Abstract
Barrett’s esophagus (BE) is an asymptomatic, pre-malignant condition of the esophagus that can progress to esophageal adenocarcinoma (EAC). BE arises typically in individuals with long-standing gastroesophageal reflux disease (GERD). The neoplastic progression of BE has been extensively studied histologically and defined as a metaplasia- dyplasia- carcinoma sequence. However the genetic basis of this process is poorly understood. It is conceived that preclinical models of BE may facilitate discovery of molecular markers due to ease of longitudinal sampling. Clinical markers to stratify the patients at higher risk are vital to institute appropriate therapeutic intervention since EAC has very poor prognosis. We developed a dynamic in-vitro BE carcinogenesis (BEC) model by exposing naïve Barrett’s epithelium cell line (BAR-T) to acid and bile at pH4 (B4), 5min/day for a year. The BEC model acquired malignant characteristics after chronic repeated exposure to B4 similar to the sequential progression of BE to EAC in vivo.AimTo study cytogenetic changes during progressive transformation in the BEC model.ResultsWe observed that the BAR-T cells progressively acquired several chromosomal abnormalities in the BEC model. Evidence of chromosomal loss (-Y) rearrangements [t(10;16) and dup (11q)] and clonal selection appeared during the early stages of the BEC model. Clonal selection resulted in a stabilized monoclonal population of cells that had a changed morphology and formed colony in soft agar. BAR-T cells grown in parallel without any exposure did not show any of these abnormalities.ConclusionsProlonged acid and bile exposure induced chromosomal aberrations and clonal selection in benign BAR-T cells. Since aneuploidy preceded morphological/dysplastic changes in the BEC model, chromosomal aberrations may be an early predictor of BE progression. The [t(10;16) and dup(11q)] aberrations identified in this study harbor several genes associated with cancer and may be responsible for neoplastic behavior of cells. After further validation, in-vivo, they may be clinically useful for diagnosis of BE, progressing to dysplasia/esophageal adenocarcinoma.
Highlights
Barrett’s esophagus (BE) is a specialized columnar intestinal metaplasia containing goblet cells that replaces the native esophageal squamous mucosa in individuals with long-standing gastroesophageal reflux disease (GERD)
Since aneuploidy preceded morphological/dysplastic changes in the BE carcinogenesis (BEC) model, chromosomal aberrations may be an early predictor of BE progression
In-vivo, they may be clinically useful for diagnosis of BE, progressing to dysplasia/esophageal adenocarcinoma
Summary
Barrett’s esophagus (BE) is a specialized columnar intestinal metaplasia containing goblet cells that replaces the native esophageal squamous mucosa in individuals with long-standing gastroesophageal reflux disease (GERD). BE is a pre-malignant condition of the esophagus that can progress to esophageal adenocarcinoma (EAC) with poor prognosis [1]. Patients with histological BE are 30– 125 times more susceptible to developing EAC compared to those without BE. The genetic basis of BE pathogenesis is poorly understood. Progressive genetic instability and clonal selection has been proposed as possible basis of neoplastic evolution in BE [2]. 0.5-1% of BE patients progress to EAC annually [8], large cohorts have to be followed over several years to obtain statistically relevant data [2,9]. A preclinical model of BE would facilitate longitudinal sampling to follow development and progression of neoplasia from non neoplastic epithelium [10]
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