Wang Li-E, Cheng Lie, Spitz Margaret R, Wei Qingyi
Department of Epidemiology, The University of Texas M.D. Anderson Cancer Center, Houston, TX, USA.
Lung Cancer. 2003 Oct;42(1):1-8. doi: 10.1016/s0169-5002(03)00276-9.
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.
烟草致癌物可损伤DNA，导致细胞凋亡。细胞凋亡能力（AC）可能存在个体差异，若基因组完整性不能通过有效的DNA修复得以恢复，这种差异可能解释与肺癌风险相关的AC差异。为验证遗传决定的AC与肺癌风险相关这一假说，我们对68例新诊断的未经治疗的肺癌患者和74例无癌对照者进行了一项病例对照试点研究。我们通过使用末端脱氧尿苷三磷酸核苷酸末端标记法和流式细胞术，测量了他们培养的外周血淋巴细胞在体外暴露于一种最终烟草致癌物苯并[a]芘二醇环氧化物（BPDE）后的AC。我们还通过聚合酶链反应-限制性片段长度多态性分析，研究了参与控制凋亡途径的基因Fas中-A670G多态性的频率。在将细胞暴露于4μM BPDE 5小时后，我们观察到肺癌患者的AC（155.2±143.9%）显著低于对照组（216.6±184.6%）（P<0.05）。在逻辑回归模型中，校正年龄、性别族裔、吸烟状况和凋亡基线后，低AC是肺癌的独立危险因素（校正比值比（OR）=2.69，95%置信区间（CI）=1.18 - 6.15）。虽然Fas -A670G多态性不是肺癌的独立危险因素，但它似乎可调节风险。Fas -670 AG和GG基因型者中，与较低AC相关的肺癌风险校正OR为4.00（95%CI=1.48 - 10.80），Fas -670AA基因型者中为0.97（95%CI=0.18 - 5.30）。这些数据表明，凋亡途径的改变可能是肺癌的一个危险因素，且这种风险可能受Fas -A670G多态性的调节。需要更大规模的前瞻性研究来验证这些发现。
