DNA Repair Capacity and Risk of Pre-malignant Lesion in Lung Epithelium

肺上皮 DNA 修复能力和癌前病变风险

• 批准号: 7603074
• 负责人: Hua Zhao
• 金额: $ 6.97万
• 依托单位: ROSWELL PARK CANCER INSTITUTE CORP
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-04-06 至 2011-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7603074
• 关键词: 7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide; 8-hydroxy-2' -deoxyguanosine; Animals; Applications Grants; Base Excision Repairs; Biological Assay; Bronchoscopy; Buffaloes; Carcinogens; Cells; Chemoprevention; Clinic; Clinical Data; DNA Adducts; DNA Damage; DNA Repair; Data; Detection; Development; Diet Modification; Epidemiologic Studies; Epithelium; Event; Genetic; Genomic Instability; Goals; Grant; Human; Hydrogen Peroxide; Individual; Inflammation; Lesion; Link; Lung; Lymphocyte; Malignant neoplasm of lung; Metabolic Activation; Metaplasia; Metaplastic; Molecular; Morbidity - disease rate; Mutagens; Mutation Fixation; Natural History; Nature; Nucleotide Excision Repair; Patients; Peroxidases; Plasmids; Population; Premalignant; Process; Questionnaires; Reactive Oxygen Species; Recording of previous events; Risk; Role; Roswell Park Cancer Institute; Sampling; Screening procedure; Subgroup; System; Testing; United States National Institutes of Health; base; cancer epidemiology; carcinogenesis; chemical carcinogen; cohort; genotoxicity; high risk; intervention program; lung cancer screening; lung carcinogenesis; mortality; neutrophil; oxidative DNA damage; programs; repaired; response

DESCRIPTION (provided by applicant): This RO3 grant application is in response to NIH Small Grants Program for Cancer Epidemiology (PA-06- 294).Detecting pre-malignant lesions in central airway in high risk population has significant implication in decreasing lung cancer morbidity and mortality. However, the natural history of these lesions is unclear, especially for low grade lesions, such as metaplastia. Inflammation has been recognized as an important factor in lung carcinogenesis. Animal studies, as well as molecular epidemiological studies in humans, have provided evidence that the influx of neutrophils into the airways may be an important process linking inflammation with carcinogenesis. It is hypothesized that the genotoxicity of neutrophils, including induction of oxidative DNA damage through release of reactive oxygen species (ROS) and myeloperoxidase (MPO)-related metabolic activation of chemical carcinogens, is a crucial etiological factor in this carcinogenic response. There are extensive DNA repair systems that can correct DNA damage caused by ROS and MPO-related carcinogen activation before cell replication and mutation fixation. For instance, ROS-caused base damages are mainly repaired by base excision repair (BER) and nucleotide excision repair (NER); DNA adducts caused by MPO- related carcinogen activation are repaired by NER. However, DNA repair capacity (DRC) is substantially variable among individuals in the population, and suboptimal DRC of DNA damage might increase genomic instability and hence, increase risk of pre-malignant lesion and eventual lung cancer development. Although inflammation appears to be important in the nature history of lung pre-malignant lesions, so far there is no study to investigate whether DRC of inflammation caused DNA damage is associated with development of pre- malignant lesions in lung epithelium. Therefore, we propose this study to test the hypothesis that DRC of inflammation caused DNA damage may predict pre-malignant lesion development in lung epithelium. In this study, we will use samples and questionnaire data from a cohort of lung cancer high risk patients underwent autofluorescent brochoscopy (AFB) screening at the Lung Cancer Screening Clinic at the Roswell Park Cancer Institute in Buffalo NY between the years of 1998 } 2006. In Specific Aim 1, we will determine the role of DRC of ROS caused DNA damage in development of pre-malignant (metaplastic and dysplastic) lesions in lung epithelium. To achieve this goal, we will apply mutagen sensitivity assay to quantify levels of H2O2 induced 8-OH-dG in lymphocytes reflecting systemic BER capacity. Then, we will correlate levels of H2O2 induced 8-OH-dG in lymphocytes with baseline status pre-malignant (metaplastic and dysplastic) lesions in lung epithelium in individuals at high risk of lung cancer. In Specific Aim 2, we will determine the role of DRC of DNA adducts caused by MPO-related carcinogen activation in development of pre-malignant (metaplastic and dysplastic) lesions in lung epithelium. To achieve this goal, we will apply host cell reactivation (HCR) assay to quantify DRC of BPDE induced DNA adducts in plasmid pGL-3-luc in lymphocytes reflecting systemic NER capacity. Then, we will correlate levels of DRC of BPDE induced DNA adducts in lymphocytes with baseline status pre-malignant (metaplastic and dysplastic) lesions in lung epithelium in individuals at high risk of lung cancer. Project Narrative Detecting pre-malignant lesions in central airway in high risk population has significant implication in decreasing lung cancer morbidity and mortality. However, the natural history of these lesions is unclear, especially for low grade lesions, such as metaplasia. Inflammation has been recognized as an important factor in lung carcinogenesis. Animal studies, as well as molecular epidemiological studies in humans, have provided evidence that the influx of neutrophils into the airways may be an important process linking inflammation with carcinogenesis. It is hypothesized that the genotoxicity of neutrophils, including induction of oxidative DNA damage through release of reactive oxygen species (ROS) and myeloperoxidase (MPO)-related metabolic activation of chemical carcinogens, is a crucial etiological factor in this carcinogenic response. There are extensive DNA repair systems that can correct DNA damage caused by ROS and MPO-related carcinogen activation before cell replication and mutation fixation. DNA repair capacity (DRC) is substantially variable among individuals in the population, and suboptimal DRC of DNA damage might increase genomic instability and hence, increase risk of pre-malignant lesion and eventual lung cancer development. Although inflammation appears to be important in the nature history of lung pre-malignant lesions, so far there is no study to investigate whether DRC of inflammation caused DNA damage is associated with development of pre- malignant lesions in lung epithelium. Therefore, we propose this study to test the hypothesis that DRC of inflammation caused DNA damage may predict pre-malignant lesion development in lung epithelium. The study will further our understanding of the genetic events leading to the development of pre-malignant lesions; explore the genetic basis of inflammation and pre-malignant lesions; and eventually elucidate the multi-step of lung carcinogenesis. The information from this study will also provide a means of identifying a subgroup that are most likely to develop lung cancer. Such individuals may then be targeted for specific intervention programs such as chemoprevention and dietary modification.

