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

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.

P-OGC95 Understanding the molecular age of Barrett’s oesophagus in a population-representative sample of patients

Background The incidence of oesophageal adenocarcinoma (OAC) increases dramatically with patient age but only a small proportion of patients with diagnosed Barrett’s oesophagus (BO), the precursor to OAC, will develop dysplasia and/or cancer. Beyond chronological age, biomarkers of progression that capture biological aging offer largely untapped potential for objectively identifying BO patients at highest risk of progression, who could undergo personalised surveillance at shorter intervals. We have developed computational tools to determine tissue-specific aging using genome-wide methylation data as a “molecular clock” for estimating patient-specific BO dwell times at the time of incident diagnosis that cannot be clinically measured by other means. Methods Using the population-based Northern Ireland BO register in a retrospective study, we have identified 46 non-dysplastic BO patients who have 2-4 serial endoscopic biopsies each, and have not progressed to OAC (age range 29-77 years). FFPE biopsies for 10 age-matched patients who had prevalent HGD/OAC at index BO diagnosis were also retrieved. DNA has been extracted, quantified using fluorescence, quality checked through qPCR, and prepared for Illumina EPIC methylation arrays. We created a Python package called “MethylDrift” to determine genome-wide aging rates in patient data. Model outputs are used in the molecular clock for BO tissue age. Results We used MethylDrift to quantify aging rates in both cross-sectional data (population-level epigenetic drift) and longitudinal data within the same patients to obtain individual aging rates. Computational analyses using our previously developed Bayesian framework for the BO molecular clock will be applied to estimate the molecular age of BO in patients, i.e., how long the patient has been living with BO since onset of metaplasia. Results will be compared between age groups, birth cohorts, sex, and importantly between dysplastic and non-dysplastic BO to evaluate biomarker potential. Data analysis is ongoing, and the final results will be presented at the meeting. Conclusions Our results from this nested case-control study demonstrate feasibility and generate pilot data on molecular age as a proxy of BO duration at the time of incident diagnosis, in a large population-based registry of patients with BO. This will inform our computational tools for determining biological aging and can be applied in future work to investigate progression risk according to molecular age. Ultimately, this biomarker could inform surveillance frequency for BO patients, enable earlier detection of neoplastic progression, leading to improved patient outcomes and optimal distribution of limited endoscopy capacity for surveillance.

P-OGC38 The Impact of the COVID-19 Pandemic on Barrett’s Oesophagus and Oesophago-gastric Cancer

Background The COVID-19 pandemic has placed an inexorable strain on endoscopy services worldwide, affecting the diagnosis of oesophago-gastric (OG) cancer and Barrett’s oesophagus (BO). As coronavirus infection rates rose many professional bodies advised that all endoscopy, except emergency and essential procedures be stopped immediately. We sought to quantify the decline in OG cancer and BO diagnoses following implementation of British Society of Gastroenterology (BSG) guidance related to COVID-19 and the psychosocial effects on BO patients. Methods We examined OG cancer and BO diagnoses in Northern Ireland from March-September 2020 and compared them with the three-year average number of patients during the same time period (corresponding to weeks 10-37) between 2017-2019 by utilising Northern Ireland Cancer Registry (NICR) data. The psychosocial impact of COVID-19 was assessed using an online survey, which included validated WHOQOL-BREF and EQ-5D-5L quality of life measures, and was completed by 24 BO patients from April-May 2020. Results Between March and September 2020 in Northern Ireland, the proportion of OG cancer and BO diagnoses declined by 26.6% and 59.3%, respectively, compared to expected levels. In April, BO diagnoses fell by 95.5% but by September, whilst OG cancer rates had returned to baseline, BO cases remained supressed by approximately 20%. We estimate that these declines in diagnosis represent 53 ‘missed’ OG cancer and 236 ‘missed’ BO diagnoses. In the online survey sample, BO patients reported consistently lower quality of life scores than population norms, and highlighted a number of concerns with regard to their health and care. Conclusions The COVID-19 pandemic has resulted in an abrupt decline in OG cancer and BO diagnoses and has profoundly impacted the wellbeing of BO patients. Our study represents the first report of the impact of COVID-19 on the diagnosis of BO. Strategies to mitigate the ongoing effects of the pandemic are urgently required to preserve the ability to rapidly detect and diagnose cancer and pre-malignant conditions.