Molecular Biology of Barrett’s Adenocarcinoma

Abstract

ObjectiveTo review the current knowledge on the genetic alterations involved in the development and progression of Barrett's esophagus-associated neoplastic lesions. Summary Background DataBarrett's esophagus (BE) is a premalignant condition in which the normal squamous epithelium of the esophagus is replaced by metaplastic columnar epithelium. BE predisposes patients to the development of esophageal adenocarcinoma. Endoscopic surveillance can detect esophageal adenocarcinomas when they are early and curable, but most of the adenocarcinomas are detected at an advanced stage. Despite advances in multimodal therapy, the prognosis for invasive esophageal adenocarcinoma is poor. A better understanding of the molecular evolution of the Barrett's metaplasia to dysplasia to adenocarcinoma sequence may allow improved diagnosis, therapy, and prognosis. MethodsThe authors reviewed data from the published literature to address what is known about the molecular changes thought to be important in the pathogenesis of BE-associated neoplastic lesions. ResultsThe progression of Barrett's metaplasia to adenocarcinoma is associated with several changes in gene structure, gene expression, and protein structure. Some of the molecular alterations already showed promise as markers for early cancer detection or prognostication. Among these, alterations in the p53 and p16 genes and cell cycle abnormalities or aneuploidy appear to be the most important and well-characterized molecular changes. However, the exact sequence of events is not known, and probably multiple molecular pathways interact and are involved in the progression of BE to adenocarcinoma. ConclusionsFurther research into the molecular biology of BE-associated adenocarcinoma will enhance our understanding of the genetic events critical for the initiation and progression of Barrett's adenocarcinoma, leading to more effective surveillance and treatment.Since 1970, the incidence of adenocarcinomas of the esophagus has increased in many countries at a rate that exceeds that of any other malignancy.

Clinical Use of p53 in Barrett's Esophagus

“…Mutations of the p53 gene are the most prevalent genetic lesions in human cancers, occurring in at least 50% of tumors (25). Approximately 90% of the mutations in p53 are point mutations (20).…”

Effects of Helicobacter pylori infection on genetic instability, the aberrant CpG island methylation status and the cellular phenotype in Barrett's esophagus in a Japanese population

“…16,17 The hypermethylation of CpG islands represents an important epigenetic mechanism for silencing tumor-suppressor genes and tumor associated genes during carcinogenesis. 18,19 Although molecular alterations have been recognized to be an important mechanism underlying the progression from SIM to EAC, 20,21 there has so far been limited data regarding either the genetic or epigenetic abnormalities in both SIM of BE with/without H. pylori infection.…”

The CHEK2*1100delC mutation has no major contribution in oesophageal carcinogenesis

“…Like in breast carcinoma, mutations of the p53 gene appear to play an important role in the development of oesophageal squamous cell carcinoma, dysplastic Barrett's epithelium and the progression to oesophageal adenocarcinoma (Casson et al, 1991;Neshat et al, 1994;Wu et al, 1998). Ample studies have reported mutations in p53 in oesophageal carcinomas, with mutation frequencies varying from 40 to 90% (Jankowski et al, 1999;Mandard et al, 2000;Wijnhoven et al, 2001;Jenkins et al, 2002). As CHEK2 and p53 are thought to be participants of the same biological pathway, we aimed to establish whether CHEK2*1100delC confers susceptibility to oesophageal cancer, by determining the frequency of the mutation among an unselected series of oesophageal cancers and precursor lesions.…”