Recurring Translocations in Barrett's Esophageal Adenocarcinoma.

Manisha Bajpai,Anshuman Panda,Kristen Birudaraju,Amitabh Chak,James Van Gurp,Kiron M Das,Hana Aviv,Parisa Javidian

doi:10.3389/fgene.2021.674741

Abstract

Barrett’s esophagus (BE) is a premalignant metaplasia in patients with chronic gastroesophageal reflux disease (GERD). BE can progress to esophageal adenocarcinoma (EA) with less than 15% 5-year survival. Chromosomal aneuploidy, deletions, and duplication are early events in BE progression to EA, but reliable diagnostic assays to detect chromosomal markers in premalignant stages of EA arising from BE are lacking. Previously, we investigated chromosomal changes in an in vitro model of acid and bile exposure-induced Barrett’s epithelial carcinogenesis (BEC). In addition to detecting changes already known to occur in BE and EA, we also reported a novel recurring chromosomal translocation t(10:16) in the BE cells at an earlier time point before they undergo malignant transformation. In this study, we refine the chromosomal event with the help of fluorescence microscopy techniques as a three-way translocation between chromosomes 2, 10, and 16, t(2:10;16) (p22;q22;q22). We also designed an exclusive fluorescent in situ hybridization for esophageal adenocarcinoma (FISH-EA) assay that detects these chromosomal breakpoints and fusions. We validate the feasibility of the FISH-EA assay to objectively detect these chromosome events in primary tissues by confirming the presence of one of the fusions in paraffin-embedded formalin-fixed human EA tumors. Clinical validation in a larger cohort of BE progressors and non-progressors will confirm the specificity and sensitivity of the FISH-EA assay in identifying malignant potential in the early stages of EA.

Highlights

Esophageal adenocarcinoma (EA) is a deadly disease with less than 15% 5-year survival that has increased in incidence worldwide in the last two decades (Brown et al, 2008; Jung, 2011)
We describe a set of three recurring translocations t(2;10)(p22;q22), t(10;16)(q22;q22), and t(2;16)(p22;q22); development of a fluorescence in situ hybridization for esophageal adenocarcinoma (FISH-EA) assay with specific probes that span the translocation breakpoints using cells from the in vitro Barrett’s epithelial carcinogenesis (BEC) model; and detection of one of the fusions resulting from t(2:16) in primary human esophageal adenocarcinoma tumors
The same translocations recurred in six independent replicates of BEC20W cells exposed to ABS

Summary

Introduction

Esophageal adenocarcinoma (EA) is a deadly disease with less than 15% 5-year survival that has increased in incidence worldwide in the last two decades (Brown et al, 2008; Jung, 2011). BE follows a histological progression from metaplasia → low-grade dysplasia (LGD) → high-grade dysplasia (HGD) → EA. The relative risk of developing adenocarcinoma increases with advanced histological grade. Translocations in Barrett’s Esophageal Adenocarcinoma with LGD face a 13% annual risk and the patients with HGD have a 40% 5-year risk of progression to EA (Reid et al, 1988a; Spechler et al, 2011a,b). While the recommendations for BE endoscopic surveillance are well defined (Reid et al, 1988b; Wang and Sampliner, 2008), histologic BE staging suffers from inter- and intraobserver variability (Spechler, 2005). The reliability and adequacy of current methods for EA surveillance is controversial (Spechler, 2020), and reliable “biomarkers” for accurate prediction of risk of progression from BE to EA are necessary (Gorospe and Wong Kee Song, 2016)

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Conclusion