Abstract
Extrachromosomal DNA (ecDNA) amplification has been observed in at least 30 different cancer types and is associated with worse patient outcomes. This has been linked to increased oncogene dosage because both oncogenes and associated enhancers can occupy ecDNA. New data challenge the view that only oncogene dosage is affected by ecDNA, and raises the possibility that ecDNA could disrupt genome-wide gene expression. Recent investigations suggest that ecDNA localizes to specialized nuclear bodies (hubs) in which they can act in trans as ectopic enhancers for genes on other ecDNA or chromosomes. Moreover, ecDNA can reintegrate into the genome, possibly further disrupting the gene regulatory landscape in tumor cells. In this Perspective, we discuss the emerging properties of ecDNA and highlight promising avenues to exploit this new knowledge for the development of ecDNA-directed therapies for cancer.
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Acknowledgements
We apologize to colleagues whose work was not discussed or cited due to space constraints. We thank G. Wahl, K. Astrahantseff, J. Glaser, K. Helmsauer and R. Koche for fruitful discussions. A.G.H. is supported by Deutsche Forschungsgemeinschaft (no. 398299703) and the European Research Council under the European Union’s Horizon 2020 research and innovation program (grant agreement no. 949172).
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A.G.H wrote the manuscript. E.V.L. designed the figures and contributed to the manuscript text. L.B. contributed to the text and the reference list.
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van Leen, E., Brückner, L. & Henssen, A.G. The genomic and spatial mobility of extrachromosomal DNA and its implications for cancer therapy. Nat Genet 54, 107–114 (2022). https://doi.org/10.1038/s41588-021-01000-z
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DOI: https://doi.org/10.1038/s41588-021-01000-z
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