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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\u00a0pathology 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\u00a0cycle checkpoint, DNA repair and chromosomal instability; and epigenetic silencing of\u00a0Wnt signalling and cell\u00a0cycle genes. Timing analysis reveals molecular events triggering genomic instability with more clonal expansion\u00a0in dysplastic samples. Overall genomic complexity occurs early in the Barrett\u2019s natural history and may inform the potential for cancer beyond the clinically discernible phenotype.<\/jats:p>","DOI":"10.1038\/s41467-022-28237-4","type":"journal-article","created":{"date-parts":[[2022,3,17]],"date-time":"2022-03-17T07:04:45Z","timestamp":1647500685000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":41,"title":["Multi-omic cross-sectional cohort study of pre-malignant Barrett\u2019s esophagus reveals early structural variation and retrotransposon activity"],"prefix":"10.1038","volume":"13","author":[{"given":"A. 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