title: Enzymatic MPG DNA repair assays for two different oxidative DNA lesions reveal associations with increased lung cancer risk.
abstract: DNA repair is a major mechanism for minimizing mutations and reducing cancer risk. Here, we present the development of reproducible and specific enzymatic assays for methylpurine DNA glycosylase (MPG) repairing the oxidative lesions 1,N6-ethenoadenine (εA) and hypoxanthine (Hx) in peripheral blood mononuclear cells protein extracts. Association of these DNA repair activities with lung cancer was determined using conditional logistic regression with specimens from a population-based case-control study with 96 lung cancer cases and 96 matched control subjects. The mean MPG-εA in case patients was 15.8 units/μg protein (95% CI 15.3-16.3), significantly higher than in control subjects-15.1 (14.6-15.5), *P = 0.011. The adjusted odds ratio for lung cancer associated with a one SD increase in MPG-εA activity (2.48 units) was significantly bigger than 1 (OR = 1.6, 95% CI = 1.1-2.4; *P = 0.013). When activity of OGG1, a different DNA repair enzyme for oxidative damage, was included in the model, the estimated odds ratio/SD for a combined MPG-εA-OGG1 score was 2.6 (95% CI 1.6-4.2) *P = 0.0001, higher than the odds ratio for each single assay. The MPG enzyme activity assays described provide robust functional risk biomarkers, with increased MPG-εA activity being associated with increased lung cancer risk, similar to the behavior of MPG-Hx. This underscores the notion that imbalances in DNA repair, including high DNA repair, usually perceived as beneficial, can cause cancer risk. Such DNA repair risk biomarkers may be useful for risk assessment of lung cancer and perhaps other cancer types, and for early detection techniques such as low-dose CT.
authors.affiliation: Department of Biological Chemistry, Weizmann Institute of Science, Rehovot 76100, Israel, Department of Community Medicine and Epidemiology, Carmel Medical Center, Bruce Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, and Clalit Health Services National Cancer Control Center, Haifa, Israel, Department of General Thoracic Surgery, Rambam Health Care Campus, Haifa, Israel, Department of Industrial Engineering and Management, Ben Gurion University of the Negev, Beer Sheva 84105, Israel and Biostatistics Unit, Gertner Institute for Epidemiology and Public Health Policy Sheba Medical Center Tel Hashomer 52621, Israel.
authors.forename: Yael
authors.initials: Y
authors.lastname: Leitner-Dagan
authors.affiliation: Department of Biological Chemistry, Weizmann Institute of Science, Rehovot 76100, Israel, Department of Community Medicine and Epidemiology, Carmel Medical Center, Bruce Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, and Clalit Health Services National Cancer Control Center, Haifa, Israel, Department of General Thoracic Surgery, Rambam Health Care Campus, Haifa, Israel, Department of Industrial Engineering and Management, Ben Gurion University of the Negev, Beer Sheva 84105, Israel and Biostatistics Unit, Gertner Institute for Epidemiology and Public Health Policy Sheba Medical Center Tel Hashomer 52621, Israel.
authors.forename: Ziv
authors.initials: Z
authors.lastname: Sevilya
authors.affiliation: Department of Community Medicine and Epidemiology, Carmel Medical Center, Bruce Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, and Clalit Health Services National Cancer Control Center, Haifa, Israel.
authors.forename: Mila
authors.initials: M
authors.lastname: Pinchev
authors.affiliation: Department of General Thoracic Surgery, Rambam Health Care Campus, Haifa, Israel.
authors.forename: Ran
authors.initials: R
authors.lastname: Kremer
authors.affiliation: Department of Biological Chemistry, Weizmann Institute of Science, Rehovot 76100, Israel, Department of Community Medicine and Epidemiology, Carmel Medical Center, Bruce Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, and Clalit Health Services National Cancer Control Center, Haifa, Israel, Department of General Thoracic Surgery, Rambam Health Care Campus, Haifa, Israel, Department of Industrial Engineering and Management, Ben Gurion University of the Negev, Beer Sheva 84105, Israel and Biostatistics Unit, Gertner Institute for Epidemiology and Public Health Policy Sheba Medical Center Tel Hashomer 52621, Israel.
authors.forename: Dalia
authors.initials: D
authors.lastname: Elinger
authors.affiliation: Department of Community Medicine and Epidemiology, Carmel Medical Center, Bruce Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, and Clalit Health Services National Cancer Control Center, Haifa, Israel.
authors.forename: Hedy S
authors.initials: HS
authors.lastname: Rennert
authors.affiliation: Department of Industrial Engineering and Management, Ben Gurion University of the Negev, Beer Sheva 84105, Israel and.
authors.forename: Edna
authors.initials: E
authors.lastname: Schechtman
authors.affiliation: Biostatistics Unit, Gertner Institute for Epidemiology and Public Health Policy Sheba Medical Center Tel Hashomer 52621, Israel.
authors.forename: Laurence
authors.initials: L
authors.lastname: Freedman
authors.affiliation: Department of Community Medicine and Epidemiology, Carmel Medical Center, Bruce Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, and Clalit Health Services National Cancer Control Center, Haifa, Israel.
authors.forename: Gad
authors.initials: G
authors.lastname: Rennert
authors.affiliation: Department of Biological Chemistry, Weizmann Institute of Science, Rehovot 76100, Israel, Department of Community Medicine and Epidemiology, Carmel Medical Center, Bruce Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, and Clalit Health Services National Cancer Control Center, Haifa, Israel, Department of General Thoracic Surgery, Rambam Health Care Campus, Haifa, Israel, Department of Industrial Engineering and Management, Ben Gurion University of the Negev, Beer Sheva 84105, Israel and Biostatistics Unit, Gertner Institute for Epidemiology and Public Health Policy Sheba Medical Center Tel Hashomer 52621, Israel tamar.paz-elizur@weizmann.ac.il zvi.livneh@weizmann.ac.il.
authors.forename: Zvi
authors.initials: Z
authors.lastname: Livneh
authors.affiliation: Department of Biological Chemistry, Weizmann Institute of Science, Rehovot 76100, Israel, Department of Community Medicine and Epidemiology, Carmel Medical Center, Bruce Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, and Clalit Health Services National Cancer Control Center, Haifa, Israel, Department of General Thoracic Surgery, Rambam Health Care Campus, Haifa, Israel, Department of Industrial Engineering and Management, Ben Gurion University of the Negev, Beer Sheva 84105, Israel and Biostatistics Unit, Gertner Institute for Epidemiology and Public Health Policy Sheba Medical Center Tel Hashomer 52621, Israel tamar.paz-elizur@weizmann.ac.il.
authors.forename: Tamar
authors.initials: T
authors.lastname: Paz-Elizur
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D000368:Aged; D002294:Carcinoma, Squamous Cell / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D016022:Case-Control Studies; D004249:DNA Damage / Q000235:genetics*; D045647:DNA Glycosylases / Q000378:metabolism; D004260:DNA Repair / Q000235:genetics*; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000378:metabolism / Q000473:pathology; D008168:Lung / Q000378:metabolism; D008175:Lung Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D009367:Neoplasm Staging; D018384:Oxidative Stress; D011379:Prognosis
chemical_list: C092514:MPEG1 protein, human; D008565:Membrane Proteins; D045647:DNA Glycosylases; C479058:oxoguanine glycosylase 1, human