Disentangling oncogenic amplicons in esophageal adenocarcinoma

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, Sriganesh Jammula, Adrienn Blasko, Xiaodun Li, Samuel Aparicio, Simon Tavaré, Karol Nowicki-Osuch and Rebecca C. Fitzgerald ()
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Alvin Wei Tian Ng: University of Cambridge
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
Simon Tavaré: Columbia University
Karol Nowicki-Osuch: Columbia University
Rebecca C. Fitzgerald: University of Cambridge

Nature Communications, 2024, vol. 15, issue 1, 1-13

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-47619-4

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