title: Less efficient g2-m checkpoint is associated with an increased risk of lung cancer in African Americans.
abstract: 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 gamma-radiation-induced G2-M arrest and lung cancer risk. Peripheral blood lymphocytes were cultured for 90 hours, exposed to 1.0 Gy gamma-radiation, and harvested at 3 hours after gamma-radiation treatment. gamma-Radiation-induced G2-M arrest was measured as the percentage of mitotic cells in untreated cultures minus the percentage of mitotic cells in gamma-radiation-treated cultures from the same subject. The mean percentage of gamma-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 gamma-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.
authors.affiliation: Laboratory of Human Carcinogenesis, National Cancer Institute, Bethesda, MD 20892-4255, USA.
authors.forename: Yun-Ling
authors.initials: YL
authors.lastname: Zheng
authors.forename: Christopher A
authors.initials: CA
authors.lastname: Loffredo
authors.forename: Anthony J
authors.initials: AJ
authors.lastname: Alberg
authors.forename: Zhipeng
authors.initials: Z
authors.lastname: Yu
authors.forename: Raymond T
authors.initials: RT
authors.lastname: Jones
authors.forename: Donna
authors.initials: D
authors.lastname: Perlmutter
authors.forename: Lindsey
authors.initials: L
authors.lastname: Enewold
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Krasna
authors.forename: Rex
authors.initials: R
authors.lastname: Yung
authors.forename: Peter G
authors.initials: PG
authors.lastname: Shields
authors.forename: Curtis C
authors.initials: CC
authors.lastname: Harris
mesh_terms: D001741:Black or African American; D000368:Aged; D044383:Black People; D002289:Carcinoma, Non-Small-Cell Lung / Q000097:blood / Q000235:genetics / Q000473:pathology*; D016022:Case-Control Studies; D002455:Cell Division / Q000235:genetics / Q000528:radiation effects*; D004307:Dose-Response Relationship, Radiation; D005260:Female; D016195:G2 Phase / Q000235:genetics / Q000528:radiation effects*; D005720:Gamma Rays; D006801:Humans; D008175:Lung Neoplasms / Q000097:blood / Q000235:genetics / Q000473:pathology*; D008214:Lymphocytes / Q000166:cytology / Q000528:radiation effects; D008297:Male; D008875:Middle Aged; D012307:Risk Factors