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. ? ?
