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

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.

• Authors: Zhe Jin, Yulan Cheng, Wen Gu, Yingye Zheng, Fumiaki Sato, Yuriko Mori, Alexandru V Olaru, Bogdan C Paun, Jian Yang, Takatsugu Kan, Tetsuo Ito, James P Hamilton, Florin M Selaru, Rachana Agarwal, Stefan David, John M Abraham, Herbert C Wolfsen, Michael B Wallace, Nicholas J Shaheen, Kay Washington, Jean Wang, Marcia Irene Canto, Achyut Bhattacharyya, Mark A Nelson, Paul D Wagner, Yvonne Romero, Kenneth K Wang, Ziding Feng, Richard E Sampliner, Stephen J Meltzer
• Journal: Cancer research (Cancer Res) Vol. 69 Issue 10 Pg. 4112-5 (May 15 2009) ISSN: 1538-7445 [Electronic] United States
• PMID: 19435894 (Publication Type: Journal Article, Multicenter Study, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Biomarkers
• CDKN2A protein, human
• Core Binding Factor Alpha 3 Subunit
• Cyclin-Dependent Kinase Inhibitor p16
• Membrane Proteins
• Neoplasm Proteins
• Runx3 protein, human
• TMEFF2 protein, human

Topics

• Age Factors
• Barrett Esophagus (pathology, physiopathology)
• Biomarkers (blood, metabolism)
• Core Binding Factor Alpha 3 Subunit (genetics)
• Cyclin-Dependent Kinase Inhibitor p16
• Disease Progression
• Double-Blind Method
• Endoscopy
• Esophageal Neoplasms (epidemiology, pathology)
• Gene Expression Regulation
• Gene Expression Regulation, Neoplastic
• Humans
• Membrane Proteins (genetics)
• Neoplasm Proteins (genetics)
• Polymerase Chain Reaction
• Predictive Value of Tests
• Promoter Regions, Genetic
• ROC Curve
• Reproducibility of Results
• Risk Assessment