Fas A670G polymorphism, apoptotic capacity in lymphocyte cultures, and risk of lung cancer.
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.
D015123:7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide / Q000633:toxicity; D017209:Apoptosis; D002273:Carcinogens / Q000633:toxicity; D016022:Case-Control Studies; D002478:Cells, Cultured; D005260:Female; D005434:Flow Cytometry; D005838:Genotype; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics* / Q000378:metabolism; D008214:Lymphocytes / Q000187:drug effects / Q000473:pathology*; D008297:Male; D008875:Middle Aged; D010865:Pilot Projects; D016133:Polymerase Chain Reaction; D011110:Polymorphism, Genetic; D012150:Polymorphism, Restriction Fragment Length; D012307:Risk Factors; D019014:fas Receptor / Q000235:genetics*
D002273:Carcinogens; D019014:fas Receptor; D015123:7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide