DNA Repair Biomarkers for Cancer Risk Assessment and Ea*

描述(申请人提供)：DNA修复成为癌症发病机制中的一个重要因素，发现在几种易患癌症的遗传性疾病中，容易发生突变的是编码DNA修复蛋白的基因。这项拟议研究的长期目标是利用分子对DNA修复机制的了解来预防癌症，开发一种用于癌症风险评估的电池DNA修复生物标记物，并将其应用于大规模筛查。PI在最近的一项研究中迈出了这一方向的第一步，在该研究中，建立了一种功能性酶活性分析方法，用于修复人外周血单核细胞提取物中氧化DNA损伤的8-氧鸟苷。使用该分析获得的证据表明，OGG1DNA修复活性降低是肺癌的一个危险因素。拟议的研究旨在扩大和扩大最初的研究。具体地说，它建议：(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前体池中消除氧化损伤的核苷酸。(2)利用这些测试进行实验室内的重复性研究。(3)进行原则证明的小规模病例对照研究，以检查正在调查的DNA修复和损伤预防活动水平降低是否与肺癌风险有关。(4)探讨肺癌患者外周血单个核细胞DNA修复活性与肺组织DNA修复活性的相关性。然后，将利用早期检测研究网络内的测试启动实验室间可重复性研究。未来的成功验证将使其能够采取进一步的必要步骤，然后才能应用于公共卫生，以预防癌症为目的的大规模人群筛查。

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.