Sensitivity to DNA damage induced by benzo(a)pyrene diol epoxide and risk of lung cancer: A case-control analysis

Levels of DNA adducts vary greatly in vivo, attributable to individual diff erences in enzymatic bioactivation of benzo(a)pyrene, We developed an assay to measure the levels of DNA adducts induced in vitro by benzo(a)pyrene di ol epoxide (BPDE), a bioactivated form of benzo(a)pyrene, In this large mol ecular epidemiological study of lung cancer, we tested the hypothesis that the level of in vitro BPDE-induced adducts is associated with risk of lung cancer. This hospital-based case-control study included 221 newly diagnosed lung cancer cases and 229 healthy controls frequency matched on age, sex, ethnicity, and smoking status. Short-term cultured peripheral blood lymphoc ytes from each subject were exposed in vitro to BPDE (4 muM) for 5 h, and t he P-32-postlabeling method was then used to measure BPDE-induced DNA adduc ts in the host cells. Overall, the patients had significantly higher levels of BPDE-DNA adducts than did the controls (mean a SD per 10(7) nucleotides , 93.2 +/- 89.3 for cases versus 63.7 +/- 61.1 for controls; P = 0.001), Un ivariate and multivariate logistic regression analyses were performed to ca lculate the crude and adjusted odds ratios and their 95% confidence interva ls. When the median adduct level of controls (46/10(7) nucleotides) was use d as the cutoff point, 64% of cases had higher levels (odds ratio, 2.15; 95 % confidence interval, 1.39-3.33, adjusted for age, sex, ethnicity, body ma ss index, recent weight loss, pack-years smoked, smoking in the last 24 h, and family history of cancer). Stratified analyses showed consistently high er levels of BPDE-induced adducts in cases than in controls, regardless of subgroup of age, sex, ethnicity, body mass index, recent weight loss, pack- years smoked, smoking in the last 24 h, and family history of cancer. A sig nificant dose-response relationship between the quartile levels of BPDE-ind uced DNA adducts and the risk of lung cancer was observed (trend test, P < 0.001), The significant association between the level of in vitro BPDE-indu ced DNA adducts and risk for lung cancer suggests that subjects very sensit ive to BPDE-induced DNA damage may have a suboptimal ability to remove the BPDE-DNA adducts and so are susceptible to tobacco carcinogen exposure and, therefore, may be at increased risk of lung cancer.