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When CNAs first occur is unknown. Here we show that CNAs typically form in BO many decades prior to first clinical detection of BO or cancer, and often during childhood. Using a novel molecular clock analysis, we analysed spatiotemporal longitudinal whole genome data from 80 individuals within BO surveillance. Chr 9p loss of heterozygosity (LOH) tended to be the first CNA event typically occurring at age 10-30 years. Genome doubling (GD) also typically originated multiple decades prior to cancer develop. Patients who progressed to OAC had an enrichment of CNAs late in life. CNA rate was more predictive of cancer risk than CNA burden. Analysis of OAC whole genomes confirmed the early-life origins of cancer-associated CNAs. The malignant transformation potential of BO may be set during the first decades of life, enabling early cancer interception.<\/jats:p>","DOI":"10.64898\/2026.10.16.26365037","type":"posted-content","created":{"date-parts":[[2026,10,21]],"date-time":"2026-10-21T20:25:13Z","timestamp":1792614313000},"source":"Crossref","is-referenced-by-count":0,"title":["Protracted copy number alteration evolution in Barrett\u2019s oesophagus leading to oesophageal cancer"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1946-4780","authenticated-orcid":false,"given":"Calum","family":"Gabbutt","sequence":"first","affiliation":[{"name":"Centre for Evolution and Cancer, Institute of Cancer Research, London, UK"},{"name":"Centre for Haematology, Department of Immunology and Inflammation, Imperial College London, London, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5851-9441","authenticated-orcid":false,"given":"Angel","family":"Fern\u00e1ndez-Sanrom\u00e1n","sequence":"additional","affiliation":[{"name":"Centre for Evolution and Cancer, Institute of Cancer Research, London, UK"},{"name":"CNIO, Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9500-1644","authenticated-orcid":false,"given":"Heather","family":"Grant","sequence":"additional","affiliation":[{"name":"Centre for Evolution and Cancer, Institute of Cancer Research, London, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0156-3636","authenticated-orcid":false,"given":"Salvatore","family":"Milite","sequence":"additional","affiliation":[{"name":"Human Technopole, Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4794-8777","authenticated-orcid":false,"given":"William CH","family":"Cross","sequence":"additional","affiliation":[{"name":"The Rare Malignancies and Cancer Evolution Lab, School of Biological Sciences, University of Reading, Reading, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicholas A","family":"Wright","sequence":"additional","affiliation":[{"name":"Barts Cancer Institute, Queen Mary University of London, London, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0745-7076","authenticated-orcid":false,"given":"Carlo C","family":"Maley","sequence":"additional","affiliation":[{"name":"Arizona Cancer Evolution Center; 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