DNA Promoter Hypermethylation ofp16andAPCPredicts... : Official journal of the American College of Gastroenterology | ACG (original) (raw)

ORIGINAL CONTRIBUTIONS: ESOPHAGUS

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

Wang, Jean S. MD, PhD1; Guo, Mingzhou MD, PhD2,3; Montgomery, Elizabeth A. MD4; Thompson, Richard E. PhD5; Cosby, Hilary RN1; Hicks, Lisa RN1; Wang, Shelun MD2,6; Herman, James G. MD2; Canto, Marcia I. MD1,2

1Department of Medicine (Gastroenterology), Johns Hopkins University, Baltimore, Maryland, USA; 2Department of Oncology, Johns Hopkins University, Baltimore, Maryland, USA; 3Department of Gastroenterology, Chinese PLA General Hospital, Beijing, P.R. China; 4Department of Pathology, Johns Hopkins University, Baltimore, Maryland, USA; 5Department of Biostatistics, Johns Hopkins University, Baltimore, Maryland, USA; 6Department of Oncology, 306 Hospital, PLA, Beijing, P.R. China.

Correspondence: Jean S. Wang, MD, PhD, Department of Medicine (Gastroenterology), Blalock 412, Johns Hopkins Hospital, 600 North Wolfe Street, Baltimore, Maryland 21287, USA. E-mail: [email protected]

Received 24 September 2008; accepted 15 April 2009

Abstract

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 ( n = 17), BE ( n = 102), and adenocarcinoma ( n = 42). 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 ( n = 7) vs. patients who did not progress ( n = 50).

RESULTS:

None of the patients with normal esophagus had p16 or APC hypermethylation. Hypermethylation was prevalent in BE 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 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%; 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 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), 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 BE. Absence of p16 and APC hypermethylation is associated with a benign course.