New models of neoplastic progression in Barrett's oesophagus

Research in Barrett's oesophagus, and neoplastic progression to OAC (oesophageal adenocarcinoma), is hobbled by the lack of good pre-clinical models that capture the evolutionary dynamics of Barrett's cell populations. Current models trade off tractability for realism. Computational models are perhaps the most tractable and can be used both to interpret data and to develop intuitions and hypotheses for neoplastic progression. Tissue culture models include squamous cell lines, Barrett's oesophagus cell lines and OAC cell lines, although it was recognized recently that BIC-1, SEG-1 and TE-7 are not true OAC cell lines. Some of the unrealistic aspects of the micro-environment in two-dimensional tissue culture may be overcome with the development of three-dimensional organotypic cultures of Barrett's oesophagus. The most realistic, but least tractable, model is a canine surgical model that generates reflux and leads to an intestinal metaplasia. Alternatively, rat surgical models have gained popularity and should be tested for the common genetic features of Barrett's oesophagus neoplastic progression in humans including loss of CDKN2A (cyclin-dependent kinase inhibitor 2A) and TP53 (tumour protein 53), generation of aneuploidy and realistic levels of genetic diversity. This last feature will be important for studying the effects of cancer-prevention interventions. In order to study the dynamics of progression and the effects of an experimental intervention, there is a need to follow animals longitudinally, with periodic endoscopic biopsies. This is now possible and represents an exciting opportunity for the future.

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Novel biomarkers for risk stratification of Barrett’s oesophagus associated neoplastic progression–epithelial HMGB1 expression and stromal lymphocytic phenotype

British Journal of Cancer ◽

10.1038/s41416-019-0685-1 ◽

2019 ◽

Vol 122 (4) ◽

pp. 545-554 ◽

Cited By ~ 2

Author(s):

Ross J. Porter ◽

Graeme I. Murray ◽

Daniel P. Brice ◽

Russell D. Petty ◽

Mairi H. McLean

Keyword(s):

B Lymphocyte ◽

Immune Cell ◽

Barrett’S Oesophagus ◽

Oesophageal Adenocarcinoma ◽

Cell Phenotype ◽

Neoplastic Progression ◽

Tissue Samples ◽

P53 Expression ◽

Barrett's Oesophagus ◽

Hmgb1 Expression

Abstract Background The incidence of oesophageal adenocarcinoma is increasing globally. Barrett’s oesophagus (BO) is a pre-malignant condition with no biomarker to risk stratify those at highest risk of dysplasia and malignant transformation. Methods Subcellular epithelial protein (HMGB1, p53, RUNX3) expression, alongside expression of CD20, CD4, CD8 and Foxp3 to characterise stromal B lymphocyte, and helper, cytotoxic and regulatory T-lymphocyte cell infiltrate, respectively, was assessed by immunohistochemistry in 218 human tissue samples including normal oesophageal/gastric biopsies (n = 39), BO (non-dysplasia, dysplasia, non-dysplastic background from progressors to dysplasia or cancer, n = 121) and oesophageal adenocarcinoma (n = 58). Results There is a dynamic subcellular epithelial expression of HMGB1 (loss of nuclear, emergence of cytoplasmic), associated with epithelial p53 expression and differential immune cell phenotype in oesophageal neoplastic progression. We identify a protein signature and lymphocyte infiltrate in non-dysplastic BO when progressive disease (dysplasia or adenocarcinoma) is present but not histologically represented in the biopsied field. There is a dynamic stromal lymphocytic infiltrate in oesophageal neoplastic progression. Conclusions This data reveals novel insights into the microenvironment of BO and progression towards cancer and identifies a novel high-risk biomarker of disease progression to aid surveillance strategies to identify early progression and impact future incidence of oesophageal cancer.

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Subtypes of Barrett’s oesophagus and oesophageal adenocarcinoma based on genome-wide methylation analysis

Gut ◽

10.1136/gutjnl-2017-314544 ◽

2018 ◽

Vol 68 (3) ◽

pp. 389-399 ◽

Cited By ~ 11

Author(s):

Ming Yu ◽

Sean K Maden ◽

Matthew Stachler ◽

Andrew M Kaz ◽

Jessica Ayers ◽

...

