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 (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.