Deficient G₂-M and S Checkpoints are Associated with Increased Lung Cancer Risk: A Case-Control Analysis

Abstract

Loss or attenuation of cell cycle checkpoint function can compromise the fidelity of DNA due to insufficient time to repair DNA damage. We evaluated cell cycle checkpoints in 747 patients with lung cancer and 745 controls by measuring the proportions of cultured peripheral blood lymphocytes in G₂-M and S phases. As an indicator of G₂-M phase or S phase cell cycle checkpoint function, the γ-radiation–induced cell accumulation index at G₂-M or S phase was defined as (percentage of cells in G₂-M or S with ionizing radiation exposure − percentage of cells in G₂-M or S without ionizing radiation exposure) / (percentage of cells in G₂-M or S without ionizing radiation exposure). We found that the median cell accumulation index was significantly lower in patients than that in controls at both the G₂-M phase (0.774 versus 0.882, P = 0.002) and the S phase (0.226 versus 0.243, P = 0.001). When the median value for the cell accumulation index at the G₂-M or S phase in the controls was used as the cutoff point, the reduced indices at G₂-M and S phases were associated with 1.28-fold (95% confidence interval, 1.04-1.58) and 1.30-fold (95% confidence interval, 1.06-1.61) increased lung cancer risks, respectively. Analyses stratified by histology showed some heterogeneity. Additionally, cell accumulation indices at both G₂-M and S phases were not associated with clinical stages. We conclude that attenuated functions of G₂-M and S cell cycle checkpoints might be susceptibility markers for lung cancer. (Cancer Epidemiol Biomarkers Prev 2007;6(7):1517–22)