A lung cancer risk classifier comprising genome maintenance genes measured in normal bronchial epithelial cells

• Published in: BMC cancer 2017-05, Vol.17 (1), p.301-301, Article 301
• Main Authors: Yeo, Jiyoun, Crawford, Erin L, Zhang, Xiaolu, Khuder, Sadik, Chen, Tian, Levin, Albert, Blomquist, Thomas M, Willey, James C
• Format: Article
• Language: English
• Subjects: Adenocarcinoma; Amino acids; Animal models; Antioxidants - analysis; Antioxidants - metabolism; Asbestos; Basal cells; Biomarkers; Biomarkers, Tumor - analysis; Biomarkers, Tumor - genetics; Biomarkers, Tumor - metabolism; Biopsy; Bronchi - cytology; Bronchi - metabolism; Bronchoscopy; Bronchus; c-Myc protein; Cancer screening; Carcinogenesis; Cell cycle; Cigarette smoke; Colon; Computed tomography; Cytology; Deoxyribonucleic acid; DNA; DNA repair; Epithelial Cells - cytology; Epithelial Cells - metabolism; Epithelium; Gene expression; Gene regulation; Genome maintenance; Genomes; Genomics; Humans; Low dose helical CT screening; Lung cancer; Lung cancer risk; Lung cancer risk test biomarker; Lung cancer screening; Lung Neoplasms - diagnosis; Lung Neoplasms - epidemiology; Lung Neoplasms - genetics; Lung Neoplasms - metabolism; Medical screening; Metabolism; Methods; Mutation; Polymerase Chain Reaction; Reproducibility of Results; Respiratory tract; Retrospective Studies; Ribonucleic acid; Risk Assessment; RNA; ROC Curve; Smoking; Stem cells; Studies; Tomography, Spiral Computed
• ISSN: 1471-2407; 1471-2407
• DOI: 10.1186/s12885-017-3287-4

Annual low dose CT (LDCT) screening of individuals at high demographic risk reduces lung cancer mortality by more than 20%. However, subjects selected for screening based on demographic criteria typically have less than a 10% lifetime risk for lung cancer. Thus, there is need for a biomarker that better stratifies subjects for LDCT screening. Toward this goal, we previously reported a lung cancer risk test (LCRT) biomarker comprising 14 genome-maintenance (GM) pathway genes measured in normal bronchial epithelial cells (NBEC) that accurately classified cancer (CA) from non-cancer (NC) subjects. The primary goal of the studies reported here was to optimize the LCRT biomarker for high specificity and ease of clinical implementation. Targeted competitive multiplex PCR amplicon libraries were prepared for next generation sequencing (NGS) analysis of transcript abundance at 68 sites among 33 GM target genes in NBEC specimens collected from a retrospective cohort of 120 subjects, including 61 CA cases and 59 NC controls. Genes were selected for analysis based on contribution to the previously reported LCRT biomarker and/or prior evidence for association with lung cancer risk. Linear discriminant analysis was used to identify the most accurate classifier suitable to stratify subjects for screening. After cross-validation, a model comprising expression values from 12 genes (CDKN1A, E2F1, ERCC1, ERCC4, ERCC5, GPX1, GSTP1, KEAP1, RB1, TP53, TP63, and XRCC1) and demographic factors age, gender, and pack-years smoking, had Receiver Operator Characteristic area under the curve (ROC AUC) of 0.975 (95% CI: 0.96-0.99). The overall classification accuracy was 93% (95% CI 88%-98%) with sensitivity 93.1%, specificity 92.9%, positive predictive value 93.1% and negative predictive value 93%. The ROC AUC for this classifier was significantly better (p