DNA Promoter Hypermethylation of p16 and APC Predicts Neoplastic Progression in Barrett's Esophagus

Abstract

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.

Increased phosphorylation on residue S795 of the retinoblastoma protein in esophageal adenocarcinoma

“…Aberrancy of p16, such as mutations, methylations and deletions, are some of the earliest events in cancer (16). P16 is also involved in the pathogenesis of EAC with a number of P16 alterations such as gene locus loss, LOH (loss of heterozygosity), mutations and methylation being present in BE, the pre-malignant stage of EAC (17)(18)(19)(20) and consequently increasing with increasing tissue dysplasia (17,18,20). In a number of cancers it has been shown that aberration of p16 affect phosphorylation status of Rb (21,22).…”

Acid-induced p16 hypermethylation contributes to development of esophageal adenocarcinoma via activation of NADPH oxidase NOX5-S

“…Hypermethylation (an increase in the methylation) of p16 gene promoter is present at a much higher frequency in BE with dysplasia and EA than in Barrett's intestinal metaplasia (25, 38, 40 -41). Detection of p16 hypermethylation may be used to predict the neoplastic progression (24,38). Therefore, hypermethylation of p16 gene promoter is an important mechanism inactivating p16.…”

Loss of P16 in Esophageal Adenocarcinoma Detected by Fluorescence in situ Hybridization and Immunohistochemistry

“…Alternative mechanisms like p16 promoter methylation or p16 gene mutation could be the reasons for loss of p16 protein expression in this case. Methylation of p16 promoter is considered as common mechanism of p16 gene derailment during molecular pathogenesis of EAC, whereas p16 gene mutation is less probable [15,36,37,38,39]. It is plausible also that very small deletion of p16 could occur, which does not delete the entire LSI p16 probe target and consequently cannot be detected by FISH technique.…”