title: Early Detection of Lung Cancer Using DNA Promoter Hypermethylation in Plasma and Sputum.
abstract: 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, andZFP42).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.
authors.affiliation: Sidney Kimmel Cancer Center, Department of Oncology, The Johns Hopkins University School of Medicine, Baltimore, Maryland.|Department of Surgery, The Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors.forename: Alicia
authors.initials: A
authors.lastname: Hulbert
authors.affiliation: Department of Neurosurgery, The Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors.forename: Ignacio
authors.initials: I
authors.lastname: Jusue-Torres
authors.affiliation: Department of Mechanical Engineering, The Johns Hopkins University, Baltimore, Maryland.
authors.forename: Alejandro
authors.initials: A
authors.lastname: Stark
authors.affiliation: Sidney Kimmel Cancer Center, Department of Oncology, The Johns Hopkins University School of Medicine, Baltimore, Maryland.|Department of Thoracic Surgery, Second Xiangya Hospital of Central South University, Changsha, Hunan, PR China.
authors.forename: Chen
authors.initials: C
authors.lastname: Chen
authors.affiliation: Department of Surgery, The Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors.forename: Kristen
authors.initials: K
authors.lastname: Rodgers
authors.affiliation: Department of Surgery, The Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors.forename: Beverly
authors.initials: B
authors.lastname: Lee
authors.affiliation: Department of Surgery, The Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors.forename: Candace
authors.initials: C
authors.lastname: Griffin
authors.affiliation: Department of Surgery, The Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors.forename: Andrew
authors.initials: A
authors.lastname: Yang
authors.affiliation: Sidney Kimmel Cancer Center, Department of Oncology, The Johns Hopkins University School of Medicine, Baltimore, Maryland.|Department of Biostatistics, The Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland.
authors.forename: Peng
authors.initials: P
authors.lastname: Huang
authors.affiliation: Department of Medicine, Medical University of South Carolina, Charleston, South Carolina.
authors.forename: John
authors.initials: J
authors.lastname: Wrangle
authors.affiliation: Lung Cancer Program, Lovelace Respiratory Research Institute, Albuquerque, New Mexico.
authors.forename: Steven A
authors.initials: SA
authors.lastname: Belinsky
authors.affiliation: Sidney Kimmel Cancer Center, Department of Oncology, The Johns Hopkins University School of Medicine, Baltimore, Maryland.|Department of Mechanical Engineering, The Johns Hopkins University, Baltimore, Maryland.|Department of Biomedical Engineering and Institute for NanoBioTechnology, The Johns Hopkins University, School of Medicine, Baltimore, Maryland.
authors.forename: Tza-Huei
authors.initials: TH
authors.lastname: Wang
authors.affiliation: Department of Surgery, The Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors.forename: Stephen C
authors.initials: SC
authors.lastname: Yang
authors.affiliation: Sidney Kimmel Cancer Center, Department of Oncology, The Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors.forename: Stephen B
authors.initials: SB
authors.lastname: Baylin
authors.affiliation: Sidney Kimmel Cancer Center, Department of Oncology, The Johns Hopkins University School of Medicine, Baltimore, Maryland.|Department of Surgery, The Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors.forename: Malcolm V
authors.initials: MV
authors.lastname: Brock
authors.affiliation: Sidney Kimmel Cancer Center, Department of Oncology, The Johns Hopkins University School of Medicine, Baltimore, Maryland. hermanj3@upmc.edu.|Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania.
authors.forename: James G
authors.initials: JG
authors.lastname: Herman
mesh_terms: D000368:Aged; D019540:Area Under Curve; D014408:Biomarkers, Tumor / Q000032:analysis / Q000235:genetics*; D002289:Carcinoma, Non-Small-Cell Lung / Q000097:blood / Q000175:diagnosis* / Q000235:genetics; D016022:Case-Control Studies; D004247:DNA / Q000032:analysis*; D019175:DNA Methylation / Q000235:genetics; D055088:Early Detection of Cancer / Q000379:methods*; D005260:Female; D020869:Gene Expression Profiling / Q000379:methods; D006801:Humans; D008175:Lung Neoplasms / Q000097:blood / Q000175:diagnosis* / Q000235:genetics; D008297:Male; D008875:Middle Aged; D011401:Promoter Regions, Genetic / Q000235:genetics; D012372:ROC Curve; D060888:Real-Time Polymerase Chain Reaction; D012680:Sensitivity and Specificity; D013183:Sputum / Q000737:chemistry; D059467:Transcriptome
chemical_list: D014408:Biomarkers, Tumor; D004247:DNA