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The genomic and spatial mobility of extrachromosomal DNA and its implications for cancer therapy

Nature Genetics volume 54, pages 107–114 (2022)Cite this article

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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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Fig. 1: Schematic view of noncanonical ecDNA activities related to genomic and spatial mobility.
Fig. 2: Formation and reintegration of ecDNA.
Fig. 3: ecDNA interactions in cis and in trans.
Fig. 4: Potential ecDNA-directed therapies.

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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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  1. Department of Pediatric Oncology/Hematology, Charité-Universitätsmedizin Berlin, Berlin, Germany

    Eric van Leen & Anton G. Henssen

  2. Experimental and Clinical Research Center of the MDC and Charité Berlin, Berlin, Germany

    Eric van Leen & Anton G. Henssen

  3. Max-Delbrück-Centrum für Molekulare Medizin, Berlin, Germany

    Lotte Brückner & Anton G. Henssen

  4. Berlin Institute of Health, Berlin, Germany

    Anton G. Henssen

  5. German Cancer Consortium, Partner Site Berlin, and German Cancer Research Center, Heidelberg, Germany

    Anton G. Henssen

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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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