TY  - JOUR
AU  - Ng, Alvin Wei Tian
AU  - McClurg, Dylan Peter
AU  - Wesley, Ben
AU  - Zamani, Shahriar A
AU  - Black, Emily
AU  - Miremadi, Ahmad
AU  - Giger, Olivier
AU  - Hoopen, Rogier Ten
AU  - Devonshire, Ginny
AU  - Redmond, Aisling M
AU  - Grehan, Nicola
AU  - Jammula, Sriganesh
AU  - Blasko, Adrienn
AU  - Li, Xiaodun
AU  - Aparicio, Samuel
AU  - Tavaré, Simon
AU  - Clinical, Oesophageal Cancer
AU  - Nowicki-Osuch, Karol
AU  - Fitzgerald, Rebecca C
TI  - Disentangling oncogenic amplicons in esophageal adenocarcinoma.
JO  - Nature Communications
VL  - 15
IS  - 1
SN  - 2041-1723
CY  - [London]
PB  - Nature Publishing Group UK
M1  - DKFZ-2024-02655
SP  - 4074
PY  - 2024
AB  - 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.
KW  - Humans
KW  - Esophageal Neoplasms: genetics
KW  - Esophageal Neoplasms: pathology
KW  - Adenocarcinoma: genetics
KW  - Adenocarcinoma: pathology
KW  - Organoids: pathology
KW  - Gene Amplification
KW  - DNA Methylation
KW  - Oncogenes: genetics
KW  - Male
KW  - Sequence Analysis, DNA: methods
KW  - Clonal Evolution: genetics
KW  - Female
LB  - PUB:(DE-HGF)16
C6  - pmid:38744814
C2  - pmc:PMC11094127
DO  - DOI:10.1038/s41467-024-47619-4
UR  - https://inrepo02.dkfz.de/record/295835
ER  -