A multicenter, double-blinded validation study of methylation biomarkers for progression prediction in Barrett's esophagus.

Publication Type:

Journal Article

Source:

Cancer research, Volume 69, Issue 10, p.4112-5 (2009)

Keywords:

2009, Age Factors, Barrett Esophagus, Biological Markers, Core Binding Factor Alpha 3 Subunit, DISEASE PROGRESSION, Double-Blind Method, Endoscopy, Esophageal Neoplasms, Gene Expression Regulation, Gene Expression Regulation, Neoplastic, Humans, Membrane Proteins, Neoplasm Proteins, Polymerase Chain Reaction, Predictive Value of Tests, Promoter Regions, Genetic, Public Health Sciences Division, Reproducibility of Results, Risk Assessment, ROC Curve, Shared Resources

Abstract:

Esophageal adenocarcinoma risk in Barrett's esophagus (BE) is increased 30- to 125-fold versus the general population. Among all BE patients, however, neoplastic progression occurs only once per 200 patient-years. Molecular biomarkers are therefore needed to risk-stratify patients for more efficient surveillance endoscopy and to improve the early detection of progression. We therefore performed a retrospective, multicenter, double-blinded validation study of eight BE progression prediction methylation biomarkers. Progression or nonprogression were determined at 2 years (tier 1) and 4 years (tier 2). Methylation was assayed in 145 nonprogressors and 50 progressors using real-time quantitative methylation-specific PCR. Progressors were significantly older than nonprogressors (70.6 versus 62.5 years; P < 0.001). We evaluated a linear combination of the eight markers, using coefficients from a multivariate logistic regression analysis. Areas under the ROC curve (AUC) were high in the 2-year, 4-year, and combined data models (0.843, 0.829, and 0.840; P < 0.001, <0.001, and <0.001, respectively). In addition, even after rigorous overfitting correction, the incremental AUCs contributed by panels based on the 8 markers plus age versus age alone were substantial (Delta-AUC = 0.152, 0.114, and 0.118, respectively) in all 3 models. A methylation biomarker-based panel to predict neoplastic progression in BE has potential clinical value in improving both the efficiency of surveillance endoscopy and the early detection of neoplasia.