Gastroenterology

Gastroenterology

Volume 115, Issue 6, December 1998, Pages 1381-1386
Gastroenterology

Alimentary Tract
Hypermethylation of the CDKN2/p16 promoter during neoplastic progression in Barrett's esophagus☆,☆☆

https://doi.org/10.1016/S0016-5085(98)70016-2Get rights and content

Abstract

Background & Aims: Inactivation of the CDKN2/p16INK4A tumor-suppressor gene is one of the most frequent genetic alterations in human malignancies. In esophageal adenocarcinomas, mutations of the p16 gene or homozygous deletions of the gene locus 9p21 are rare. This study investigated whether p16 promoter hypermethylation is an alternative mechanism for p16 gene inactivation during neoplastic progression in Barrett's esophagus. Methods: A methylation-specific polymerase chain reaction protocol was applied. A total of 95 specimens from 14 patients with Barrett's esophagus were analyzed longitudinally. The p16 promoter status was compared with histomorphological findings. Results: p16 promoter hypermethylation was detected in 9 of the 10 patients who had displayed dysplasia at some time during surveillance, whereas none of the patients who had not displayed dysplasia during surveillance had p16 promoter hypermethylation. p16 promoter hypermethylation was detected in 3% (2 of 67) of the samples without dysplasia, 60% (3 of 5) of the samples with lesions indefinite for dysplasia, 55.6% (10 of 18) of the specimens with low-grade dysplasia, and 75% (3 of 4) of the specimens with high-grade dysplasia. Conclusions: These data suggest that p16 promoter hypermethylation is a common mechanism of p16 gene inactivation during neoplastic progression in Barrett's esophagus.

GASTROENTEROLOGY 1998;115:1381-1386

Section snippets

Patients and tissue samples

Fourteen patients with Barrett's esophagus who were involved in routinely performed surveillance programs were enrolled in this longitudinal study. Because of the retrospective study design, no standardized biopsy sampling protocol was used. Barrett's esophagus was diagnosed if replacement of squamous epithelium in the distal esophagus was endoscopically detected and if the histopathologic analysis of biopsy specimens proved the presence of specialized Barrett's epithelium. Dysplasia was

Patients and tissue samples

Characteristics of patients and retrieved tissue samples are shown in Table 1. Ninety-five archival paraffin blocks were retrieved for further investigation. In each block, differing numbers of biopsy specimens had been embedded. Because no standardized biopsy sampling protocol was applied, there was a range of 1–11 biopsy specimens per endoscopic procedure. The mean number of biopsy specimens per endoscopic procedure was 3.9 (Table 1). Sixty-seven blocks contained Barrett's epithelium without

Discussion

Previous studies have shown that the gene locus 9p21 is one of the most frequent regions of allelic loss in adenocarcinomas of the esophagus.25 However, although premalignant and malignant Barrett's esophagus have been reported to display LOH of 9p21 in approximately 90% of all cases,15 a minority show a point mutation in the remaining allele.15, 26 These data suggest either the presence of a tumor suppressor other than p16 or alternative mechanisms of p16 gene inactivation. In this context,

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    ☆

    Address requests for reprints to: Bodo Klump, M.D., Department of Medicine I, University Hospital of Tübingen, Otfried-Müller-Strasse 10, D-72076 Tübingen, Germany. e-mail: bodo.klump@uni-tuebin gen.de; fax: (49) 7071-294457.

    ☆☆

    Supported by grants from the Federal Ministry of Education, Science, Research and Technology (Fö 01K59602) and the Interdisciplinary Clinical Research Center (IKFZ) Tübingen.

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    Copyright © 1998 American Gastroenterological Association. Published by Elsevier Inc. All rights reserved.