Abstract
control study of eight methylation biomarkers in BE. Progressors (Ps) were defined as BE patients with index biopsies showing no dysplasia, indefinite for dysplasia, or low-grade dysplasia (LGD) at endoscopy performed ≥6 months prior to a diagnosis of either highgrade dysplasia or EAC. Nonprogressors (NPs) were defined as patients undergoing at least 3 surveillance endoscopic examinations who never progressed beyond LGD. Ps were considered as a single combined group and in two tiers: progression within 2 years or 4 years. Methylation was assessed in 145 NPs and 50 Ps using real-time quantitative methylation-specific PCR. RESULTS: Ps were significantly older than NPs (70.6 vs. 62.5 years, p < 0.001). Normalized methylation values of HPP1, p16 and RUNX3 were significantly higher in Ps than in NPs (0.456, 0.138, and 0.104 vs. 0.273, 0.069 and 0.063; p = 0.0025, 0.0066 and 0.0002, respectively). We also evaluated a linear combination of the 8 markers using coefficients from a multivariate logistic regression analysis. Based on this model, areas under the ROC curve (AUCs) were high in the 2-year, 4-year and combined models (0.843, 0.829 and 0.840; p<0.001, respectively). Even after rigorous correction for potential overfitting, incremental AUCs in panels consisting of the eight markers plus age vs. age alone were large (delta-AUC = 0.152, 0.114 and 0.118, respectively) in all three models. With specificity at 0.9 or 0.8, sensitivities (0.443 and 0.629 for the combined model, 0.607 and 0.721 for the 2-year model, and 0.465 and 0.606 for the 4-year model, respectively) exceeded or approached 50% in all three models based on the 8-marker panel alone. Furthermore, at 0.9 or 0.8 specificities, sensitivities (0.457 and 0.757 for the combined model, 0.536 and 0.786 for the 2-year model, and 0.450 and 0.724 for the 4-year model, respectively) exceeded or approached 50% in all three models based on the 8-marker-plus-age panel. CONCLUSIONS: A methylation biomarker-based panel to stratify progression risk in BE patients has the potential to improve both efficacy of surveillance endoscopy and early detection of neoplasia.
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