Clonal transitions and phenotypic evolution in Barrett esophagus
Clonal transitions and phenotypic evolution in Barrett esophagus
Abstract Background & AimsBarrett esophagus (BE) is a risk factor for the development of esophageal adenocarcinoma, however our understanding of how Barrett esophagus evolves is still poorly understood. We demonstrate that dynamic clonal phenotypic changes occur at the gland level, the mechanism by which these changes evolve, and how diversity may play a role in progression. MethodsWe analyzed the distribution and diversity of gland phenotype between and within BE biopsies and the background mucosa of those that had progressed to dysplasia or developed BE post-esophagectomy, using immunohistochemistry and H&E analysis. Clonal relationships between distinct gland types were determined by laser capture microdissection sequencing of the mitochondrial genome. ResultsFive different non-dysplastic gland phenotypes were identified in a cohort of 64 patients biopsies taken at the same physical location in the esophagus; most non-dysplastic patients showed a single gland phenotype per biopsy, but some showed two or three gland types. We reveal a shared common ancestor between parietal cell-containing oxynto-cardiac glands and goblet cell-containing specialized Barrett glands through a shared somatic mtDNA mutation. We also reveal a similar relationship between specialized and cardiac-type glands, and specialized and Paneth cell-containing glands. The diversity of gland types was significantly increased adjacent to dysplasia compared to non-dysplastic BE and patients with post-esophagectomy BE, suggesting that gland diversity evolves in BE patients over time. ConclusionsWe have shown that the range of BE phenotypes represent an evolutionary process and that changes in gland diversity may play a role in progression. Furthermore, we demonstrate common ancestry between gastric and intestinal glands in BE. Graphic abstractmedrxiv;2021.03.31.21252894v1/UFIG1F1ufig1A) The cardiac gland as the basic unit of Barrett esophagus that can evolve into phenotypes that adapt to the esophageal microenvironment. B) Phenotypic diversity of non-dysplastic glands is associated with the presence of dysplasia or cancer in patients with BE.
Carlotti Emanuela、Dunn Lorna、Elia George、ChinAleong Joanne、Griffin S Michael、Wright Nicholas A、Lovat Laurence、Hughes Frances、Hackett Richard J、Preston Sean L、Evans James A、McDonald Stuart AC、Passman Adam、Jansen Marnix、Woodland Philip、Rodriguez-Justo Manuel、McClean Mairi H、Lin Meng-Lay、Porter Ross J
Clonal dynamics in epithelia laboratory, Epithelial stem cell laboratory, Centre for Cancer Genomics and Computational Biology, Barts Cancer Institute, Queen Mary University of LondonNothern Institute for Cancer Research, Newcastle UniversityClonal dynamics in epithelia laboratory, Epithelial stem cell laboratory, Centre for Cancer Genomics and Computational Biology, Barts Cancer Institute, Queen Mary University of LondonDepartment of Histopathology, Barts Health NHS Trust, Royal London HospitalNothern Institute for Cancer Research, Newcastle University||Royal College of Surgeons of EdinburghClonal dynamics in epithelia laboratory, Epithelial stem cell laboratory, Centre for Cancer Genomics and Computational Biology, Barts Cancer Institute, Queen Mary University of LondonOeosophagogastric Disorders Centre, Department of Gastroenterology, University College London HospitalsDepartment of Surgery, Barts Health NHS Trust, Royal London HospitalClonal dynamics in epithelia laboratory, Epithelial stem cell laboratory, Centre for Cancer Genomics and Computational Biology, Barts Cancer Institute, Queen Mary University of LondonDepartment of Endoscopy Unit, Barts Health NHS Trust, Royal London HospitalClonal dynamics in epithelia laboratory, Epithelial stem cell laboratory, Centre for Cancer Genomics and Computational Biology, Barts Cancer Institute, Queen Mary University of LondonClonal dynamics in epithelia laboratory, Epithelial stem cell laboratory, Centre for Cancer Genomics and Computational Biology, Barts Cancer Institute, Queen Mary University of LondonClonal dynamics in epithelia laboratory, Epithelial stem cell laboratory, Centre for Cancer Genomics and Computational Biology, Barts Cancer Institute, Queen Mary University of LondonDepartment of Cellular Pathology, University College London Hospitals||UCL Cancer Institute, University College LondonDepartment of Endoscopy Unit, Barts Health NHS Trust, Royal London HospitalResearch Department of Tissue and Energy, UCL Division of Surgical and Interventional Science, University College London Medical SchoolDepartment of Gastroenterology, University of AberdeenClonal dynamics in epithelia laboratory, Epithelial stem cell laboratory, Centre for Cancer Genomics and Computational Biology, Barts Cancer Institute, Queen Mary University of LondonDepartment of Gastroenterology, University of Aberdeen
基础医学内科学肿瘤学
Carlotti Emanuela,Dunn Lorna,Elia George,ChinAleong Joanne,Griffin S Michael,Wright Nicholas A,Lovat Laurence,Hughes Frances,Hackett Richard J,Preston Sean L,Evans James A,McDonald Stuart AC,Passman Adam,Jansen Marnix,Woodland Philip,Rodriguez-Justo Manuel,McClean Mairi H,Lin Meng-Lay,Porter Ross J.Clonal transitions and phenotypic evolution in Barrett esophagus[EB/OL].(2025-03-28)[2025-05-01].https://www.medrxiv.org/content/10.1101/2021.03.31.21252894.点此复制
评论