title: Prospective study of urinary excretion of 7-methylguanine and the risk of lung cancer: Effect modification by mu class glutathione-S-transferases.
abstract: Nitrosamines are mainly mutagenic through methylation of DNA. 7-Methylguanine (m(7)Gua) is a product of base excision repair and spontaneous depurination of such lesions in DNA and a metabolite from RNA. Associations between urinary excretion of m(7)Gua and risk of lung cancer were examined in a population-based cohort of 25,717 men and 27,972 women aged 50-64 years. During 3-7 years follow-up 260 cases with lung cancer were identified and a subcohort of 263 individuals matched on sex, age and smoking duration was selected for comparison. Urine collected at entry was analyzed for m(7)Gua by HPLC. Effect modification by glutathione-S-transferases GSTM1, GSTM3, GSTT1 and GSTP1 was investigated. We found higher excretion of m(7)Gua among current smokers than among former smokers. The IRR (incidence rate ratio) of lung cancer was 1.20 (95% CI: 1.00-1.43) per doubling of m(7)Gua excretion in unadjusted analysis and 1.12 (95% CI: 0.93-1.35) after adjustment for smoking status, intensity and duration at entry. This association was mainly present among current smokers. Comparing the highest with the lowest tertile of m(7)Gua excretion the IRR of lung cancer was 1.75 (95% CI: 1.04-2.95) irrespective of genotype and 2.75 (95% CI: 1.33-5.81) in subjects with GSTM1 null genotype. If not caused by residual confounding by smoking a possible association between m(7)Gua excretion and lung cancer supports the importance of methylation of guanine. The finding of an association between m(7)Gua excretion and lung cancer risk mainly among current smokers and subjects with GSTM1 null genotype supports causality in this respect.
authors.affiliation: Department of Environmental and Occupational Health, University of Copenhagen, Denmark. s.loft@pubhealth.ku.dk
authors.forename: Steffen
authors.initials: S
authors.lastname: Loft
authors.forename: Peter
authors.initials: P
authors.lastname: Svoboda
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Kasai
authors.forename: Anne
authors.initials: A
authors.lastname: Tjønneland
authors.forename: Peter
authors.initials: P
authors.lastname: Møller
authors.forename: Mette
authors.initials: M
authors.lastname: Sørensen
authors.forename: Kim
authors.initials: K
authors.lastname: Overvad
authors.forename: Herman
authors.initials: H
authors.lastname: Autrup
authors.forename: Ole
authors.initials: O
authors.lastname: Raaschou-Nielsen
mesh_terms: D005260:Female; D005787:Gene Frequency; D005838:Genotype; D051549:Glutathione S-Transferase pi / Q000235:genetics; D005982:Glutathione Transferase / Q000235:genetics; D006147:Guanine / Q000031:analogs & derivatives* / Q000652:urine; D006801:Humans; D016014:Linear Models; D008175:Lung Neoplasms / Q000235:genetics / Q000473:pathology* / Q000652:urine; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D011446:Prospective Studies; D012042:Registries / Q000706:statistics & numerical data; D012307:Risk Factors; D012907:Smoking
chemical_list: D051549:Glutathione S-Transferase pi; D005982:Glutathione Transferase; D006147:Guanine; C008450:7-methylguanine; C413545:glutathione S-transferase T1; C483009:GSTM3 protein, human; C496556:GSTP1 protein, human