Clonal Transitions and Phenotypic Evolution in Barrett’s Esophagus,Gastroenterology

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Clonal Transitions and Phenotypic Evolution in Barrett’s Esophagus
Gastroenterology ( IF 25.7 ) Pub Date : 2021-12-29 , DOI: 10.1053/j.gastro.2021.12.271
James A Evans ₁ , Emanuela Carlotti ₁ , Meng-Lay Lin ₁ , Richard J Hackett ₁ , Magnus J Haughey ₂ , Adam M Passman ₁ , Lorna Dunn ₃ , George Elia ₁ , Ross J Porter ₄ , Mairi H McLean ₄ , Frances Hughes ₅ , Joanne ChinAleong ₆ , Philip Woodland ₇ , Sean L Preston ₇ , S Michael Griffin ₈ , Laurence Lovat ₉ , Manuel Rodriguez-Justo ₁₀ , Weini Huang ₂ , Nicholas A Wright ₁₁ , Marnix Jansen ₁₂ , Stuart A C McDonald ₁

Affiliation

Clonal Dynamics in Epithelia Laboratory, Queen Mary University of London, London, United Kingdom.
School of Mathematical Sciences, Queen Mary University of London, London, United Kingdom.
Northern Institute for Cancer Research, Newcastle University, Newcastle, United Kingdom.
Department of Gastroenterology, University of Aberdeen, Aberdeen, United Kingdom.
Department of Surgery, Barts Health NHS Trust, Royal London Hospital, London, United Kingdom.
Department of Histopathology, Barts Health NHS Trust, Royal London Hospital, London, United Kingdom.
Endoscopy Unit, Barts Health NHS Trust, Royal London Hospital, London, United Kingdom.
School of Mathematical Sciences, Queen Mary University of London, London, United Kingdom; Royal College of Surgeons of Edinburgh, Edinburgh, United Kingdom.
Oeosophagogastric Disorders Centre, Department of Gastroenterology, University College London Hospitals, London, United Kingdom; Research Department of Tissue and Energy, University College London Division of Surgical and Interventional Science, University College London, London, United Kingdom.
Department of Cellular Pathology, University College London Hospitals, London, United Kingdom.
Epithelial Stem Cell Laboratory, Centre for Cancer Genomics and Computational Biology, Barts Cancer Institute, Queen Mary University of London, London, United Kingdom.
Department of Cellular Pathology, University College London Hospitals, London, United Kingdom; UCL Cancer Institute, University College London, London, United Kingdom.

Background & Aims

Barrett’s esophagus (BE) is a risk factor for esophageal adenocarcinoma but our understanding of how it evolves is poorly understood. We investigated BE gland phenotype distribution, the clonal nature of phenotypic change, and how phenotypic diversity plays a role in progression.

Methods

Using immunohistochemistry and histology, we analyzed the distribution and the diversity of gland phenotype between and within biopsy specimens from patients with nondysplastic BE and those who had progressed to dysplasia or had developed postesophagectomy BE. Clonal relationships were determined by the presence of shared mutations between distinct gland types using laser capture microdissection sequencing of the mitochondrial genome.

Results

We identified 5 different gland phenotypes in a cohort of 51 nondysplastic patients where biopsy specimens were taken at the same anatomic site (1.0–2.0 cm superior to the gastroesophageal junction. Here, we observed the same number of glands with 1 and 2 phenotypes, but 3 phenotypes were rare. We showed a common ancestor between parietal cell-containing, mature gastric (oxyntocardiac) and goblet cell-containing, intestinal (specialized) gland phenotypes. Similarly, we have shown a clonal relationship between cardiac-type glands and specialized and mature intestinal glands. Using the Shannon diversity index as a marker of gland diversity, we observed significantly increased phenotypic diversity in patients with BE adjacent to dysplasia and predysplasia compared to nondysplastic BE and postesophagectomy BE, suggesting that diversity develops over time.

Conclusions

We showed that the range of BE phenotypes represents an evolutionary process and that changes in gland diversity may play a role in progression. Furthermore, we showed a common ancestry between gastric and intestinal-type glands in BE.

中文翻译：

巴雷特食管的克隆转变和表型进化

背景与目标

巴雷特食管 (BE) 是食管腺癌的危险因素，但我们对其如何演变的了解知之甚少。我们研究了BE腺体表型分布、表型变化的克隆性质以及表型多样性如何在进展中发挥作用。

方法

使用免疫组织化学和组织学，我们分析了非发育不良 BE 患者和已进展为发育不良或已发生食管切除术后 BE 患者的活检标本之间和内部腺体表型的分布和多样性。使用线粒体基因组的激光捕获显微切割测序，通过不同腺体类型之间是否存在共享突变来确定克隆关系。

结果

我们在 51 名非发育不良患者的队列中确定了 5 种不同的腺体表型，这些患者的活检标本是在同一解剖部位（比胃食管交界处高 1.0-2.0 厘米）采集的。在这里，我们观察到具有 1 种和 2 种表型的腺体数量相同，但是3种表型是罕见的，我们显示了包含壁细胞的成熟胃腺（心泌酸腺）和包含杯状细胞的肠腺（特殊）表型之间的共同祖先，同样，我们也显示了心型腺和特殊腺和特定腺之间的克隆关系。使用香农多样性指数作为腺体多样性的标志，我们观察到与非发育不良 BE 和食管切除术后 BE 患者相比，邻近发育不良和发育前期的 BE 患者的表型多样性显着增加，表明多样性随着时间的推移而发展。