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Pattern of Antioxidant and DNA Repair Gene Expression in Normal Airway Epithelium Associated with Lung Cancer Diagnosis

¹ Departments of Medicine and Pathology, University of Toledo Medical Center, Toledo, Ohio; ² Innovative Analytics, Kalamazoo, Michigan; and ³ Gene Express, Inc., Wilmington, North Carolina

Requests for reprints: James C. Willey, University of Toledo Health Sciences Campus, Room 0012, Ruppert Building, 3000 Arlington Avenue, Toledo, OH 43614. Phone: 419-383-3541; Fax: 419-383-6244; E-mail: james.willey2{at}utoledo.edu.

In previous studies, we reported that key antioxidant and DNA repair genes are regulated differently in normal bronchial epithelial cells of lung cancer cases compared with non–lung cancer controls. In an effort to develop a biomarker for lung cancer risk, we evaluated the transcript expressions of 14 antioxidant, DNA repair, and transcription factor genes in normal bronchial epithelial cells (HUGO names CAT, CEBPG, E2F1, ERCC4, ERCC5, GPX1, GPX3, GSTM3, GSTP1, GSTT1, GSTZ1, MGST1, SOD1, and XRCC1). A test comprising these 14 genes accurately identified the lung cancer cases in two case-control studies. The receiver operating characteristic–area under the curve was 0.82 (95% confidence intervals, 0.68–0.91) for the first case-control set (25 lung cancer cases and 24 controls), and 0.87 (95% confidence intervals, 0.73–0.96) for the second set (18 cases and 22 controls). For each gene included in the test, the key difference between cases and controls was altered distribution of transcript expression among cancer cases compared with controls, with more lung cancer cases expressing at both extremes among all genes (Kolmorogov-Smirnov test, D = 0.0795; P = 0.041). A novel statistical approach was used to identify the lower and upper boundaries of transcript expression that optimally classifies cases and controls for each gene. Based on the data presented here, there is an increased prevalence of lung cancer diagnosis among individuals that express a threshold number of key antioxidant, DNA repair, and transcription factor genes at either very high or very low levels in the normal airway epithelium. [Cancer Res 2009;69(22):8629–35]

Key Words: Lung cancer risk • biomarker • DNA repair • bronchial epithelial cells • airway epithelial cells