Extrachromosomal DNA micronucleation constrains tumour fitness and improves patient survival

Brückner, L.; Xu, R.; Tang, J.; Gnanasekar, A.; Herrmann, A.; Wong, I.T.L.; Zhang, S.; Tu, F.; Pilon, M.; Kukalev, A.; Pardon, K.; Sidorova, O.; Atta, J.; Yu, Q.; Montouri, G.; Pradella, D.; Ilić, M.; Suina, K.; Novais-Cruz, M.; Kaltenbach, S.; Treue, D.; Giurgiu-Kraljič, M.; Herzog, S.; Hollinger, A.S.; Wittstruck, N.; Fernandez, M.; Wolozyn, N.; Becker, F.; Louma, V.R.; Yan, X.; Schmargon, R.; Dörr, J.; Gamlin, D.; Lehmann, A.; Gürgen, D.; Richter, M.; Dubois, F.; 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.; Ventura, A.; Pombo, A.; Huang, W.; Scheer, M.; Werner, B.; Chang, H.Y.; Mischel, P.S.; Henssen, A.G.

Extrachromosomal DNA micronucleation constrains tumour fitness and improves patient survival

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Item Type:	Preprint
Title:	Extrachromosomal DNA micronucleation constrains tumour fitness and improves patient survival
Creators Name:	Brückner, L., Xu, R., Tang, J., Gnanasekar, A., Herrmann, A., Wong, I.T.L., Zhang, S., Tu, F., Pilon, M., Kukalev, A., Pardon, K., Sidorova, O., Atta, J., Yu, Q., Montouri, G., Pradella, D., Ilić, M., Suina, K., Novais-Cruz, M., Kaltenbach, S., Treue, D., Giurgiu-Kraljič, M., Herzog, S., Hollinger, A.S., Wittstruck, N., Fernandez, M., Wolozyn, N., Becker, F., Louma, V.R., Yan, X., Schmargon, R., Dörr, J., Gamlin, D., Lehmann, A., Gürgen, D., Richter, M., Dubois, F., 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., Ventura, A., Pombo, A., Huang, W., Scheer, M., Werner, B., Chang, H.Y., Mischel, P.S. and Henssen, A.G.
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
Related to:	URL URL Type https://github.com/henssen-lab/ecMN Software

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