Introduction Prediction of progression to cancer in patients with Barrett’s esophagus 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 Barrett’s esophagus. Methods We first performed a cross-sectional study to evaluate the prevalence of gene hypermethylation in biopsies from patients with normal esophagus (n=17), Barrett’s esophagus (n=102), and adenocarcinoma (n=42). We then performed a nested case-control study comparing gene hypermethylation in Barrett’s esophagus patients who progressed from baseline pathology to high-grade dysplasia or cancer (n=7) versus patients who did not progress (n=50). Results None of the patients with normal esophagus had p16 or APC hypermethylation. Hypermethylation was prevalent in Barrett’s esophagus without dysplasia or low-grade dysplasia (p16=31% and APC=50%; p<0.01) and high-grade dysplasia or adenocarcinoma (p16=54% and APC=68%; p<0.001) compared to 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 to those who did not progress for both p16 (100% vs. 33%; p=0.008) and APC (86% vs. 40%; p=0.02). Hypermethylation of both p16 and APC was a strong predictor of subsequent progression to cancer during a mean follow-up time of 4.1 years (adjusted OR [95% CI]=14.97 [1.73,inf], p=0.01). 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 Barrett’s esophagus. Absence of p16 and APC hypermethylation is associated with a benign course.

Background-This study examined the interaction between restraint stress and ethanol drinking in mice that consume low and high amounts of ethanol.