Keyword(s):

Dna Methylation ◽

Cell Lines ◽

Massively Parallel Sequencing ◽

T Test ◽

Barrett’S Oesophagus ◽

Oesophageal Adenocarcinoma ◽

Aberrant Methylation ◽

Barrett's Oesophagus ◽

Genome Wide

ObjectiveTo identify and characterise DNA methylation subtypes in oesophageal adenocarcinoma (EAC) and its precursor Barrett’s oesophagus (BE).DesignWe performed genome-wide DNA methylation profiling on samples of non-dysplastic BE from cancer-free patients (n=59), EAC (n=23), normal squamous oesophagus (n=33) and normal fundus (n=9), and identified methylation subtypes using a recursively partitioned mixture model. We assessed genomic alterations for 9 BE and 22 EAC samples with massively parallel sequencing of 243 EAC-associated genes, and we conducted integrative analyses with transcriptome data to identify epigenetically repressed genes. We also carried out in vitro experiments treating EAC cell lines with 5-Aza-2'-Deoxycytidine (5-Aza-dC), short hairpin RNA knockdown and anticancer therapies.ResultsWe identified and validated four methylation subtypes of EAC and BE. The high methylator subtype (HM) of EAC had the greatest number of activating events in ERBB2 (p<0.05, Student’s t-test) and the highest global mutation load (p<0.05, Fisher’s exact test). PTPN13 was silenced by aberrant methylation in the HM subtype preferentially and in 57% of EACs overall. In EAC cell lines, 5-Aza-dC treatment restored PTPN13 expression and significantly decreased its promoter methylation in HM cell lines (p<0.05, Welch’s t-test). Inhibition of PTPN13 expression in the SK-GT-4 EAC cell line promoted proliferation, colony formation and migration, and increased phosphorylation in ERBB2/EGFR/Src kinase pathways. Finally, EAC cell lines showed subtype-specific responses to topotecan, SN-38 and palbociclib treatment.ConclusionsWe identified and characterised methylator subtypes in BE and EAC. We further demonstrated the biological and clinical relevance of EAC methylator subtypes, which may ultimately help guide clinical management of patients with EAC.

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P189 PREDICTORS OF BARRETT’S OESOPHAGUS PROGRESSION : WHERE ARE WE?

Diseases of the Esophagus ◽

10.1093/dote/doz092.189 ◽

2019 ◽

Vol 32 (Supplement_2) ◽

Author(s):

Jamel* Sara ◽

Thie Amy ◽

Tukaniva Karina ◽

R Markar Sheraz ◽

B Hanna George

Keyword(s):

Risk Stratification ◽

Diagnostic Accuracy ◽

Early Stage ◽

Pooled Analysis ◽

P53 Mutation ◽

Barrett’S Oesophagus ◽

Oesophageal Adenocarcinoma ◽

Neoplastic Progression ◽

Barrett's Oesophagus ◽

Biomarker Research

Abstract Introduction Barrett’s esophagus (BE) is a well-established precursor lesion for oesophageal adenocarcinoma, which carries an overall poor prognosis (1-2). Patients diagnosed with Barrett’s oesophagus therefore undergo regular endoscopic surveillance to detect neoplastic lesions at an early stage to allow curative treatments (3). The low incidence of esophageal adenocarcinoma (EAC) in Barrett’s oesophagus patients highlights the need for risk stratification tools of patients on surveillance. In this review, we present current potential biomarkers and their associated diagnostic accuracy for the prediction of progression in BE. Materials and methods We searched MEDLINE, EMBASE, Web of Science, CENTRAL and Pubmed publisher. All studies on factors of Be progression were included. Two authors independently assessed the trials and extracted data. Quality assessment of studies was performed using QUADAS scoring. Pooled analysis was performed through Medusa software. Results The inclusion criteria were met by 25 studies. All the studies evaluated diagnostic accuracy of the biomarker to detect progression of Barrett’s to high grade dysplasia (HGD) and EAC. The biomarkers were p53 mutation in 6 studies, Methylation in 4 studies, Clinical factors in 7 studies and genetic factors in 5 studies and other biomarkers in 7 studies. The pooled sensitivity and specificity for BO were 83.4 % [95 % confidence interval (CI): 68-95 %] and 75.6 % (95 % CI: 68-88 %), respectively. In particular, the use of p53 and methylation in BO patients appeared to be associated with a good diagnostic accuracy to predict neoplastic progression in BE. Therefore, further biomarker research may provide promising results in risk stratification and prediction of progression to HGD and oesophageal adenocarcinoma in context of BE. Conclusions The evidence from this systematic review is suggestive of a crucial role of biomarkers in prediction of BE progression. Further work in translating biomarkers for routine clinical use may eventually lead to accurate risk stratification.

