Early Detection of Lung Cancer Using DNA Promoter Hypermethylation in Plasma and Sputum

• Published in: Clinical cancer research Vol. 23; no. 8; pp. 1998 - 2005
• Main Authors: Hulbert, Alicia, Jusue-Torres, Ignacio, Stark, Alejandro, Chen, Chen, Rodgers, Kristen, Lee, Beverly, Griffin, Candace, Yang, Andrew, Huang, Peng, Wrangle, John, Belinsky, Steven A., Wang, Tza-Huei, Yang, Stephen C., Baylin, Stephen B., Brock, Malcolm V., Herman, James G.
• Format: Journal Article
• Language: English
• Published: United States American Association for Cancer Research Inc 15.04.2017
• Subjects: Aged; Area Under Curve; Beads; Biomarkers, Tumor - analysis; Biomarkers, Tumor - genetics; Cancer; Cancer screening; Carcinoma, Non-Small-Cell Lung - blood; Carcinoma, Non-Small-Cell Lung - diagnosis; Carcinoma, Non-Small-Cell Lung - genetics; Case-Control Studies; Computed tomography; Confidence intervals; Deoxyribonucleic acid; Diagnostic systems; DNA; DNA - analysis; DNA methylation; DNA Methylation - genetics; Early Detection of Cancer - methods; Experimental design; Female; Gene Expression Profiling - methods; Genes; Humans; Lung cancer; Lung Neoplasms - blood; Lung Neoplasms - diagnosis; Lung Neoplasms - genetics; Male; Medical screening; Middle Aged; Nodules; Plasma; Prediction models; Promoter Regions, Genetic - genetics; Real-Time Polymerase Chain Reaction; ROC Curve; Sensitivity; Sensitivity and Specificity; Sputum; Sputum - chemistry; Transcriptome
• ISSN: 1078-0432; 1557-3265
• DOI: 10.1158/1078-0432.CCR-16-1371

Purpose: CT screening can reduce death from lung cancer. We sought to improve the diagnostic accuracy of lung cancer screening using ultrasensitive methods and a lung cancer–specific gene panel to detect DNA methylation in sputum and plasma. Experimental Design: This is a case–control study of subjects with suspicious nodules on CT imaging. Plasma and sputum were obtained preoperatively. Cases (n = 150) had pathologic confirmation of node-negative (stages I and IIA) non–small cell lung cancer. Controls (n = 60) had non-cancer diagnoses. We detected promoter methylation using quantitative methylation-specific real-time PCR and methylation-on-beads for cancer-specific genes (SOX17, TAC1, HOXA7, CDO1, HOXA9, and ZFP42). Results: DNA methylation was detected in plasma and sputum more frequently in people with cancer compared with controls (P < 0.001) for five of six genes. The sensitivity and specificity for lung cancer diagnosis using the best individual genes was 63% to 86% and 75% to 92% in sputum, respectively, and 65% to 76% and 74% to 84% in plasma, respectively. A three-gene combination of the best individual genes has sensitivity and specificity of 98% and 71% using sputum and 93% and 62% using plasma. Area under the receiver operating curve for this panel was 0.89 [95% confidence interval (CI), 0.80–0.98] in sputum and 0.77 (95% CI, 0.68–0.86) in plasma. Independent blinded random forest prediction models combining gene methylation with clinical information correctly predicted lung cancer in 91% of subjects using sputum detection and 85% of subjects using plasma detection. Conclusions: High diagnostic accuracy for early-stage lung cancer can be obtained using methylated promoter detection in sputum or plasma. Clin Cancer Res; 23(8); 1998–2005. ©2016 AACR.