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: 7472957
• 负责人: Hua Zhao
• 金额: $ 6.91万
• 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 2010-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7472957
• 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; Peroxidase; 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; 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)： 此次R03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)。在高危人群中检测中央呼吸道癌前病变对降低肺癌发病率和死亡率具有重要意义。然而，这些病变的自然病史尚不清楚，特别是对于低度病变，如化生。炎症已被认为是肺癌发生的重要因素。动物研究以及人类的分子流行病学研究都提供了证据，表明中性粒细胞进入呼吸道可能是将炎症与致癌联系起来的一个重要过程。中性粒细胞的遗传毒性，包括通过释放活性氧物种(ROS)和髓过氧化物酶(MPO)相关的化学致癌物的代谢激活而诱导DNA氧化损伤，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)修复；MPO相关致癌物激活引起的DNA加合物则由NER修复。然而，DNA修复能力(DRC)在人群中的个体之间存在很大差异，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。虽然炎症在肺部癌前病变的自然史中占有重要地位，但目前还没有研究表明炎症引起的DRC引起的DNA损伤是否与肺上皮癌前病变的发生有关。因此，我们建议这项研究来检验炎症引起的DNA损伤的DRC可能预测肺上皮细胞癌前病变的发展这一假设。在这项研究中，我们将使用1998年至2006年间在纽约州布法罗市罗斯威尔公园癌症研究所的肺癌筛查诊所接受自动荧光支气管镜(AFB)筛查的一组肺癌高危患者的样本和问卷数据。在特定的目标1中，我们将确定ROS引起的DNA损伤的DRC在肺上皮癌前病变(化生和异型增生)发生中的作用。为了实现这一目标，我们将应用诱变剂敏感性试验来定量H_2O_2诱导的淋巴细胞中8-OH-DG的水平，以反映全身BER能力。然后，我们将把H_2O_2诱导的淋巴细胞中8-OH-DG的水平与肺癌高危个体中肺上皮细胞癌前病变(化生和异型)的基线状态相关联。在特定的目标2中，我们将确定由MPO相关致癌物激活引起的DNA加合物DRC在肺上皮癌前病变(化生和异型增生)发生中的作用。为了实现这一目标，我们将应用宿主细胞再激活(HCR)方法来定量BPDE诱导的DNA加合物在淋巴细胞中的DRC，以反映全身NER的能力。然后，我们将把BPDE诱导的淋巴细胞DNA加合物的DRC水平与肺癌高危个体癌前病变(化生和异型增生)的基线状态相关联。在高危人群中检测中央呼吸道癌前病变对降低肺癌发病率和死亡率具有重要意义。然而，这些病变的自然病史尚不清楚，特别是对于低度病变，如化生。炎症已被认为是肺癌发生的重要因素。动物研究以及人类的分子流行病学研究都提供了证据，表明中性粒细胞进入呼吸道可能是将炎症与致癌联系起来的一个重要过程。中性粒细胞的遗传毒性，包括通过释放活性氧物种(ROS)和髓过氧化物酶(MPO)相关的化学致癌物的代谢激活而诱导DNA氧化损伤，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)在人群中的个体之间有很大的差异，DNA损伤的DRC次佳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。虽然炎症在肺部癌前病变的自然史中占有重要地位，但目前还没有研究表明炎症引起的DRC引起的DNA损伤是否与肺上皮癌前病变的发生有关。因此，我们建议这项研究来检验炎症引起的DNA损伤的DRC可能预测肺上皮细胞癌前病变的发展这一假设。这项研究将进一步加深我们对导致癌前病变发生的遗传事件的理解，探索炎症和癌前病变的遗传学基础，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手段来识别最有可能患肺癌的亚群。然后，这些人可能会成为特定干预计划的目标，如化学预防和饮食调整。