Tobacco
carcinogens can damage
DNA, leading to apoptosis. There may be individual variation in apoptotic capacity (AC), and this variation may explain difference in AC associated with risk of
lung cancer, if genome integrity is not restored by efficient DNA repair. To test the hypothesis that genetically determined AC is associated with risk of
lung cancer, we conducted a pilot case-control study of 68 patients with newly diagnosed, untreated
lung cancer and 74
cancer-free controls. We measured the AC of their cultured peripheral blood lymphocytes in response to in vitro exposure to an ultimate tobacco
carcinogen,
benzo[a]pyrene diol
epoxide (
BPDE), by using terminal dUTP
nucleotide end labeling and flow cytometry. We also investigated the frequency of the -A670G polymorphism in Fas, a gene involved in controlling the apoptotic pathway, by using polymerase chain reaction-restriction fragment length polymorphism analysis. After exposing the cells to 4 microM
BPDE for 5 h, we observed a significantly lower AC in
lung cancer patients (155.2+/-143.9%) than in the controls (216.6+/-184.6%) (P<0.05). Low AC was an independent risk factor (adjusted odds ratio (OR)=2.69, 95% confidence interval (CI)=1.18-6.15) for
lung cancer after adjustment for age, sex, ethnicity, smoking status and apoptotic baseline in a logistic regression model. Although the Fas -A670G polymorphism was not an independent risk factor for
lung cancer, it appeared to modulate the risk. The adjusted
ORs for
lung cancer risk associated with lower AC were 4.00 (95% CI=1.48-10.80) among those with the Fas -670 AG and GG genotypes and 0.97 (95% CI=0.18-5.30) among those with the Fas -670AA genotype. These data suggest that alteration in the apoptotic pathway may be a risk factor for
lung cancer and this risk may be modulated by the Fas -A670G polymorphism. Larger prospective studies are needed to verify these findings.