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Extrachromosomal DNA in the cancerous transformation of Barrett’s oesophagus

Author

Listed:
  • Jens Luebeck

    (University of California at San Diego
    University of California at San Diego)

  • Alvin Wei Tian Ng

    (University of Cambridge
    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
    Sungkyunkwan University)

  • Sriganesh Jammula

    (University of Cambridge)

  • Yudou He

    (UC San Diego Health
    University of California at San Diego
    University of California at San Diego)

  • 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
    University of California at San Diego
    University of California at San Diego)

  • Brian J. Reid

    (Fred Hutchinson Cancer Center
    University of Washington
    University of Washington)

  • Rebecca C. Fitzgerald

    (University of Cambridge)

  • Thomas G. Paulson

    (Fred Hutchinson Cancer Center)

  • Howard Y. Chang

    (Stanford University
    Stanford University)

  • Sihan Wu

    (University of Texas Southwestern Medical Center)

  • Vineet Bafna

    (University of California at San Diego
    University of California at San Diego)

  • Paul S. Mischel

    (Stanford University School of Medicine
    Stanford University)

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.

Suggested Citation

  • 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. Verha, 2023. "Extrachromosomal DNA in the cancerous transformation of Barrett’s oesophagus," Nature, Nature, vol. 616(7958), pages 798-805, April.
  • Handle: RePEc:nat:nature:v:616:y:2023:i:7958:d:10.1038_s41586-023-05937-5
    DOI: 10.1038/s41586-023-05937-5
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    Cited by:

    1. Alvin Wei Tian Ng & Dylan Peter McClurg & Ben Wesley & Shahriar A. Zamani & Emily Black & Ahmad Miremadi & Olivier Giger & Rogier ten Hoopen & Ginny Devonshire & Aisling M. Redmond & Nicola Grehan & S, 2024. "Disentangling oncogenic amplicons in esophageal adenocarcinoma," Nature Communications, Nature, vol. 15(1), pages 1-13, December.
    2. Shixiang Wang & Chen-Yi Wu & Ming-Ming He & Jia-Xin Yong & Yan-Xing Chen & Li-Mei Qian & Jin-Ling Zhang & Zhao-Lei Zeng & Rui-Hua Xu & Feng Wang & Qi Zhao, 2024. "Machine learning-based extrachromosomal DNA identification in large-scale cohorts reveals its clinical implications in cancer," Nature Communications, Nature, vol. 15(1), pages 1-17, December.
    3. Katelyn L. Mortenson & Courtney Dawes & Emily R. Wilson & Nathan E. Patchen & Hailey E. Johnson & Jason Gertz & Swneke D. Bailey & Yang Liu & Katherine E. Varley & Xiaoyang Zhang, 2024. "3D genomic analysis reveals novel enhancer-hijacking caused by complex structural alterations that drive oncogene overexpression," Nature Communications, Nature, vol. 15(1), pages 1-15, December.

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