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Gut. 2018 Nov;67(11):1942-1949. doi: 10.1136/gutjnl-2017-314026. Epub 2017 Oct 30.

Methylation panel is a diagnostic biomarker for Barrett's oesophagus in endoscopic biopsies and non-endoscopic cytology specimens.

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MRC Cancer Unit, Hutchison/MRC Research Centre, University of Cambridge, Cambridge, UK.
Department of Histopathology, Addenbrooke's Hospital, Cambridge, UK.



Barrett's oesophagus is a premalignant condition that occurs in the context of gastro-oesophageal reflux. However, most Barrett's cases are undiagnosed because of reliance on endoscopy. We have developed a non-endoscopic tool: the Cytosponge, which when combined with trefoil factor 3 immunohistochemistry, can diagnose Barrett's oesophagus. We investigated whether a quantitative methylation test that is not reliant on histopathological analysis could be used to diagnose Barrett's oesophagus.


Differentially methylated genes between Barrett's and normal squamous oesophageal biopsies were identified from whole methylome data and confirmed using MethyLight PCR in biopsy samples of squamous oesophagus, gastric cardia and Barrett's oesophagus. Selected genes were then tested on Cytosponge BEST2 trial samples comprising a pilot cohort (n=20 cases, n=10 controls) and a validation cohort (n=149 cases, n=129 controls).


Eighteen genes were differentially methylated in patients with Barrett'soesophagus compared with squamous controls. Hypermethylation of TFPI2, TWIST1, ZNF345 and ZNF569 was confirmed in Barrett's biopsies compared with biopsies from squamous oesophagus and gastric cardia (p<0.05). When tested in Cytosponge samples, these four genes were hypermethylated in patients with Barrett's oesophagus compared with patients with reflux symptoms (p<0.001). The optimum biomarker to diagnose Barrett's oesophagus was TFPI2 with a sensitivity and specificity of 82.2% and 95.7%, respectively.


TFPI2, TWIST1, ZNF345 and ZNF569 methylation have promise as diagnostic biomarkers for Barrett's oesophagus when used in combination with a simple and cost effective non-endoscopic cell collection device.


barrett’s; biomarker; cytosponge; hypermethylation; non-endoscopic cell sampling; reflux

[Indexed for MEDLINE]
Free PMC Article

Conflict of interest statement

Competing interests: Since this study was conducted, the Cytosponge™-TFF3 technology has been licensed to Covidien GI solutions (now owned by Medtronic) by the Medical Research Council. Rebecca Fitzgerald and Maria O’Donovan are named inventors on patents pertaining to the Cytosponge™. Covidien Solutions and Medtronic have not been privy to this manuscript or the data therein. All other authors declare no conflicts of interest.

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