Extrachromosomal DNA in the cancerous transformation of Barrett’s oesophagus

Jens Luebeck, Alvin Wei Tian Ng, Patricia C. Galipeau, Xiaohong Li, Carissa A. Sanchez, Annalise C. Katz-Summercorn, Hoon Kim, Sriganesh Jammula, Yudou He, Scott M. Lippman, Roel G. W. Verhaak, Carlo C. Maley, Ludmil B. Alexandrov, Brian J. Reid, Rebecca C. Fitzgerald (), Thomas G. Paulson (), Howard Y. Chang (), Sihan Wu (), Vineet Bafna () and Paul S. Mischel ()
Additional contact information
Jens Luebeck: University of California at San Diego
Alvin Wei Tian Ng: University of Cambridge
Patricia C. Galipeau: Fred Hutchinson Cancer Center
Xiaohong Li: Fred Hutchinson Cancer Center
Carissa A. Sanchez: Fred Hutchinson Cancer Center
Annalise C. Katz-Summercorn: University of Cambridge
Hoon Kim: Sungkyunkwan University
Sriganesh Jammula: University of Cambridge
Yudou He: UC San Diego Health
Scott M. Lippman: UC San Diego Health
Roel G. W. Verhaak: The Jackson Laboratory for Genomic Medicine
Carlo C. Maley: Arizona State University
Ludmil B. Alexandrov: UC San Diego Health
Brian J. Reid: Fred Hutchinson Cancer Center
Rebecca C. Fitzgerald: University of Cambridge
Thomas G. Paulson: Fred Hutchinson Cancer Center
Howard Y. Chang: Stanford University
Sihan Wu: University of Texas Southwestern Medical Center
Vineet Bafna: University of California at San Diego
Paul S. Mischel: Stanford University School of Medicine

Nature, 2023, vol. 616, issue 7958, 798-805

Abstract: Abstract Oncogene amplification on extrachromosomal DNA (ecDNA) drives the evolution of tumours and their resistance to treatment, and is associated with poor outcomes for patients with cancer1–6. At present, it is unclear whether ecDNA is a later manifestation of genomic instability, or whether it can be an early event in the transition from dysplasia to cancer. Here, to better understand the development of ecDNA, we analysed whole-genome sequencing (WGS) data from patients with oesophageal adenocarcinoma (EAC) or Barrett’s oesophagus. These data included 206 biopsies in Barrett’s oesophagus surveillance and EAC cohorts from Cambridge University. We also analysed WGS and histology data from biopsies that were collected across multiple regions at 2 time points from 80 patients in a case–control study at the Fred Hutchinson Cancer Center. In the Cambridge cohorts, the frequency of ecDNA increased between Barrett’s-oesophagus-associated early-stage (24%) and late-stage (43%) EAC, suggesting that ecDNA is formed during cancer progression. In the cohort from the Fred Hutchinson Cancer Center, 33% of patients who developed EAC had at least one oesophageal biopsy with ecDNA before or at the diagnosis of EAC. In biopsies that were collected before cancer diagnosis, higher levels of ecDNA were present in samples from patients who later developed EAC than in samples from those who did not. We found that ecDNAs contained diverse collections of oncogenes and immunomodulatory genes. Furthermore, ecDNAs showed increases in copy number and structural complexity at more advanced stages of disease. Our findings show that ecDNA can develop early in the transition from high-grade dysplasia to cancer, and that ecDNAs progressively form and evolve under positive selection.

Date: 2023
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DOI: 10.1038/s41586-023-05937-5

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