Inherited genetic risk factors common to COPD and lung cancer.

描述(申请人提供)：慢性阻塞性肺疾病(COPD)和肺癌是美国和世界范围内发病率和死亡率的主要原因。吸入香烟烟雾是已知和可预防的主要原因，但只有10%-15%的重度吸烟者会患上这些疾病。这表明，香烟烟雾暴露与遗传易感因素相互作用，以确定风险。虽然一些易感基因是已知的，但它们在这两种疾病的风险中所占比例都不到5%。迫切需要确定这些疾病的更多可遗传易感因素，以解释大多数COPD和肺癌风险。这项拟议的项目将使用正常支气管上皮细胞(NBEC)和从CA148572获得资金收集的血液样本，这些样本来自600名50岁以上、吸烟史超过20包的非肺癌患者，以及150名肺癌患者的单独队列。这里的目的是确定抗氧化剂和DNA修复基因转录调控的个体间差异在COPD和肺癌风险中的作用。中心假设是，遗传的DNA变异与COPD和肺癌的风险增加有关，其中许多表现为关键抗氧化剂、DNA修复和转录因子基因转录丰度分散增加。为了支持我们的假设，我们最近发现了一种肺癌风险测试(LCRT)，它包含14个基因的转录丰度值，包括9个抗氧化基因、3个DNA修复基因和2个转录因子基因。对于这些基因中的每一个，与匹配的对照组相比，肺癌受试者的转录丰度值分布在更大的范围内。此外，遗传的DNA变异会导致LCRT组成的基因转录调控的变异。我们计划验证我们的中心假设，并通过追求以下两个特定目标来实现这一应用的目标：目的1.确定关键的抗氧化剂和DNA修复基因是否增加了COPD患者正常支气管上皮细胞中转录丰度的分散，以及包含这些基因子集的多基因测试是否是COPD患病率的准确测试。目的2.鉴定导致COPD和/或肺癌患病率相关基因转录丰度离散度增加的DNA变异。我们预计Aim 1将提供证据，证明关键抗氧化剂、DNA修复和转录因子基因转录丰度离散度较高与COPD风险相关，就像它对肺癌一样，并将产生COPD风险增加的候选生物标记物。目的2将提供与关键基因转录丰度离散度增加相关的DNA变体的鉴定，这些基因具有参与COPD和肺癌发病的高可能性。这项研究与公共卫生有关，因为它将导致生物标志物的开发，以便在筛查和/或化学预防试验中进行选择，并为化学预防和治疗药物的开发提供药物靶点。这些进展预计将降低死亡率和医疗成本。 公共卫生相关性：这项拟议的项目与NCI和NHLBI的任务相关，因为其结果预计将1)导致开发生物标记物，用于更密切的监测和选择，用于COPD和肺癌风险人群的筛查和/或化学预防试验，2)为COPD和肺癌风险的遗传基础提供证据，以及3)为开发COPD和肺癌的化学预防和治疗药物提供药物靶点。此外，拟议中的研究还将对600名有COPD和肺癌风险的非肺癌受试者的正常支气管上皮细胞提供进一步的表征，这将支持其他COPD和肺癌研究人员的研究，包括那些参与HL-11-002机制的研究。建议的方法是创新的，建议的方法可能会使发现慢性阻塞性肺疾病和肺癌的遗传风险因素方面取得更快的进展。

DESCRIPTION (provided by applicant): Chronic Obstructive Pulmonary Disease (COPD) and lung cancer are leading causes of morbidity and mortality both in the United States and worldwide. Inhalation of cigarette smoke is the primary known and preventable cause but only 10-15% of heavy smokers develop these diseases. This suggests that cigarette smoke exposure interacts with inherited susceptibility factors to determine risk. While some susceptibility genes are known, they account for less than 5% of risk for either disease. There is urgent need to identify additional heritable susceptibility factors for these diseases that explain the majority of COPD and lung cancer risk. This proposed project will use normal bronchial epithelial cell (NBEC) and blood samples collected through funding from CA148572 from a cohort of 600 non-lung cancer subjects over age 50, with more than 20 pack-years smoking history, and a separate cohort of 150 lung cancer subjects. The objective here is to determine the role of inter-individual variation in antioxidant and DNA repair gene transcript regulation in conferring risk for both COPD and lung cancer. The central hypothesis is that inherited DNA variants are associated with increased risk for both COPD and lung cancer and that many of these manifest as increased transcript abundance dispersion in key antioxidant, DNA repair, and transcription factor genes. In support of our hypothesis, we recently identified a lung cancer risk test (LCRT) that comprises transcript abundance values of 14 genes, including nine anti-oxidant, three DNA repair, and two transcription factor genes. For each of these genes, transcript abundance values were dispersed over a greater range in lung cancer subjects compared to matched controls. In addition, inherited DNA variation causes variation in transcript regulation of genes comprised by the LCRT. We plan to test our central hypothesis and accomplish the objective of this application by pursuing the following two specific aims: Aim 1. Determine whether key antioxidant and DNA repair genes have increased dispersion of transcript abundance in Normal Bronchial Epithelial Cells of COPD cases and whether a multi-gene test comprising a subset of these genes is an accurate test for COPD prevalence. Aim 2. Identify DNA variants that contribute to increased transcript abundance dispersion of genes associated with COPD and/or Lung Cancer Prevalence. We expect that Aim 1 will produce evidence that higher transcript abundance dispersion of key antioxidant, DNA repair, and transcription factor genes is associated with risk for COPD, as it is for lung cancer and will produce a candidate biomarker for increased COPD risk. Aim 2 will provide identification of DNA variants associated with increased transcript abundance dispersion in key genes with high prior likelihood of involvement in the pathogenesis of COPD and lung cancer. This research is relevant to public health because it will lead to development of biomarkers for selection into screening and/or chemoprevention trials and provide drug targets for development of chemo-preventative and therapeutic pharmaceuticals. These developments are expected to reduce mortality and health care costs. PUBLIC HEALTH RELEVANCE: This proposed project is relevant to the mission of NCI and NHLBI because the results are expected to 1) lead to development of biomarkers for closer surveillance and selection for screening and/or chemoprevention trials for individuals at risk for COPD and lung cancer,2) provide evidence for an inherited genetic basis for COPD and lung cancer risk, and 3) provide drug targets for development of chemo-preventative and therapeutic pharmaceuticals for COPD and lung cancer. In addition, the proposed studies will provide further characterization of normal bronchial epithelial cells from a cohort of 600 non-lung cancer subjects at risk for COPD and lung cancer and this will support studies by other COPD and lung cancer investigators, including those participating in this HL-11-002 mechanism. The approach that is proposed is innovative and it is likely that the proposed methods will enable more rapid progress in discovery of hereditary genetic risk factors for COPD and lung cancer.