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Less Efficient G₂-M Checkpoint Is Associated with an Increased Risk of Lung Cancer in African Americans

¹ Laboratory of Human Carcinogenesis, National Cancer Institute, Bethesda, Maryland; ² Cancer Genetics and Epidemiology Program, Georgetown University, Washington, District of Columbia; Departments of ³ Epidemiology and ⁴ Pulmonary Medicine, Johns Hopkins Medical Institutions; and ⁵ Department of Pathology and Surgery, Greenebaum Cancer Center, University of Maryland School of Medicine, Baltimore, Maryland

Requests for reprints: Curtis C. Harris, Laboratory of Human Carcinogenesis, Center For Cancer Research, National Cancer Institute, 37 Convent Drive, Building 37, Room 3068, Bethesda, MD 20892-4255. Phone: 301-496-2048; Fax: 301-496-0497; E-mail: curtis_harris{at}nih.gov.

Cell cycle checkpoints play critical roles in the maintenance of genomic integrity. The inactivation of checkpoint genes by genetic and epigenetic mechanisms is frequent in all cancer types, as a less-efficient cell cycle control can lead to genetic instability and tumorigenesis. In an on-going case-control study consisting of 216 patients with non–small cell lung cancer, 226 population-based controls, and 114 hospital-based controls, we investigated the relationship of -radiation-induced G₂-M arrest and lung cancer risk. Peripheral blood lymphocytes were cultured for 90 hours, exposed to 1.0 Gy -radiation, and harvested at 3 hours after -radiation treatment. -Radiation-induced G₂-M arrest was measured as the percentage of mitotic cells in untreated cultures minus the percentage of mitotic cells in -radiation-treated cultures from the same subject. The mean percentage of -radiation-induced G₂-M arrest was significantly lower in cases than in population controls (1.18 versus 1.44, P < 0.01) and hospital controls (1.18 versus 1.40, P = 0.01). When dichotomized at the 50th percentile value in combined controls (population and hospital controls), a lower level of -radiation-induced G₂-M arrest was associated with an increased risk of lung cancer among African Americans after adjusting for baseline mitotic index, age, gender, and pack-years of smoking [adjusted odd ratio (OR), 2.25; 95% confidence interval (95% CI), 0.97-5.20]. A significant trend of an increased risk of lung cancer with a decreased level of G₂-M arrest was observed (P_trend = 0.02) among African Americans, with a lowest-versus-highest quartile adjusted OR of 3.74 (95% CI, 0.98-14.3). This trend was most apparent among African American females (P_trend < 0.01), with a lowest-versus-highest quartile adjusted OR of 11.75 (95% CI, 1.47-94.04). The results suggest that a less-efficient DNA damage–induced G₂-M checkpoint is associated with an increased risk of lung cancer among African Americans. Interestingly, we observed a stronger association of DNA damage–induced G₂-M arrest and lung cancer among African Americans when compared with Caucasians. If replicated, these results may provide clues to the exceedingly high lung cancer incidence experienced by African Americans.

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