Protracted copy number alteration evolution in Barrett’s oesophagus leading to oesophageal cancer

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Abstract
Detection of copy number alterations (CNAs) in Barrett’s oesophagus (BO) predicts oesophageal adenocarcinoma (OAC) risk. 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.
Funding Information
  • Wellcome Trust (202778/Z/16/Z)
  • NIH (U54 CA217376)
  • NIH (U2C CA233254)
  • NIH (R21 CA257980)
  • NIH (R01 CA140657)
  • Instituto de Salud Carlos III (CEX2019-000891- S)
  • Spanish Ministry of Science and Innovation (MCIN/AEI/10.13039/501100011033)
  • La Caixa Foundation (100010434; LCF/BQ/DR21/11880009)
  • European Molecular Biology Organization (EMBO Scientific Exchange Grant 10898)
  • Congressionally Directed Medical Research Programs (BC132057)

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