描述（由申请人提供）： 此 RO3 拨款申请是为了响应 NIH 癌症流行病学小额拨款计划 (PA-06-294)。检测高危人群中央气道的癌前病变对于降低肺癌发病率和死亡率具有重要意义。然而，这些病变的自然史尚不清楚，特别是低度病变，例如化生。炎症已被认为是肺癌发生的重要因素。动物研究以及人类分子流行病学研究提供的证据表明，中性粒细胞流入气道可能是将炎症与致癌作用联系起来的重要过程。据推测，中性粒细胞的遗传毒性，包括通过释放活性氧 (ROS) 和髓过氧化物酶 (MPO) 相关化学致癌物的代谢激活诱导氧化 DNA 损伤，是这种致癌反应的关键病因。有广泛的 DNA 修复系统可以在细胞复制和突变固定之前纠正由 ROS 和 MPO 相关致癌物激活引起的 DNA 损伤。例如，ROS引起的碱基损伤主要通过碱基切除修复（BER）和核苷酸切除修复（NER）来修复；由 MPO 相关致癌物激活引起的 DNA 加合物由 NER 修复。然而，DNA 修复能力 (DRC) 在人群中存在很大差异，DNA 损伤的次优 DRC 可能会增加基因组的不稳定性，从而增加癌前病变和最终肺癌发展的风险。尽管炎症在肺恶前病变的自然史中似乎很重要，但迄今为止还没有研究探讨炎症DRC引起的DNA损伤是否与肺上皮癌前病变的发展相关。因此，我们提出这项研究来检验炎症 DRC 引起的 DNA 损伤可能预测肺上皮癌前病变发展的假设。在本研究中，我们将使用 1998 年至 2006 年期间在纽约州布法罗罗斯威尔公园癌症研究所肺癌筛查诊所接受自体荧光支气管镜检查 (AFB) 筛查的肺癌高危患者队列的样本和问卷数据。在具体目标 1 中，我们将确定 ROS 引起的 DNA 损伤的 DRC 在癌前病变（化生性和发育异常性）发展中的作用。 肺上皮病变。为了实现这一目标，我们将应用诱变剂敏感性测定来量化反映系统 BER 能力的淋巴细胞中 H2O2 诱导的 8-OH-dG 的水平。然后，我们将淋巴细胞中 H2O2 诱导的 8-OH-dG 水平与肺癌高危个体肺上皮恶变前（化生和发育不良）病变的基线状态相关联。在具体目标 2 中，我们将确定 MPO 相关致癌物激活引起的 DNA 加合物 DRC 在肺上皮癌前（化生和发育不良）病变发展中的作用。为了实现这一目标，我们将应用宿主细胞再激活 (HCR) 测定来量化淋巴细胞中质粒 pGL-3-luc 中 BPDE 诱导的 DNA 加合物的 DRC，反映全身 NER 能力。然后，我们将淋巴细胞中 BPDE 诱导的 DNA 加合物的 DRC 水平与肺癌高危个体肺上皮恶变前（化生和发育不良）病变的基线状态相关联。项目叙述检测高危人群中央气道的癌前病变对于降低肺癌发病率和死亡率具有重要意义。然而，这些病变的自然史尚不清楚，特别是低度病变，例如化生。炎症已被认为是肺癌发生的重要因素。动物研究以及人类分子流行病学研究提供的证据表明，中性粒细胞流入气道可能是将炎症与致癌作用联系起来的重要过程。据推测，中性粒细胞的遗传毒性，包括通过释放活性氧 (ROS) 和髓过氧化物酶 (MPO) 相关化学致癌物的代谢激活诱导氧化 DNA 损伤，是这种致癌反应的关键病因。有广泛的 DNA 修复系统可以在细胞复制和突变固定之前纠正由 ROS 和 MPO 相关致癌物激活引起的 DNA 损伤。 DNA 修复能力 (DRC) 在人群中存在很大差异，DNA 损伤的次优 DRC 可能会增加基因组的不稳定性，从而增加癌前病变和最终发生肺癌的风险。尽管炎症在肺恶前病变的自然史中似乎很重要，但迄今为止还没有研究探讨炎症DRC引起的DNA损伤是否与肺上皮癌前病变的发展相关。因此，我们提出这项研究来检验炎症 DRC 引起的 DNA 损伤可能预测肺上皮癌前病变发展的假设。该研究将进一步加深我们对导致癌前病变发展的遗传事件的理解；探索炎症和癌前病变的遗传基础；并最终阐明肺癌发生的多步骤。这项研究的信息还将提供一种识别最有可能患肺癌的亚组的方法。然后，这些人可能会成为特定干预计划的目标，例如化学预防和饮食调整。