DNA Repair Biomarkers for Cancer Risk & Early Detection

描述（申请人提供）：DNA修复成为癌症发病的重要因素，在一些遗传性癌症易感性疾病中，发现编码DNA修复蛋白的基因发生易感突变。该研究的长期目标是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，从而利用对DNA修复机制的分子理解来预防癌症。PI在最近的一项研究中迈出了这一方向的第一步，该研究开发了一种功能性酶活性测定方法，用于修复人外周血单个核细胞提取物中氧化DNA损伤的8-氧鸟嘌呤。利用该分析获得的证据表明，OGG1 DNA修复活性降低是肺癌的一个危险因素。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，用于修复由氧化应激形成的DNA损伤，并用于从DNA前体池中消除氧化损伤的核苷酸。(2)用这些试验进行实验室内的可重复性研究。(3)进行原则性的小规模病例对照研究，以检验所研究的DNA修复和损伤预防活动水平的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修复活性与肺组织的相关性。然后将在早期发现研究网络内开展实验室间可重复性研究。未来的成功验证将使我们能够采取进一步的必要步骤，然后才能将其应用于公共卫生领域，进行大规模人群筛查，以预防癌症。

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.