Journal Article

DKFZ-2024-02655

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Disentangling oncogenic amplicons in esophageal adenocarcinoma.

Ng, A. W. T. ; McClurg, D. P. ; Wesley, B. ; Zamani, S. A. ; Black, E. ; Miremadi, A. ; Giger, O. ; Hoopen, R. T. ; Devonshire, G. ; Redmond, A. M. ; Grehan, N. ; Jammula, S. ; Blasko, A. ; Li, X. ; Aparicio, S. ; Tavaré, S. ; Clinical, O. C. ; Stratification, M. (Collaboration Author) ; Nowicki-Osuch, K. ; Fitzgerald, R. C. ; Edwards, P. A. W. (Contributor) ; Grehan, N. (Contributor) ; Nutzinger, B. (Contributor) ; Loreno, C. (Contributor) ; Abbas, S. (Contributor) ; Freeman, A. (Contributor) ; Smyth, E. C. (Contributor) ; O'Donovan, M. (Contributor) ; Miremadi, A. (Contributor) ; Malhotra, S. (Contributor) ; Tripathi, M. (Contributor) ; Cheah, C. (Contributor) ; Coles, H. (Contributor) ; Millington, C. (Contributor) ; Eldridge, M. (Contributor) ; Secrier, M. (Contributor) ; Jammula, S. (Contributor) ; Davies, J. (Contributor) ; Crichton, C. (Contributor) ; Carroll, N. (Contributor) ; Hardwick, R. H. (Contributor) ; Safranek, P. (Contributor) ; Hindmarsh, A. (Contributor) ; Sujendran, V. (Contributor) ; Hayes, S. J. (Contributor) ; Ang, Y. (Contributor) ; Sharrocks, A. (Contributor) ; Preston, S. R. (Contributor) ; Bagwan, I. (Contributor) ; Save, V. (Contributor) ; Skipworth, R. J. E. (Contributor) ; Hupp, T. R. (Contributor) ; O'Neill, J. R. (Contributor) ; Tucker, O. (Contributor) ; Beggs, A. (Contributor) ; Taniere, P. (Contributor) ; Puig, S. (Contributor) ; Contino, G. (Contributor) ; Underwood, T. J. (Contributor) ; Walker, R. C. (Contributor) ; Grace, B. L. (Contributor) ; Lagergren, J. (Contributor) ; Gossage, J. (Contributor) ; Davies, A. (Contributor) ; Chang, F. (Contributor) ; Mahadeva, U. (Contributor) ; Goh, V. (Contributor) ; Ciccarelli, F. D. (Contributor) ; Sanders, G. (Contributor) ; Berrisford, R. (Contributor) ; Chan, D. (Contributor) ; Cheong, E. (Contributor) ; Kumar, B. (Contributor) ; Sreedharan, L. (Contributor) ; Parsons, S. L. (Contributor) ; Soomro, I. (Contributor) ; Kaye, P. (Contributor) ; Saunders, J. (Contributor) ; Lovat, L. (Contributor) ; Haidry, R. (Contributor) ; Scott, M. (Contributor) ; Sothi, S. (Contributor) ; Lishman, S. (Contributor) ; Hanna, G. B. (Contributor) ; Peters, C. J. (Contributor) ; Moorthy, K. (Contributor) ; Grabowska, A. (Contributor) ; Turkington, R. (Contributor) ; McManus, D. (Contributor) ; Coleman, H. (Contributor) ; Petty, R. D. (Contributor) ; Bartlet, F. (Contributor)

2024
Nature Publishing Group UK [London]

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Please use a persistent id in citations: doi:10.1038/s41467-024-47619-4

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.

Keyword(s): Humans (MeSH) ; Esophageal Neoplasms: genetics (MeSH) ; Esophageal Neoplasms: pathology (MeSH) ; Adenocarcinoma: genetics (MeSH) ; Adenocarcinoma: pathology (MeSH) ; Organoids: pathology (MeSH) ; Gene Amplification (MeSH) ; DNA Methylation (MeSH) ; Oncogenes: genetics (MeSH) ; Male (MeSH) ; Sequence Analysis, DNA: methods (MeSH) ; Clonal Evolution: genetics (MeSH) ; Female (MeSH)

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Contributing Institute(s):

1. NWG Tumorgenese und molekulare Krebsprävention (C150)

Research Program(s):

1. 313 - Krebsrisikofaktoren und Prävention (POF4-313) (POF4-313)

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