Cell cycle checkpoints, DNA damage/repair, and lung cancer risk.
Cell cycle checkpoints, DNA damage/repair, and lung cancer risk.
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DOI：
10.1158/0008-5472.349.65.1
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发表时间：
2005-01
期刊：
影响因子：
11.2
通讯作者：
Xifeng Wu;J. Roth;Hua Zhao;S. Luo;Yun-Ling Zheng;Silvia S Chiang;M. Spitz
中科院分区：
文献类型：
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作者：
Xifeng Wu;J. Roth;Hua Zhao;S. Luo;Yun-Ling Zheng;Silvia S Chiang;M. Spitz
鉴于细胞周期控制和 DNA 修复能力的缺陷可能导致肿瘤发生，我们假设肺癌患者比健康对照更有可能表现出细胞周期检查点和/或 DNA 修复能力的缺陷（通过细胞对体外致癌物暴露的反应来衡量）。在一项正在进行的病例对照研究中，我们对 155 名新诊断的肺癌患者和 153 名健康对照进行了研究，我们使用彗星试验来研究细胞周期检查点和 DNA 损伤/修复能力在肺肿瘤发生中的作用。伽玛辐射诱导和苯并(a)芘二醇环氧化物诱导的Olive尾矩中值（测量DNA损伤的彗星试验参数）在病例组中显着高于对照组（分别为5.31和4.22）（分别为4.42和2.83；P < 0.001）。伽玛辐射和苯并(a)芘二醇环氧化物诱导的彗星的较高尾矩分别与肺癌风险升高2.32倍和4.49倍显着相关。病例中伽马辐射诱导的 S 期和 G(2) 期细胞增加中位数（分别为 22.2% 和 12.2%）显着低于对照组（分别为 31.1% 和 14.9%；P < 0.001）。 S 期和 G(2) 期持续时间越短，患肺癌的风险分别增加 4.54 倍和 1.85 倍。还观察到伽马辐射引起的 S 和 G(2) 相频率增加与诱变剂引起的彗星之间的联合效应。此外，我们发现在对照组中，S 期随着尾矩的增加而减少。这项研究意义重大，因为它提供了第一个分子流行病学证据，将细胞周期检查点和 DNA 损伤/修复能力的缺陷与肺癌风险升高联系起来。
Given that defects in cell cycle control and DNA repair capacity may contribute to tumorigenesis, we hypothesized that patients with lung cancer would be more likely than healthy controls to exhibit deficiencies in cell cycle checkpoints and/or DNA repair capacity as gauged by cellular response to in vitro carcinogen exposure. In an ongoing case-control study of 155 patients with newly diagnosed lung cancer and 153 healthy controls, we used the comet assay to investigate the roles of cell cycle checkpoints and DNA damage/repair capability in lung tumorigenesis. The median gamma-radiation-induced and benzo(a)pyrene diol epoxide-induced Olive tail moments, the comet assay parameter for measuring DNA damage, were significantly higher in the case group (5.31 and 4.22, respectively) than in the control group (4.42 and 2.83, respectively; P < 0.001). Higher tail moments of gamma-radiation and benzo(a)pyrene diol epoxide-induced comets were significantly associated with 2.32- and 4.49-fold elevated risks, respectively, of lung cancer. The median gamma-radiation-induced increases of cells in the S and G(2) phases were significantly lower in cases (22.2% and 12.2%, respectively) than in controls (31.1% and 14.9%, respectively; P < 0.001). Shorter durations of the S and G(2) phases resulted in 4.54- and 1.85-fold increased risks, respectively, of lung cancer. Also observed were joint effects between gamma-radiation-induced increases of S and G(2) phase frequencies and mutagen-induced comets. In addition, we found that in controls, the S phase decreased as tail moment increased. This study is significant because it provides the first molecular epidemiologic evidence linking defects in cell cycle checkpoints and DNA damage/repair capacity to elevated lung cancer risk.