Multi-omic cross-sectional cohort study of pre-malignant Barrett's esophagus reveals early structural variation and retrotransposon activity

The alterations associated with progression from Barrett's esophagus (BE) to esophageal adenocarcinoma are not fully characterised. Here, the authors perform a multi-omics analysis of a longitudinally-sampled BE patient cohort, identifying the impact of structural variants, including mobile elements, and the timing of molecular events during progression. Barrett's esophagus is a pre-malignant lesion that can progress to esophageal adenocarcinoma. We perform a multi-omic analysis of pre-cancer samples from 146 patients with a range of outcomes, comprising 642 person years of follow-up. Whole genome sequencing reveals complex structural variants and LINE-1 retrotransposons, as well as known copy number changes, occurring even prior to dysplasia. The structural variant burden captures the most variance across the cohort and genomic profiles do not always match consensus clinical pathology dysplasia grades. Increasing structural variant burden is associated with: high levels of chromothripsis and breakage-fusion-bridge events; increased expression of genes related to cell cycle checkpoint, DNA repair and chromosomal instability; and epigenetic silencing of Wnt signalling and cell cycle genes. Timing analysis reveals molecular events triggering genomic instability with more clonal expansion in dysplastic samples. Overall genomic complexity occurs early in the Barrett's natural history and may inform the potential for cancer beyond the clinically discernible phenotype.

Automated summary

In this study, a multi-omics analysis was performed on a cohort of Barrett's esophagus patients, revealing the impact of structural variants on disease progression and molecular events. The results show that genomic complexity occurs early in Barrett's esophagus and is associated with increased gene expression related to chromosomal instability, cell cycle, and DNA repair.