%0 Journal Article
%A Ng, Alvin Wei Tian
%A McClurg, Dylan Peter
%A Wesley, Ben
%A Zamani, Shahriar A
%A Black, Emily
%A Miremadi, Ahmad
%A Giger, Olivier
%A Hoopen, Rogier Ten
%A Devonshire, Ginny
%A Redmond, Aisling M
%A Grehan, Nicola
%A Jammula, Sriganesh
%A Blasko, Adrienn
%A Li, Xiaodun
%A Aparicio, Samuel
%A Tavaré, Simon
%A Clinical, Oesophageal Cancer
%A Nowicki-Osuch, Karol
%A Fitzgerald, Rebecca C
%T Disentangling oncogenic amplicons in esophageal adenocarcinoma.
%J Nature Communications
%V 15
%N 1
%@ 2041-1723
%C [London]
%I Nature Publishing Group UK
%M DKFZ-2024-02655
%P 4074
%D 2024
%X 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.
%K Humans
%K Esophageal Neoplasms: genetics
%K Esophageal Neoplasms: pathology
%K Adenocarcinoma: genetics
%K Adenocarcinoma: pathology
%K Organoids: pathology
%K Gene Amplification
%K DNA Methylation
%K Oncogenes: genetics
%K Male
%K Sequence Analysis, DNA: methods
%K Clonal Evolution: genetics
%K Female
%F PUB:(DE-HGF)16
%9 Journal Article
%$ pmid:38744814
%2 pmc:PMC11094127
%R 10.1038/s41467-024-47619-4
%U https://inrepo02.dkfz.de/record/295835