Abstract
Barrett's esophagus (BE) is the only well-known precursor lesion of esophageal adenocarcinoma (EA). The exact estimates of the annual progression rate from BE to EA vary from 0.07% to 3.6%. The identification of BE patients at higher risk to progress to EA is hence mandatory, although difficult to accomplish. In search of novel BE biomarkers we analyzed the efficacy of hERG1 potassium channels in predicting BE progression to EA. Once tested by immunohistochemistry (IHC) on bioptic samples, hERG1 was expressed in BE, and its expression levels increased during progression from BE to esophageal dysplasia (ED) and EA. hERG1 was also over-expressed in the metaplastic cells arising in BE lesions obtained in different BE mouse models, induced either surgically or chemically. Furthermore, transgenic mice which over express hERG1 in the whole gastrointestinal tract, developed BE lesions after an esophago-jejunal anastomosis more frequently, compared to controls. A case-control study was performed on 104 bioptic samples from newly diagnosed BE patients further followed up for at least 10 years. It emerged a statistically significant association between hERG1 expression status and risk of progression to EA. Finally, a novel fluorophore- conjugated recombinant single chain variable fragment antibody (scFv-hERG1-Alexa488) was tested on freshly collected live BE biopsies: it could recognize hERG1 positive samples, perfectly matching IHC data.Overall, hERG1 can be considered a novel BE biomarker to be exploited for a novel endoscopic surveillance protocol, either in biopsies or through endoscopy, to identify those BE patients with higher risk to progress to EA.
Highlights
Barrett’s esophagus (BE) is a pathologic condition detectable at endoscopy and characterized by the replacement of the squamous epithelium of the distal esophagus by a columnar-type mucosa, when biopsied [1]
In a previous study, performed in a relatively small cohort of patients, we showed that BE samples are positive for hERG1 expression, whereas both normal esophageal mucosa and gastro-esophageal reflux disease (GERD) samples without or with esophagitis are hERG1 negative [16]
It is worth noting that hERG1 positivity in progressed BE (pBE) is not comparable with that observed in the whole series, since, in the case-control study, we only focused on selected patients whose lesions progressed towards esophageal dysplasia (ED) or esophageal adenocarcinoma (EA)
Summary
Barrett’s esophagus (BE) is a pathologic condition detectable at endoscopy and characterized by the replacement of the squamous epithelium of the distal esophagus by a columnar-type mucosa (i.e. intestinal metaplasia), when biopsied [1]. Patients with BE have an increased risk to develop an esophageal adenocarcinoma (EA) [3]. BE is the only wellknown pathologic precursor of EA, a process often preceded by the occurrence of dysplasia (esophageal dysplasia, ED), with a stepwise progression from low grade to high grade dysplasia, and adenocarcinoma. The wide variation in the estimates of the annual progression rate of BE to EA (0.07%–3.6%) makes it mandatory to perform endoscopic surveillance to all BE patients. The identification of BE patients at higher risk to progress to EA is difficult [4]
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