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 methylationspecific 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 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]

Molecular Pathways: Involvement of Helicobacter pylori–Triggered Inflammation in the Formation of an Epigenetic Field Defect, and Its Usefulness as Cancer Risk and Exposure Markers

“…A quantitative analysis revealed increased methylation of multiple tumor-suppressor genes, such as SOCS1, RASSF1A, and CDH1, in HCVinfected, noncancerous liver tissues (32), suggesting the importance of an epigenetic field for HCV-associated hepatocarcinogenesis. In the case of esophageal adenocarcinoma, the presence of APC and CDKN2A methylation in Barrett's metaplasia has been reported (33), and such methylation was shown to be associated with progression of Barrett's metaplasia (34). Also in the case of esophageal squamous cell carcinoma, methylation of specific genes, such as UCHL1 and HOXA9, in esophageal mucosae was associated with the risk of developing esophageal squamous cell carcinoma (35,36).…”

“…Therefore, investigators are now developing methods to estimate epigenetic cancer risk, taking life history into account, in various types of cancer. For example, a multicenter study was conducted to evaluate the validity of methylation markers to predict progression of Barrett's esophagus, and methylation of HPP1, CDKN2A, and RUNX3 were shown to be informative (34).…”

Early Diagnostic Biomarkers for Esophageal Adenocarcinoma—The Current State of Play

“…In the majority of patients, methylation changes are acquired very early during EAC development, hence these alterations could be used as an early diagnostic biomarker. Apart from discriminating patients at different stages of EAC development, DNA methylation signatures may be useful as predictors for progression from Barrett's esophagus to EAC (43,44) and for response to chemotherapy and survival in patients with EAC (45,46).…”

Differentiation and adaptation epigenetic networks: Translational research in gastric carcinogenesis

“…We have proven that methylation of p16, the G1→S conversion checkpoint gene in the cell cycle, is a powerful biomarker for predicting malignant transformation of epithelial dysplasia [5,6]. This has been consistently confirmed by a number of independent studies in different countries [7][8][9]. Recently, we have developed a p16-specific probe-based quantitative MethyLight assay for the development of a p16 methylation diagnosis kit [10].…”