ArticleNature genetics2026
Micronuclear ecDNA constrains tumor cell fitness and is associated with favorable patient survival.
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Article in Nature genetics, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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61 authors.
Lotte Brückner *Max Delbrück Center for Molecular Medicine, Berlin, Germany.ORCID http://orcid.org/0000-0002-6155-2277
Robin Xu *Department of Pediatric Oncology/Hematology, Charité-Universitätsmedizin Berlin, Berlin, Germany.ORCID http://orcid.org/0000-0002-5618-246X
Jun Tang *Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA.ORCID http://orcid.org/0009-0004-4606-2458
Aditi GnanasekarDepartment of Pathology, Stanford University School of Medicine, Stanford, CA, USA.
Alexander HerrmannDepartment of Pediatric Oncology/Hematology, Charité-Universitätsmedizin Berlin, Berlin, Germany.ORCID http://orcid.org/0009-0002-7700-6788
Ivy Tsz-Lo WongDepartment of Pathology, Stanford University School of Medicine, Stanford, CA, USA.ORCID http://orcid.org/0000-0002-9761-3422
Shu ZhangDepartment of Pathology, Stanford University School of Medicine, Stanford, CA, USA.ORCID http://orcid.org/0000-0003-2543-5943
Fengyu TuGroup of Theoretical Biology, The State Key Laboratory of Bio-control, School of Life Sciences, Sun Yat-sen University, Guangzhou, People's Republic of China.ORCID http://orcid.org/0000-0001-8748-7250
Madison PilonDepartment of Pediatric Oncology/Hematology, Charité-Universitätsmedizin Berlin, Berlin, Germany.ORCID http://orcid.org/0000-0001-9060-4817
Alexander KukalevMax Delbrück Center for Molecular Medicine, Berlin, Germany.ORCID http://orcid.org/0000-0001-5847-3773
Katharina PardonDepartment of Pediatric Oncology/Hematology, Charité-Universitätsmedizin Berlin, Berlin, Germany.
Olga SidorovaDepartment of Pediatric Oncology/Hematology, Charité-Universitätsmedizin Berlin, Berlin, Germany.ORCID http://orcid.org/0009-0004-1459-1662
Joshua AttaDepartment of Pediatric Oncology/Hematology, Charité-Universitätsmedizin Berlin, Berlin, Germany.
Qinghao YuDepartment of Pediatric Oncology/Hematology, Charité-Universitätsmedizin Berlin, Berlin, Germany.
Giulia MontuoriDepartment of Pediatric Oncology/Hematology, Charité-Universitätsmedizin Berlin, Berlin, Germany.
Davide PradellaCancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA.ORCID http://orcid.org/0000-0002-8649-7817
Mila IlićOncode Institute and Princess Máxima Center for Pediatric Oncology, Utrecht, The Netherlands.ORCID http://orcid.org/0000-0003-4664-9393
Kentaro SuinaDepartment of Neurosurgery, School of Medicine, Yale University, New Haven, CT, USA.
Marco Novais-CruzOncode Institute and Princess Máxima Center for Pediatric Oncology, Utrecht, The Netherlands.
Sarah KaltenbachInstitute of Molecular Biology, Mainz, Germany.
Denise TreueInstitute of Pathology, Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Berlin, Germany.
Mădălina Giurgiu-KraljičDepartment of Pediatric Oncology/Hematology, Charité-Universitätsmedizin Berlin, Berlin, Germany.ORCID http://orcid.org/0000-0001-5007-7442
Sergej HerzogMax Delbrück Center for Molecular Medicine, Berlin, Germany.
Ann-Sophie HollingerDepartment of Pediatric Oncology/Hematology, Charité-Universitätsmedizin Berlin, Berlin, Germany.
Nadine WittstruckDepartment of Pediatric Oncology/Hematology, Charité-Universitätsmedizin Berlin, Berlin, Germany.ORCID http://orcid.org/0009-0000-4378-3226
Martina FernandezDepartment of Pediatric Oncology/Hematology, Charité-Universitätsmedizin Berlin, Berlin, Germany.
