TP53 mutations in malignant and premalignant Barrett’s esophagus

Abstract

In order to improve the efficacy of endoscopic surveillance of Barrett's esophagus, markers of neoplastic progression in addition to dysplasia are required. The aim of the present study was to assess TP53 mutational analysis as a method of identifying patients with Barrett's esophagus who are at greatest risk of adenocarcinoma, for whom endoscopic surveillance is most appropriate. TP53 mutational analysis was initially performed on premalignant and malignant tissue from 30 patients undergoing esophagectomy for adenocarcinoma, and on premalignant biopsies from 48 patients participating in a Barrett's surveillance program. Surveillance patients were followed up endoscopically and histologically for a median of 5 years following TP53 assessment. Mutational analysis was performed by single-strand conformation polymorphism analysis and direct DNA sequencing. TP53 mutations were detected in 10 of 30 esophageal adenocarcinomas, and were more common in well-differentiated carcinomas. An identical TP53 mutation was detected in carcinoma and adjacent dysplasia. Two patients with premalignant Barrett's esophagus had TP53 mutations and one of these patients developed adenocarcinoma on follow up whilst the other has not yet progressed beyond metaplasia. No patient without TP53 mutation developed high-grade dysplasia or adenocarcinoma. TP53 mutations are detected in 33% of esophageal adenocarcinomas and in 4% of premalignant Barrett's esophagus in patients undergoing endoscopic surveillance. TP53 mutation can be detected before the development of high-grade dysplasia or carcinoma, and may be useful in stratifying the risk of adenocarcinoma in patients with Barrett's esophagus.

SEL1L and Squamous Cell Carcinoma of the Esophagus

“…Most benign and malignant neoplasms of the esophagus are epithelial in origin and arise through the progression of premalignant conditions: Barrett's esophagus for adenocarcinoma and squamous dysplasia for squamous cell carcinoma (13)(14)(15). The clinical outcome is very heterogeneous and cannot be predicted satisfactorily by existing clinical or molecular prognostic factors; early detection and treatment is the most important factor in patient survival.…”

Clinical Use of p53 in Barrett's Esophagus

“…The development of these aneuploid cell populations has been shown to increase the risk of developing adenocarcinoma (57,58). Because p53 mutations are more frequent in advanced histology and also possibly participate causally in tumorigenesis, investigators began testing the hypothesis that p53 expression could predict progression to adenocarcinomas (59)(60)(61)(62)(63)(64)(65)(66). These studies are summarized in Table 2.…”

“…In another prospective surveillance program, DNA sequencing was used to identify p53 mutations and determine whether screening for these mutations could be of utility (66). Only 4% (2 of 48) of patients with metaplasia/low-grade dysplasia had detectable p53 mutations.…”

Low grade dysplasia in Barrett’s esophagus: Should we worry?

“…Further the presence of 17p loss of heterozygosity (LOH), which is thought to represent inactivation of p53 has been demonstrated to be a strong predictor of progression in BE [28] . Indeed LOH at the sites of known tumour suppressor genes (APC, DCC, AND, TP53) may be potential biomarkers of progression in BE [29,30] . As well as loci abnormalities, epigenetic changes including hypermethylation-induced inactivation of p16 have been demonstrated to be prevalent in BE [31] and associated with an increased risk of progression in LGD [32] .…”