This Article Full Text Full Text (PDF) Supplementary Data All Versions of this Article: 0008-5472.CAN-09-0028v1 69/10/4112    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Jin, Z. Articles by Meltzer, S. J. Search for Related Content PubMed PubMed Citation Articles by Jin, Z. Articles by Meltzer, S. J.

A Multicenter, Double-Blinded Validation Study of Methylation Biomarkers for Progression Prediction in Barrett's Esophagus

¹ Gastroenterology Division, Johns Hopkins University, Baltimore, Maryland; ² Biostatistics Department, Fred Hutchinson Cancer Center, Seattle, Washington; ³ Gastroenterology Division, Mayo Clinic, Jacksonville, Florida; ⁴ Gastroenterology Division, University of North Carolina, Chapel Hill, North Carolina; ⁵ Pathology Department, Vanderbilt University, Nashville, Tennessee; ⁶ Pathology Department and ⁷ Gastroenterology Division, University of Arizona-SAVAHCS, Tucson, Arizona; ⁸ Early Detection Research Network, Bethesda, Maryland; ⁹ Gastroenterology Division, Mayo Clinic, Rochester, New York

Requests for reprints: Stephen J. Meltzer, Gastroenterology Division, Johns Hopkins University, 1503 East Jefferson Street, Baltimore, MD 21287. Phone: 410-502-6071; E-mail: smeltzer{at}jhmi.edu or Richard E. Sampliner, Gastroenterology Division, Southern Arizona VA HealthCare System, Tucson, AZ. Phone: 85723-0001; Fax: 520-792-1450; E-mail: samplinr{at}email.arizona.edu.

Key Words: Barrett esophagus • biomarker • esophageal adenocarcinoma

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 (-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. [Cancer Res 2009;69(10):4112–5]