Molecular Evolution of the Metaplasia-Dysplasia-Adenocarcinoma Sequence in the Esophagus

Abstract

The incidence of adenocarcinoma of the esophagus has been increasing in developing countries over the last three decades and probably reflects a genuine increase in the incidence of its recognized precursor lesion , Barrett's metaplasia. Despite advances in multimodality therapy , the prognosis for invasive esophageal adenocarcinoma is poor. An improved understanding of the molecular biology of this disease may allow improved diagnosis , therapy , and prognosis. We focus on recent developments in the molecular and cell biology of Barrett's metaplasia , a heterogeneous lesion affecting the transitional zone of the gastro-esophageal junction whose associated molecular alterations may vary both in nature and temporally. Early premalignant clones produce biological and genetic heterogeneity as seen by multiple p53 mutations , p16 mutations , aneuploidy , and abnormal methylation resulting in stepwise changes in differentiation , proliferation , and apoptosis , allowing disease progression under selective pressure. Abnormalities in expression of growth factors of the epidermal growth factor family and cell adhesion molecules, especially cadherin/catenin complexes , may occur early in invasion. Exploitation of these molecular events may lead to a more appropriate diagnosis and understanding of these lesions in the future. (Am J Pathol 1999, 154:965-973)

Cyclin D1 polymorphism (G870A) and risk for esophageal adenocarcinoma

“…Dysplasia frequently is associated with malignant progression, and high-grade dysplasia currently is regarded as the most reliable predictor for invasive adenocarcinoma. [1][2][3] However, because most patients with Barrett esophagus do not progress to carcinoma, the value and cost efficacy of this approach recently has been questioned. 4 Similarly, there appears to be little evidence to support routine screening of individuals with GERD.…”

“…1,2 Progression of Barrett esophagus to invasive adenocarcinoma is reflected histologically by the metaplasia-dysplasia-carcinoma sequence. 3 Because gastroesophageal reflux disease (GERD) is a risk factor for Barrett esophagus, there is a plausible link between GERD, Barrett esophagus, and esophageal adenocarcinoma. 4 However, to date, no convincing biologic mechanism explaining this progression has been established.…”

“…6 -9 The recent identification of molecular markers associated with Barrett metaplasia-dysplasia-adenocarcinoma progression may provide further insight into the molecular pathogenesis of this disease. 3,10,11 However, because GERD and Barrett esophagus are highly prevalent, and only a fraction of individuals progress to invasive adenocarcinoma, 4 it is likely that interactions between molecular and lifestyle risk factors may modulate individual susceptibility for progression to esophageal adenocarcinoma.…”

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.…”

Deoxycholic acid promotes development of gastroesophageal reflux disease and Barrett's oesophagus by modulating integrin‐αv trafficking

“…Recent developments in our understanding of oesophageal pathology suggest that alterations in the expression and function of cellular adhesion molecules are involved in benign and metaplastic oesophageal diseases 5, 32, 33. This study reports that oesophageal squamous epithelium exposed to DCA exhibits a reversible reduction in the surface expression of a subset of integrins which promotes cellular detachment and impairs adhesion (Fig.…”