The origin of human metaplastic states and their propensity for cancer is poorly understood. Barrett’s esophagus is a common metaplastic condition that increases the risk for esophageal adenocarcinoma, and its cellular origin is enigmatic. To address this, we harvested tissues spanning the gastroesophageal junction from healthy and diseased donors, including isolation of esophageal submucosal glands. A combination of single-cell transcriptomic profiling, in silico lineage tracing from methylation, open chromatin and somatic mutation analyses, and functional studies in organoid models showed that Barrett’s esophagus originates from gastric cardia through c-MYC and HNF4A-driven transcriptional programs. Furthermore, our data indicate that esophageal adenocarcinoma likely arises from undifferentiated Barrett’s esophagus cell types even in the absence of a pathologically identifiable metaplastic precursor, illuminating early detection strategies.

AimTo review the current understanding of signet-ring type oesophageal adenocarcinoma including evidence for prognosis.MethodsWe conducted a literature search of nine healthcare literature databases for articles detailing the biology and clinical outcomes of signet-ring cell adenocarcinoma of the oesophagus. The impact of signet-ring cell morphology was analysed and detailed in written text and tabular format. Current understanding of the biology of signet-ring cell adenocarcinoma of the oesophagus was summarised.ResultsSignet-ring cell carcinoma was represented in 7.61% of the 18 989 cases of oesophageal carcinoma reviewed in multiple studies. The presence of signet-ring cells conferred a worse prognosis and these tumours responded differently to conventional treatments as compared with typical adenocarcinoma. Little is known about the biological features of signet-ring cell adenocarcinoma of the oesophagus. Work in gastric lesions has identified potential targets for future treatments such as CDH1 and RHOA genes. Categorisation of signet-ring cell carcinomas by the proportion of signet-ring cells within tumours differs among clinicians despite WHO criteria for classification. The current UK guidelines for histopathological reporting of oesophageal tumours do not emphasise the importance of identifying signet-ring cells.ConclusionThe presence of signet-ring cells in oesophageal adenocarcinomas leads to poorer clinical outcomes. Current understanding of signet-ring cell biology in oesophageal cancer is limited.

After publication of the Article it has come to our attention that the cell stocks used for ATAC-seq analyses may have been contaminated. We therefore revalidated the original stocks using STR profiling and repeated ATAC-seq analysis using these new stocks. Based on their contributions to the repeat experiments, two new authors, Connor Rogerson and Christopher W. Bleaney, should be included in the author list. As a result, in the Acknowledgements section, "The authors gratefully acknowledge funding from Cancer Research UK for the OCCAMS/ICGC project, MRC Clinician Scientist Grant for TJU, MCRC CRUK clinical training fellowship for EB, Maria Secrier for her advice regarding the WGS data and Southampton ECMC Tissue Bank and the Southampton Computation modelling group for access to the IRIDIS4 computer resource. " should read: "The authors gratefully acknowledge funding from Cancer Research UK for the OCCAMS/ICGC project, MRC Clinician Scientist Grant for TJU, MCRC CRUK clinical training fellowship for EB and CWB, MCRC CRUK non-clinical training fellowship for CR. Maria Secrier for her advice regarding the WGS data and Southampton ECMC Tissue Bank and the Southampton Computation modelling group for access to the IRIDIS4 computer resource. " Furthermore, in the Author Contributions section,