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

Abstract

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 characteristicarea 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]

p53-induced Gene 3 Mediates Cell Death Induced by Glutathione Peroxidase 3

“…However, increasing evidence suggests that GPx3 also possesses tumor suppressor activity (5,9,(22)(23)(24)(25)(26)(27)(28)(29). In this study, GPx3 carries out tumor suppressor signaling at least partly through the activation of PIG3, which is a protein associated with the generation of ROS that induces cell death.…”

Transcriptomic Studies of the Airway Field of Injury Associated with Smoking-Related Lung Disease

“…This biomarker improves diagnostic accuracy when combined with traditional diagnostic bronchoscopy (16), and is independent of clinical factors as a diagnostic risk factor (17). The concept that gene expression in normal airway epithelium can be used as a biomarker of lung cancer was also used by Blomquist and colleagues to identify 14 genes (including antioxidant and DNA repair genes) whose expression was altered in brushings of normal bronchial epithelium of patients with lung cancer versus those without lung cancer (18).…”

Translating the transcriptome into tools for the early detection and prevention of lung cancer: Figure 1

“…This approach is based on the paradigm that the airway gene expression response to smoking reflects a gene-by-environment interaction that could identify that subset of smokers that are at highest risk for future lung cancer development. As proof of concept, Blomquist et al 35 found that variability in the expression level of 14 antioxidant and DNA repair genes in the cytologically normal bronchial epithelium could distinguish smokers with and without lung cancer, with an area under the curve of 0.87 in an independent cross-sectional cohort of 40 patients. While these findings suggest that an aberrant airway gene expression response to smoking associates with lung cancer, these studies have yet to be conducted in prospective studies of high-risk smokers where airway gene expression changes are observed prior to lung cancer development.…”