P-OGC44 Multi-omic cohort study of Barrett’s oesophagus reveals structural variation and retrotransposon activity to occur early in cancer evolution

Abstract Background Barrett’s oesophagus (BE) is the main risk factor for the development of oesophageal adenocarcinoma (OAC), yet few patients ever go on to progress to cancer. The acquisition of events during the metaplasia-dysplasia-cancer sequence is poorly characterised. We present a large, unbiased, multi-omics analysis of a cross-sectional cohort of pre-cancer samples, with the aim of providing a comprehensive insight into the diversity and molecular changes driving the disease to cancer. Methods We generated and integrated the genomic (50x), transcriptomic and epigenomic (850K EPIC array) landscapes of snap-frozen endoscopic biopsies from 146 patients with a range of outcomes (27 long-standing non-dysplastic; 12 prior to progression to dysplasia; 14 low-grade; 25 high-grade; 21 intramucosal carcinoma; 47 cases of BE taken adjacent to OAC) and 642 person years of follow-up. All biopsies were reviewed independently by 3 pathologists and had associated annotation with detailed clinical information. Results The total number of structural variants (SV) captured the most variance between samples. Complex SVs and LINE-1 retrotransposon activity were observed even before dysplasia had developed and increased with progression. Increasing SV burden was associated with chromothripsis (12%, 18/146) and breakage-fusion bridges (BFBs; 8%, 13/146). In more than 50% of these, the BFBs were in chromosome 17, harbouring the oncogenes ERBB2 and CDK12, for which expression was significantly higher. With progression there was increased expression of genes related to cell-cycle checkpoint, DNA repair and chromosomal instability, and the epigenetic silencing of genes in WNT-signalling and cell-cycle pathways. Conclusions Genomic complexity occurs very early in the natural history of BE and increasing genomic instability appears to tip the balance towards cancer. This may inform the potential for progression to cancer beyond the clinically discernible phenotype. Efforts to better understand the triggers for chromosomal breakages and rearrangements that underly progression will aid clinical prediction and prevention strategies.

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Global prevalence of Barrett’s oesophagus and oesophageal cancer in individuals with gastro-oesophageal reflux: a systematic review and meta-analysis

Gut ◽

10.1136/gutjnl-2020-321365 ◽

2020 ◽

pp. gutjnl-2020-321365 ◽

Cited By ~ 1

Author(s):

Leonardo Henry Eusebi ◽

Giovanna Grazia Cirota ◽

Rocco Maurizio Zagari ◽

Alexander Charles Ford

Keyword(s):

Systematic Review ◽

Meta Analysis ◽

Barrett’S Oesophagus ◽

Oesophageal Reflux ◽

Oesophageal Adenocarcinoma ◽

Low Grade ◽

Barrett's Oesophagus ◽

Global Prevalence ◽

Pooled Prevalence ◽

Geographical Regions

ObjectivesChronic gastro-oesophageal reflux might lead to the development of Barrett’s oesophagus (BO) or even oesophageal adenocarcinoma. There has been no definitive systematic review and meta-analysis of data to estimate global prevalence of BO or oesophageal adenocarcinoma in individuals with gastro-oesophageal reflux.DesignWe searched MEDLINE, Embase and Embase Classic to identify cross-sectional surveys that reported prevalence of BO or oesophageal adenocarcinoma in adults with gastro-oesophageal reflux. We extracted prevalence for all studies, both for endoscopically suspected and histologically confirmed cases. We calculated pooled prevalence according to study location, symptom frequency and sex, as well as ORs with 95% CIs.ResultsOf the 4963 citations evaluated, 44 reported prevalence of endoscopically suspected and/or histologically confirmed BO. Prevalence of BO among individuals with gastro-oesophageal reflux varied according to different geographical regions ranging from 3% to 14% for histologically confirmed BO with a pooled prevalence of 7.2% (95% CI 5.4% to 9.3%), whereas pooled prevalence for endoscopically suspected BO was 12.0% (95% CI 5.5% to 20.3%). There was heterogeneity in many of our analyses. Prevalence of BO was significantly higher in men, both for endoscopically suspected (OR=2.1; 95% CI 1.6 to 2.8) and histologically confirmed BO (OR=2.3; 95% CI 1.7 to 3.2). Dysplasia was present in 13.9% (95% CI 8.9% to 19.8%) of cases of histologically confirmed BO, 80.7% of which was low-grade.ConclusionThe prevalence of Barrett’s oesophagus among individuals with gastro-oesophageal reflux varied strikingly among countries, broadly resembling the geographical distribution of gastro-oesophageal reflux itself. Prevalence of BO was significantly higher in men.

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Impact of endoscopic biopsy surveillance of Barrett’s oesophagus on pathological stage and clinical outcome of Barrett’s carcinoma

Gut ◽

10.1136/gut.43.2.216 ◽

1998 ◽

Vol 43 (2) ◽

pp. 216-222 ◽

Cited By ~ 287

Author(s):

J W van Sandick ◽

J J B van Lanschot ◽

B W Kuiken ◽

G N J Tytgat ◽

G J A Offerhaus ◽

...

Keyword(s):

Clinical Outcome ◽

Endoscopic Biopsy ◽

Barrett’S Oesophagus ◽

Oesophageal Adenocarcinoma ◽

Low Grade ◽

Pathological Stage ◽

Barrett's Oesophagus ◽

Median Period ◽

The Impact ◽

Barrett's Carcinoma

Background—The efficacy of endoscopic biopsy surveillance of Barrett’s oesophagus in reducing mortality from oesophageal cancer has not been confirmed.Aims—To investigate the impact of endoscopic biopsy surveillance on pathological stage and clinical outcome of Barrett’s carcinoma.Methods—A clinicopathological comparison was made between patients who initially presented with oesophageal adenocarcinoma (n=54), and those in whom the cancer had been detected during surveillance of Barrett’s oesophagus (n=16).Results—The surveyed patients were known to have Barrett’s oesophagus for a median period of 42 months (range 6–144 months). Prior to the detection of adenocarcinoma or high grade dysplasia, 13 of 16 patients (81%) were previously found to have low grade dysplasia. Surgical pathology showed that surveyed patients had significantly earlier stages than non-surveyed patients (p=0.0001). Only one surveyed patient (6%) versus 34 non-surveyed patients (63%) had nodal involvement (p=0.0001). Two year survival was 85.9% for surveyed patients and 43.3% for non-surveyed patients (p=0.0029).Conclusions—The temporal course of histological progression in our surveyed patients supports the theory that adenocarcinoma in Barrett’s oesophagus develops through stages of increasing severity of dysplasia. Endoscopic biopsy surveillance of Barrett’s oesophagus permits detection of malignancy at an early and curable stage, thereby potentially reducing mortality from oesophageal adenocarcinoma.

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ENDOSCOPIC RESECTION OF LOW GRADE DYSPLASIA IN BARRETT’S OESOPHAGUS: A RETROSPECTIVE STUDY ABOUT 61 PATIENTS

10.1055/s-0040-1704359 ◽

2020 ◽

Author(s):

Fabrice Caillol ◽

Arthur Falque ◽

Margherita Pizzicannella ◽

Christian Pesenti ◽

Jean Philippe Ratone ◽

...

Keyword(s):

Retrospective Study ◽

Endoscopic Resection ◽

Barrett’S Oesophagus ◽

Low Grade ◽

Barrett's Oesophagus ◽

Low Grade Dysplasia

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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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