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Disentangling oncogenic amplicons in esophageal adenocarcinoma

Author

Listed:
  • Alvin Wei Tian Ng

    (University of Cambridge
    University of Cambridge
    Nanyang Technological University)

  • Dylan Peter McClurg

    (University of Cambridge)

  • Ben Wesley

    (Columbia University)

  • Shahriar A. Zamani

    (University of Cambridge)

  • Emily Black

    (University of Cambridge)

  • Ahmad Miremadi

    (Cambridge University Hospitals NHS Foundation Trust)

  • Olivier Giger

    (University of Cambridge)

  • Rogier ten Hoopen

    (University of Cambridge)

  • Ginny Devonshire

    (University of Cambridge)

  • Aisling M. Redmond

    (University of Cambridge)

  • Nicola Grehan

    (University of Cambridge)

  • Sriganesh Jammula

    (University of Cambridge)

  • Adrienn Blasko

    (University of Cambridge)

  • Xiaodun Li

    (University of Cambridge)

  • Samuel Aparicio

    (British Columbia Cancer Research Centre
    University of British Columbia)

  • Simon Tavaré

    (Columbia University
    Columbia University
    Columbia University)

  • Karol Nowicki-Osuch

    (Columbia University)

  • Rebecca C. Fitzgerald

    (University of Cambridge)

Abstract

Esophageal adenocarcinoma is a prominent example of cancer characterized by frequent amplifications in oncogenes. However, the mechanisms leading to amplicons that involve breakage-fusion-bridge cycles and extrachromosomal DNA are poorly understood. Here, we use 710 esophageal adenocarcinoma cases with matched samples and patient-derived organoids to disentangle complex amplicons and their associated mechanisms. Short-read sequencing identifies ERBB2, MYC, MDM2, and HMGA2 as the most frequent oncogenes amplified in extrachromosomal DNAs. We resolve complex extrachromosomal DNA and breakage-fusion-bridge cycles amplicons by integrating of de-novo assemblies and DNA methylation in nine long-read sequenced cases. Complex amplicons shared between precancerous biopsy and late-stage tumor, an enrichment of putative enhancer elements and mobile element insertions are potential drivers of complex amplicons’ origin. We find that patient-derived organoids recapitulate extrachromosomal DNA observed in the primary tumors and single-cell DNA sequencing capture extrachromosomal DNA-driven clonal dynamics across passages. Prospectively, long-read and single-cell DNA sequencing technologies can lead to better prediction of clonal evolution in esophageal adenocarcinoma.

Suggested Citation

  • 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.
  • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-47619-4
    DOI: 10.1038/s41467-024-47619-4
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    References listed on IDEAS

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