卷，接受CTS和PFT，提供血液样本，并在可用的组织块时提供。假设炎症相关基因的遗传变异有助于肺癌的发展，而这种关联因存在或不存在COPD和种族而有所不同。目的是根据炎症途径基因中的SNP和拷贝数变化来开发遗传概况，该基因可预测有和没有COPD的肺癌的易感性，而响应于烟草暴露。此外，在250例未经COPD诊断的情况下，将在正常肺组织中评估一组370个炎症途径基因的基因表达。没有其他大量病例包括肺癌和COPD的详细表型，并共同评估了同一个体中种系DNA和靶组织中的炎症基因。这项工作将使人们对肺癌发生的炎症过程有更好的了解，为鉴定高风险群体进行干预提供途径，并深入了解可能的治疗选择。