Nicole WolozynDepartment of Pediatric Oncology/Hematology, Charité-Universitätsmedizin Berlin, Berlin, Germany.
Finnja BeckerDepartment of Pediatric Oncology/Hematology, Charité-Universitätsmedizin Berlin, Berlin, Germany.ORCID http://orcid.org/0009-0003-7014-7307
Varvara-Rigina LoumaDepartment of Pediatric Oncology/Hematology, Charité-Universitätsmedizin Berlin, Berlin, Germany.
Xiaowei YanDepartment of Pathology, Stanford University School of Medicine, Stanford, CA, USA.ORCID http://orcid.org/0000-0002-4846-8812
Rachel SchmargonDepartment of Pediatric Oncology/Hematology, Charité-Universitätsmedizin Berlin, Berlin, Germany.ORCID http://orcid.org/0009-0009-3535-7185
Jan R DörrDepartment of Pediatric Oncology/Hematology, Charité-Universitätsmedizin Berlin, Berlin, Germany.
David GamlinDepartment of Pediatric Oncology/Hematology, Charité-Universitätsmedizin Berlin, Berlin, Germany.
Annika LehmannInstitute of Pathology, Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Berlin, Germany.
Dennis GürgenExperimental Pharmacology and Oncology (EPO), Berlin, Germany.
Matthias RichterAdvanced Light Microscopy, Max Delbrück Center for Molecular Medicine in the Helmholtz Association, Robert-Rössle-Straße 10, Berlin, Germany.ORCID http://orcid.org/0000-0002-5339-0781
Frank DuboisInstitute of Pathology, Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Berlin, Germany.ORCID http://orcid.org/0000-0002-7654-6208
Fabrizio SimeoniEconic Biosciences, London, United Kingdom.ORCID http://orcid.org/0000-0002-5543-6413
Betheney R PennycookEconic Biosciences, London, United Kingdom.
Alastair HamiltonEconic Biosciences, London, United Kingdom.
Ralph K LindemannEconic Biosciences, London, United Kingdom.
Courtney DawesDepartment of Biochemistry, University of Utah, Salt Lake City, UT, USA.
Gabriel BalmusUK Dementia Research Institute, University of Cambridge, Cambridge, UK.ORCID http://orcid.org/0000-0003-2872-4468
Barbara HeroDepartment of Experimental Pediatric Oncology, University Children's Hospital of Cologne, Medical Faculty, Cologne, Germany.ORCID http://orcid.org/0000-0003-4129-890X
Matthias FischerDepartment of Experimental Pediatric Oncology, University Children's Hospital of Cologne, Medical Faculty, Cologne, Germany.ORCID http://orcid.org/0000-0003-1363-1242
Vineet BafnaDepartment of Computer Science and Engineering, University of San Diego, San Diego, CA, USA.ORCID http://orcid.org/0000-0002-5810-6241
Roel VerhaakDepartment of Neurosurgery, School of Medicine, Yale University, New Haven, CT, USA.ORCID http://orcid.org/0000-0003-2773-0436
Geoffrey WahlSalk Institute for Biological Studies, San Diego, CA, USA.ORCID http://orcid.org/0000-0003-3658-2279
Yang LiuDepartment of Biochemistry, University of Utah, Salt Lake City, UT, USA.ORCID http://orcid.org/0000-0002-3889-9707
Richard P KocheCenter for Epigenetics Research, Memorial Sloan Kettering Cancer Center, New York, NY, USA.ORCID http://orcid.org/0000-0002-6820-5083
Stamatis PapathanasiouInstitute of Molecular Biology, Mainz, Germany.ORCID http://orcid.org/0000-0001-6969-044X
René MedemaOncode Institute and Princess Máxima Center for Pediatric Oncology, Utrecht, The Netherlands.
