Benzo[a]pyrene diol epoxide and bleomycin sensitivity and susceptibility to cancer of upper aerodigestive tract

Background: Tobacco smoking is an established risk factor for cancers of the upper aerodigestive tract, and measurement of chromosomal aberrations, i.e., chromatid breaks, induced in lymphocytes in vitro by bleomycin has been shown to be a predictor of risk for these cancers. In a case-control study, we recruited case subjects who were previously treated with surgery and/or radiotherapy for stage I or stage II squamous cell carcinoma of the head and neck to test the hypothesis that lymphocytic chromatid breaks induced by benzo[a]pyrene diol epoxide (BPDE), a tobacco mutagen, may also be associated with risk of developing cancers of the upper aerodigestive tract. Methods: Case subjects were matched to control subjects on the basis of age, sex, ethnicity, and smoking status. Primary lymphocytes from 67 case subjects and 81 control subjects were treated with 2 μM BPDE for 24 hours, and the frequency of induced chromatid breaks was determined. All statistical tests were two-sided. Results: Lymphocytes from case subjects compared with lymphocytes from control subjects showed significantly more breaks per cell induced by BPDE (mean ± standard deviation, 0.77 ± 0.38 versus 0.49 ± 0.25; P<.001). Lymphocytes from 64.2% of case subjects were sensitive to BPDE (using a cutoff value of ≤0.60 break per cell). Subjects in the highest quartile of chromatid breaks had an approximately 20-fold increased risk of cancer compared with those in the lowest quartile after adjustment for age, sex, ethnicity, and smoking status. The association between BPDE sensitivity and cancer risk was higher in former smokers than in current smokers and higher in younger patients than in older patients. Subjects with sensitivity to both BPDE and bleomycin were at a 19.2-fold increased risk of cancer compared with those who were not sensitive to either agent. Conclusions: Mutagen sensitivity assays may aid in identifying individuals at risk of cancer, and use of parallel assays with two mutagens may improve risk predictability.