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Cell Cycle Checkpoints, DNA Damage/Repair, and Lung Cancer Risk

Departments of ¹ Epidemiology and ² Thoracic & Cardiovascular Surgery, University of Texas M.D. Anderson Cancer Center, Houston, Texas and ³ Cancer Genetics and Epidemiology Program, Lombardi Cancer Center, Georgetown University Medical Center, Washington, District of Columbia, USA

Requests for reprints: Xifeng Wu, Department of Epidemiology, Box 189, University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030. Phone: 713-745-2485; Fax: 713-792-0807; E-mail: xwu{at}mdanderson.org

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 -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 -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 -radiation-induced increases of cells in the S and G₂ 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 G₂ phases resulted in 4.54- and 1.85-fold increased risks, respectively, of lung cancer. Also observed were joint effects between -radiation-induced increases of S and G₂ 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.

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