Epigenetic Changes Link COPD and Lung Cancer

描述（由申请人提供）：吸烟是慢性阻塞性肺疾病（COPD）和肺癌的主要致病因素，这些疾病的发病机制被认为是相关的，因为COPD患者患肺癌的风险高出2-4倍。通过启动子胞嘧啶甲基化和组蛋白修饰的基因表观遗传沉默，现在被认为是影响肺癌起始和克隆发展过程中数百个基因表达的主要和因果事件。我们对COPD吸烟者队列中发生的癌症进行了初步的巢式病例对照研究，结果表明，6个基因组中3个或更多基因的甲基化与肺癌风险增加6.5倍相关。这些研究在Lovelace吸烟者队列（LSC）的无癌吸烟者中的扩展表明，高甲基化指数（两个或多个基因甲基化）和p16和GATA4基因的甲基化与肺功能降低相关。研究还发现，该途径中的双链断裂修复能力和特定基因是痰液中基因甲基化的决定因素，p53密码子72处的脯氨酸变异对LSC中粘液细胞增生和肺功能下降具有保护作用。基于这些研究，我们假设通过组织损伤和重塑介导的COPD的发展将驱动特定基因的表观遗传沉默，从而促进肺癌的发展。在COPD吸烟者的痰液中检测这些基因可能为COPD的发生和进展以及早期癌症检测提供新的生物标志物。目的1将通过比较慢性阻塞性肺病患者和非慢性阻塞性肺病患者的腺癌中甲基化的特征，并评估p53密码子72基因型的相关性，来识别和验证甲基化作为慢性阻塞性肺病状态的功能。Aim 2将使用长期暴露于香烟烟雾中的非吸烟者的p53密码子72精氨酸与脯氨酸基因型的原代人支气管上皮细胞（BECs）来鉴定基因和受影响的途径，重点是调节组织重塑和凋亡的基因，以及多梳抑制复合体2 （PRC2）基因。目标3将分析目标1和目标2中选定基因甲基化的流行程度，该研究对200名COPD患者和400名来自LSC的对照组进行巢式横断面研究，甲基化的流行程度将在匹兹堡肺筛查研究（PLuSS）队列中进行验证。目的4将确定与COPD相关的甲基化生物标志物是否会随着时间的推移而增加，并预测肺功能的下降。将比较3-4年内肺功能显著或无下降的参与者的甲基化患病率和甲基化指数。未来的研究将评估目标3和目标4中在大型巢式肺癌病例对照研究受试者的痰液中验证的基因，以确定它们对早期COPD和癌症检测的遗传和表观遗传风险谱的贡献。总之，这些研究的综合结果将为将COPD与肺癌发展联系起来的机制提供新的见解。

DESCRIPTION (provided by applicant): Cigarette smoking is the main causative factor for Chronic Obstructive Pulmonary Disease (COPD) and lung cancer and the pathogenesis of these diseases is believed to be linked because individuals with COPD have a 2-4-fold higher risk of developing lung cancer. Epigenetic silencing of genes through promoter methylation of cytosines and histone modifications is now recognized as a major and causal event affecting expression of hundreds of genes during initiation and clonal development of lung cancer. Our initial nested, case-control study of incident cancer within a cohort of smokers with COPD showed that the concomitant methylation of three or more genes of a six gene panel was associated with a 6.5-fold increased risk for lung cancer. Extension of these studies in cancer-free smokers from the Lovelace Smokers Cohort (LSC) showed that a high methylation index (two or more genes methylated) and methylation of the p16 and GATA4 genes was associated with lower lung function. Studies also identified double-strand break repair capacity and specific genes within this pathway as determinants for gene methylation in sputum and that the proline variant at codon 72 of p53 is protective from mucous cell hyperplasia and decline of pulmonary function in the LSC. Based on these studies we hypothesize that the development of COPD mediated through tissue damage and remodeling will drive the epigenetic silencing of specific genes that in turn contribute to the development of lung cancer. The detection of these genes in sputum from smokers with COPD may provide new biomarkers for COPD development and progression, and early cancer detection. Aim 1 will identify and validate signatures for methylation as a function of COPD status by comparing the methylome in adenocarcinoma from patients with and without COPD and assess the association by genotype of p53 codon 72. Aim 2 will use primary human bronchial epithelial cells (BECs) from non smokers with the p53 codon 72 arginine versus proline genotype exposed chronically to cigarette smoke to identify genes and affected pathways with a focus on genes regulating tissue remodeling and apoptosis, and polycomb repressive complex 2 (PRC2) genes. Aim 3 will analyze the prevalence for methylation of selected genes from Aims 1 and 2 in a nested, cross-sectional study of 200 subjects with COPD and 400 controls from the LSC and the prevalence for methylation will be validated in Pittsburgh Lung Screening Study (PLuSS) Cohort. Aim 4 will determine whether methylation biomarkers found to be associated with COPD show increase in prevalence over time and predict for decline in pulmonary function. Methylation prevalence and methylation index among participants showing significant or no decline in pulmonary function over 3-4 years will be compared. Future studies will assess the genes validated under Aims 3 and 4 in sputum from subjects from a large nested lung cancer case-control study for their contribution to a developing genetic and epigenetic risk profile for early incident COPD and cancer detection. Together, the integrated results from these studies will provide novel insights into mechanisms that connect COPD to the development of lung cancer.