OBJECTIVES:Prediction of progression to cancer in patients with Barrett's esophagus (BE) is difficult using current techniques. We determined whether DNA promoter hypermethylation of genes frequently methylated in esophageal adenocarcinoma (p16 and APC) could be used as predictors of progression in BE.METHODS:We first performed a cross-sectional study to evaluate the prevalence of gene hypermethylation in biopsies from patients with normal esophagus (n17), BE (n102), and adenocarcinoma (n42). We then performed a nested case-control study comparing gene hypermethylation in BE patients who progressed from baseline pathology to high-grade dysplasia or cancer (n7) vs. patients who did not progress (n50).RESULTS:None of the patients with normal esophagus had p16 or APC hypermethylation. Hypermethylation was prevalent in BE without dysplasia or low-grade dysplasia (p1631% and APC50%; P0.01) and high-grade dysplasia or adenocarcinoma (p1654% and APC68%; P0.001) compared with normal esophagus (not detected). Patients who progressed from baseline pathology to high-grade dysplasia or cancer had higher prevalence of hypermethylation in their initial esophagus biopsies compared with those who did not progress for both p16 (100 vs. 33%; P0.008) and APC (86 vs. 40%; P0.02). Hypermethylation of both p16 and APC was a strong predictor of subsequent progression to high-grade dysplasia or cancer during a mean follow-up time of 4.1 years (odds ratio (95% confidence interval)14.97 (1.73,inf), P0.01). Among patients who were negative for both p16 and APC hypermethylation, none progressed from baseline pathology to high-grade dysplasia or cancer.CONCLUSIONS:Hypermethylation of both p16 and APC strongly predicts progression to high-grade dysplasia or cancer in patients with BE. Absence of p16 and APC hypermethylation is associated with a benign course.