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. ? ?

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project--Cooperative Agreements (U01)
Project #
5U01CA111219-03
Application #
7278823
Study Section
Special Emphasis Panel (ZCA1-SRRB-Y (M2))
Program Officer
Krueger, Karl E
Project Start
2005-09-13
Project End
2010-07-31
Budget Start
2007-09-05
Budget End
2008-07-31
Support Year
3
Fiscal Year
2007
Total Cost
$239,509
Indirect Cost
Name
Weizmann Institute of Science
Department
Type
DUNS #
600048466
City
Rehovot, Israel
State
Country
Israel
Zip Code
76100
Sevilya, Ziv; Leitner-Dagan, Yael; Pinchev, Mila et al. (2015) Development of APE1 enzymatic DNA repair assays: low APE1 activity is associated with increase lung cancer risk. Carcinogenesis 36:982-91
Leitner-Dagan, Yael; Sevilya, Ziv; Pinchev, Mila et al. (2014) Enzymatic MPG DNA repair assays for two different oxidative DNA lesions reveal associations with increased lung cancer risk. Carcinogenesis 35:2763-70
Sevilya, Ziv; Leitner-Dagan, Yael; Pinchev, Mila et al. (2014) Low integrated DNA repair score and lung cancer risk. Cancer Prev Res (Phila) 7:398-406
Leitner-Dagan, Yael; Sevilya, Ziv; Pinchev, Mila et al. (2012) N-methylpurine DNA glycosylase and OGG1 DNA repair activities: opposite associations with lung cancer risk. J Natl Cancer Inst 104:1765-9
Paz-Elizur, Tamar; Sevilya, Ziv; Leitner-Dagan, Yael et al. (2008) DNA repair of oxidative DNA damage in human carcinogenesis: potential application for cancer risk assessment and prevention. Cancer Lett 266:60-72
Paz-Elizur, Tamar; Ben-Yosef, Rami; Elinger, Dalia et al. (2006) Reduced repair of the oxidative 8-oxoguanine DNA damage and risk of head and neck cancer. Cancer Res 66:11683-9