DNA Repair Biomarkers for Cancer Risk & Early Detection

DNA 修复癌症风险生物标志物

基本信息

批准号：
7278823
负责人：
ZVI LIVNEH
金额：
$ 23.95万
依托单位：
WEIZMANN INSTITUTE OF SCIENCE
依托单位国家：
美国
项目类别：
财政年份：
2005
资助国家：
美国
起止时间：
2005-09-13 至 2010-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7278823
关键词：
8-oxo-dGTP 8-oxoguanine Adenine Nucleotides Awareness Base Excision Repairs Biological Assay Biological Markers Blood Tests Cancer Patient Carcinogens Case-Control Studies Chemicals Collaborations DNA DNA Damage DNA Repair DNA Repair Enzymes DNA lesion DNA repair protein Data Disease Early Detection Research Network Early Diagnosis Enzymes Epidemiologic Studies Future Genes Genetic Polymorphism Goals Hand Hereditary Malignant Neoplasm Human Hydrolysis Individual Integration Host Factors Investigation Laboratories Lesion Link Malignant Neoplasms Malignant neoplasm of lung Molecular Molecular Epidemiology Mutation Nucleotides OGG1 gene Outcome Oxidative Stress Pathogenesis Pathway interactions Peripheral Blood Mononuclear Cell Personal Satisfaction Population Populations at Risk Predisposition Prevention Principal Investigator Public Health Purpose Reaction Reproducibility Research Risk Risk Assessment Risk Factors Role Screening procedure Site Smoker Structure of parenchyma of lung Testing Validation Variant cancer prevention cancer risk editorial enzyme substrate epidemiology study gene repair human APEX1 protein lung cancer prevention member molecular scale oxidation oxidative DNA damage prevent repaired response smoking cessation tool

项目摘要

DESCRIPTION (provided by applicant): DNA repair emerged as an important factor in cancer pathogenesis, with the discovery that in several hereditary cancer-prone diseases, the predisposing mutations are in genes encoding DNA repair proteins. The long-term goal of the proposed research is to harness the molecular understanding of DNA repair mechanisms to cancer prevention, by developing a battery DNA repair biomarkers for cancer risk assessment, and apply them to large-scale screening. A first step in this direction was done by the PI in a recent study, in which a functional enzymatic activity assay was developed for the repair of the oxidative DNA lesion 8-oxoguanine in extracts from human peripheral blood mononuclear cells. Using that assay evidence was obtained to indicate that reduced OGG1 DNA repair activity is a risk factor in lung cancer. The proposed studies are aimed to extend and broaden that initial study. Specifically it is proposes: (1) To develop three blood tests for the repair of DNA lesions formed by oxidative stress, and for the elimination of oxidation-damaged nucleotides from the DNA precursor pool. (2) To perform within-laboratory reproducibility studies with these tests. (3) To perform proof-of-principle small-scale case-control studies in order to examine whether reduced levels of the DNA repair and damage prevention activities under investigation are associated with the risk of lung cancer. (4) To examine the correlation between the DNA repair activities in peripheral blood mononuclear cells and lung tissue from lung cancer patients. A between-laboratory reproducibility study will then be initiated with the tests within the Early Detection Research Network. Future successful validation will enable to take the further necessary steps, before application to public health can be made in large-scale population screening for purposes of cancer prevention.

描述（由申请人提供）：DNA 修复已成为癌症发病机制中的一个重要因素，人们发现，在几种易患癌症的遗传性疾病中，诱发突变位于编码 DNA 修复蛋白的基因中。该研究的长期目标是利用对DNA修复机制的分子理解来预防癌症，通过开发用于癌症风险评估的电池DNA修复生物标志物，并将其应用于大规模筛查。 PI 在最近的一项研究中朝这个方向迈出了第一步，其中开发了一种功能酶活性测定法，用于修复人外周血单核细胞提取物中的氧化性 DNA 损伤 8-氧代鸟嘌呤。使用该检测获得的证据表明 OGG1 DNA 修复活性降低是肺癌的危险因素。拟议的研究旨在扩展和扩大最初的研究。具体而言，建议： (1) 开发三种血液测试，用于修复氧化应激形成的 DNA 损伤，并从 DNA 前体库中消除氧化损伤的核苷酸。 (2) 利用这些测试进行实验室内再现性研究。 (3) 进行小规模原理验证病例对照研究，以检查所研究的 DNA 修复和损伤预防活动水平降低是否与肺癌风险相关。 (4)探讨肺癌患者外周血单个核细胞与肺组织DNA修复活性的相关性。然后将通过早期检测研究网络内的测试启动实验室间再现性研究。未来的成功验证将能够采取进一步的必要步骤，然后才能应用于公共卫生，以预防癌症为目的进行大规模人群筛查。