CpG-Island Methylator Phenotype (CIMP) and Alterations in RAS-Raf Signaling in Hereditaty Non-Polyposis Colorectal Cancers Without Mismatch Repair Deficiency (MSS HNPCC)

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.