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Faculty Opinions recommendation of Oesophageal adenocarcinoma and prior diagnosis of Barrett's oesophagus: a population-based study.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.718338089.793493545 ◽

2014 ◽

Author(s):

Hugh Barr

Keyword(s):

Population Based ◽

Barrett’S Oesophagus ◽

Oesophageal Adenocarcinoma ◽

Population Based Study ◽

Barrett's Oesophagus

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Faculty Opinions recommendation of Evolution of oesophageal adenocarcinoma from metaplastic columnar epithelium without goblet cells in Barrett's oesophagus.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.726037417.793519451 ◽

2016 ◽

Author(s):

Noam Harpaz ◽

Alexandros Polydorides

Keyword(s):

Goblet Cells ◽

Barrett’S Oesophagus ◽

Oesophageal Adenocarcinoma ◽

Columnar Epithelium ◽

Barrett's Oesophagus

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Multitrait genetic association analysis identifies 50 new risk loci for gastro-oesophageal reflux, seven new loci for Barrett’s oesophagus and provides insights into clinical heterogeneity in reflux diagnosis

Gut ◽

10.1136/gutjnl-2020-323906 ◽

2021 ◽

pp. gutjnl-2020-323906

Author(s):

Jue-Sheng Ong ◽

Jiyuan An ◽

Xikun Han ◽

Matthew H Law ◽

Priyanka Nandakumar ◽

...

Keyword(s):

Risk Factors ◽

Multiple Testing ◽

Association Studies ◽

Barrett’S Oesophagus ◽

Oesophageal Reflux ◽

Oesophageal Adenocarcinoma ◽

Specific Gene ◽

Genome Wide Association Studies ◽

Disease Heterogeneity ◽

Barrett's Oesophagus

ObjectiveGastro-oesophageal reflux disease (GERD) has heterogeneous aetiology primarily attributable to its symptom-based definitions. GERD genome-wide association studies (GWASs) have shown strong genetic overlaps with established risk factors such as obesity and depression. We hypothesised that the shared genetic architecture between GERD and these risk factors can be leveraged to (1) identify new GERD and Barrett’s oesophagus (BE) risk loci and (2) explore potentially heterogeneous pathways leading to GERD and oesophageal complications.DesignWe applied multitrait GWAS models combining GERD (78 707 cases; 288 734 controls) and genetically correlated traits including education attainment, depression and body mass index. We also used multitrait analysis to identify BE risk loci. Top hits were replicated in 23andMe (462 753 GERD cases, 24 099 BE cases, 1 484 025 controls). We additionally dissected the GERD loci into obesity-driven and depression-driven subgroups. These subgroups were investigated to determine how they relate to tissue-specific gene expression and to risk of serious oesophageal disease (BE and/or oesophageal adenocarcinoma, EA).ResultsWe identified 88 loci associated with GERD, with 59 replicating in 23andMe after multiple testing corrections. Our BE analysis identified seven novel loci. Additionally we showed that only the obesity-driven GERD loci (but not the depression-driven loci) were associated with genes enriched in oesophageal tissues and successfully predicted BE/EA.ConclusionOur multitrait model identified many novel risk loci for GERD and BE. We present strong evidence for a genetic underpinning of disease heterogeneity in GERD and show that GERD loci associated with depressive symptoms are not strong predictors of BE/EA relative to obesity-driven GERD loci.

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