biostudies-literatureMontuori GNational Institute of Neurological Disorders and StrokeDeutsche Forschungsgemeinschaft (DFG)Cancer Research UKBerlin Institute of HealthDeutsche KrebshilfeNational Institute of Neurological Disorders and Stroke (NINDS)Berlin Center for Machine LearningUK Research and InnovationDeutsche Krebshilfe (German Cancer Aid)National Cancer Institute (NCI)UK Research and Innovation (UKRI)Berlin Institute of Health (BIH)Berlin Center for Machine Learning (BZML)European Research CouncilDeutsche ForschungsgemeinschaftNational Cancer InstituteChief Scientist OfficeNINDS NIH HHSNCI NIH HHSWellcome Trust2054-2077https://www.ebi.ac.uk/biostudies/studies/S-EPMC12456741biostudies-literatureUnknown15(10)Extrachromosomal DNA (ecDNA) amplification enhances intercellular oncogene dosage variability and accelerates tumor evolution by violating foundational principles of genetic inheritance through its asymmetric mitotic segregation. Spotlighting high-risk neuroblastoma, we demonstrate how ecDNA amplification undermines the clinical efficacy of current therapies in cancers with extrachromosomal MYCN amplification. Integrating theoretical models of oncogene copy number-dependent fitness with single-cell ecDNA quantification and phenotype analyses, we reveal that ecDNA copy-number heterogeneity drives phenotypic diversity and determines treatment sensitivity through mechanisms unattainable by chromosomal oncogene amplification. We demonstrate that ecDNA copy number directly influences cell fate Cancer discoveryExtrachromosomal DNA-Driven Oncogene Dosage Heterogeneity Promotes Rapid Adaptation to Therapy in MYCN-Amplified Cancers.PMC12456741NS132780MR/V02342X/1CA030199949172R01 NS13278039829970370114107Clinician Scientist ProgramPCL/23/04P30 CA030199CRC1588161L0222Gargiulo GRosenfeldt MTRodriguez-Fos ESchmargon RKoch AMontuori GDorr JRMandal SKrieger TGWerner BHenssen AGEggert ATheißen JLehmann AGurgen DTu FDubois FPBKunkele APurshouse KSchmitt MJHui HSpanjaard BBuck VHundsdoerfer PTaschner-Mandl SChavez LGrunewald LHuang WSchallenberg SFischer MSeyboldt HQin DHelmsauer KBosco BFankhanel LCoscia FfalseExtrachromosomal DNA-Driven Oncogene Dosage Heterogeneity Promotes Rapid Adaptation to Therapy in MYCN-Amplified Cancers.Extrachromosomal DNA (ecDNA) amplification enhances intercellular oncogene dosage variability and accelerates tumor evolution by violating foundational principles of genetic inheritance through its asymmetric mitotic segregation. Spotlighting high-risk neuroblastoma, we demonstrate how ecDNA amplification undermines the clinical efficacy of current therapies in cancers with extrachromosomal MYCN amplification. Integrating theoretical models of oncogene copy number-dependent fitness with single-cell ecDNA quantification and phenotype analyses, we reveal that ecDNA copy-number heterogeneity drives phenotypic diversity and determines treatment sensitivity through mechanisms unattainable by chromosomal oncogene amplification. We demonstrate that ecDNA copy number directly influences cell fate 2025-01-01T00:00:00Z2025 Oct2026-06-04T06:54:21.62Z2026-05-06T03:12:17.145ZS-EPMC124567414077359510.1158/2159-8290.cd-24-173810.1158/2159-8290.CD-24-1738