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| Item Type: | Preprint |
|---|---|
| Title: | Extrachromosomal DNA micronucleation constrains tumour fitness and improves patient survival |
| Creators: |
Brückner, L.  ORCID: https://orcid.org/0000-0002-6155-2277, Xu, R. ORCID: https://orcid.org/0000-0002-5618-246X, Tang, J., Gnanasekar, A., Herrmann, A., Wong, I.T.L., Zhang, S., Tu, F., Pilon, M., Kukalev, A. ORCID: https://orcid.org/0000-0001-5847-3773, Pardon, K., Sidorova, O. ORCID: https://orcid.org/0009-0004-1459-1662, Atta, J., Yu, Q. ORCID: https://orcid.org/0000-0002-2151-9624, Montouri, G., Pradella, D., Ilić, M., Suina, K., Novais-Cruz, M., Kaltenbach, S., Treue, D., Giurgiu-Kraljič, M. ORCID: https://orcid.org/0000-0001-5007-7442, Herzog, S., Hollinger, A.S., Wittstruck, N., Fernandez, M., Wolozyn, N., Becker, F., Louma, V.R., Yan, X., Schmargon, R. ORCID: https://orcid.org/0009-0009-3535-7185, Dörr, J. ORCID: https://orcid.org/0000-0002-4927-6548, Gamlin, D., Lehmann, A., Gürgen, D. ORCID: https://orcid.org/0000-0001-9241-6537, Richter, M. ORCID: https://orcid.org/0000-0002-5339-0781, Dubois, F. ORCID: https://orcid.org/0000-0002-7654-6208, Simeoni, F., Pennycook, B.R., Hamilton, A., Lindemann, R.K., Dawes, C., Balmus, G., Hero, B., Fischer, M., Bafna, V., Verhaak, R., Wahl, G., Liu, Y., Koche, R.P., Papathanasiou, S., Medema, R., Spanjaard, B. ORCID: https://orcid.org/0000-0003-1309-8839, Ventura, A., Pombo, A. ORCID: https://orcid.org/0000-0002-7493-6288, Huang, W., Scheer, M., Werner, B., Chang, H.Y., Mischel, P.S. and Henssen, A.G. ORCID: https://orcid.org/0000-0003-1534-778X
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| Abstract: | Extrachromosomal DNA (ecDNA) contributes to cancer genome instability by enabling high-copy oncogene amplification, intratumoural heterogeneity and rapid genetic change. Micronuclei (MN) are frequently observed in chromosomally unstable cancers, yet their origins and relevance in ecDNA-driven tumours remain incompletely understood. Here, we investigate the relationship between ecDNA segregation errors and MN formation. We find that ecDNA frequently localizes to MN and represents a prominent source of MN content in ecDNA-positive cancer cells. Mitotic clustering of oncogene-bearing ecDNAs is associated with asymmetric inheritance and mis-segregation into MN. Transfer of oncogenes from ecDNA into MN is accompanied by reduced transcriptional output. Single-MN sequencing shows that individual MN are enriched for ecDNA to a degree that exceeds expectations from stochastic mis-segregation and that in MN oncogenes originating from multiple distinct ecDNAs coalesce. Using live-cell imaging, we observe that cells inheriting ecDNA-positive MN show limited proliferative capacity and an increased likelihood of cell death. In neuroblastoma patients with MYCN-amplified ecDNA, higher frequencies of ecDNA-positive MN at diagnosis are associated with improved event-free and overall survival. Together, these findings link ecDNA mis-segregation to MN formation and reduced cellular fitness, suggesting that ecDNA-positive MN may reflect a state of impaired oncogenic ecDNA function with potential relevance for clinical outcome. |
| Source: | bioRxiv |
| Publisher: | Cold Spring Harbor Laboratory Press |
| Article Number: | 2025.04.15.648906 |
| Date: | 19 February 2026 |
| Official Publication: | https://doi.org/10.1101/2025.04.15.648906 |
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