Bastiaan SpanjaardDepartment of Pediatric Oncology/Hematology, Charité-Universitätsmedizin Berlin, Berlin, Germany.ORCID http://orcid.org/0000-0003-1309-8839
Andrea VenturaCancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA.ORCID http://orcid.org/0000-0003-4320-9907
Ana PomboMax Delbrück Center for Molecular Medicine, Berlin, Germany.ORCID http://orcid.org/0000-0002-7493-6288
Weini HuangDepartment of Mathematics, Queen Mary University of London, London, UK.ORCID http://orcid.org/0000-0002-9016-2665
Monika ScheerDepartment of Pediatric Oncology/Hematology, Charité-Universitätsmedizin Berlin, Berlin, Germany.
Benjamin WernerEvolutionary Dynamics Group, Centre for Cancer Evolution, Barts Cancer Institute, Queen Mary University of London, London, UK.ORCID http://orcid.org/0000-0002-6857-8699
Howard Y ChangDepartments of Dermatology, Genetics, and Pathology, Stanford University School of Medicine, Stanford, CA, USA.ORCID http://orcid.org/0000-0002-9459-4393
Paul S MischelDepartment of Pathology, Stanford University School of Medicine, Stanford, CA, USA. pmischel@stanford.edu.ORCID http://orcid.org/0000-0002-4560-2211
Anton G HenssenMax Delbrück Center for Molecular Medicine, Berlin, Germany. henssenlab@gmail.com.ORCID http://orcid.org/0000-0003-1534-778X
Funding
eDyNAmiC - STANFORDOT2CA278688 · NCI · STANFORD UNIVERSITY · PI PAUL S MISCHEL · 2022 to 2026
$7.7MeDyNAmiC - UCSDOT2CA278635 · NCI · UNIVERSITY OF CALIFORNIA, SAN DIEGO · PI Vineet Bafna · 2022 to 2026
$1.8MeDyNAmiC - CHARITEOT2CA278644 · NCI · CHARITE, UNIVERSITAETSMEDIZIN BERLIN · PI HENSSEN, ANTON GEORGE · 2022 to 2024
$214kCancer Research UK (CRUK) CGCATF-2021/100012Cancer Research UK (CRUK) CGCATF-2021/100017Cancer Research UK (CRUK) CGCATF-2021/100020Cancer Research UK (CRUK) CGCATF-2021/100025Cancer Research UK (CRUK) OT2CA278635Deutsche Forschungsgemeinschaft (German Research Foundation) 377984878Deutsche Forschungsgemeinschaft (German Research Foundation) 493872418Deutsche Forschungsgemeinschaft (German Research Foundation) 70114107EC | EU Framework Programme for Research and Innovation H2020 | H2020 Priority Excellent Science | H2020 European Research Council (H2020 Excellent Science - European Research Council) 949172U.S. Department of Health & Human Services | National Institutes of Health (NIH) 398299703U.S. Department of Health & Human Services | NIH | National Cancer Institute (NCI) CA282913U.S. Department of Health & Human Services | NIH | National Cancer Institute (NCI) CGCATF-2021/100020U.S. Department of Health & Human Services | NIH | National Cancer Institute (NCI) OT2CA278635U.S. Department of Health & Human Services | NIH | National Cancer Institute (NCI) OT2CA278644U.S. Department of Health & Human Services | NIH | National Cancer Institute (NCI) OT2CA278688
Abstract
Extrachromosomal DNA (ecDNA) contributes to cancer genome instability by enabling high-copy oncogene amplification and genetic intratumoral heterogeneity. Micronuclei (MNs) are common in chromosomally unstable cancers, yet their role in ecDNA-driven tumors remains unclear. Here we investigate how ecDNA damage, mitotic segregation and MN formation are linked. We find that ecDNAs are a major source of MNs following their damage, particularly under replication stress. Replication stress promotes mitotic ecDNA clustering, asymmetric inheritance, mis-segregation into MNs and reduced transcriptional output. Single-MN sequencing reveals that multiple distinct ecDNA species coalesce within individual MNs. Cells inheriting ecDNA
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