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Keywords:

  • lung cancer;
  • smoking;
  • cohort study;
  • biomarkers;
  • 7-methylguanine;
  • glutathione-S-transferases

Abstract

Nitrosamines are mainly mutagenic through methylation of DNA. 7-Methylguanine (m7Gua) 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 m7Gua 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 m7Gua by HPLC. Effect modification by glutathione-S-transferases GSTM1, GSTM3, GSTT1 and GSTP1 was investigated. We found higher excretion of m7Gua 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 m7Gua 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 m7Gua 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 m7Gua excretion and lung cancer supports the importance of methylation of guanine. The finding of an association between m7Gua excretion and lung cancer risk mainly among current smokers and subjects with GSTM1 null genotype supports causality in this respect. © 2007 Wiley-Liss, Inc.