{"doi":"10.1101/2025.04.15.648906","title":"Extrachromosomal DNA micronucleation constrains tumour fitness and improves patient survival","abstract":"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.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2025,"id":554977,"datarank":0.27998630330755975,"base_score":1.791759469228055,"endowment":1.791759469228055,"self_citation_contribution":0.26876392038420827,"citation_network_contribution":0.011222382923351495,"self_endowment_contribution":0.26876392038420827,"citer_contribution":0.011222382923351495,"corpus_percentile":null,"corpus_rank":null,"citation_count":5,"citer_count":2,"citers_with_citation_signal":1,"citers_with_endowment":1,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9571,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":991158,"name":"Robin Xu","orcid":"0000-0002-5618-246X","position":1,"is_corresponding":false},{"id":555973,"name":"Jun Tang","orcid":"0000-0002-9788-8389","position":2,"is_corresponding":false},{"id":1365490,"name":"Aditi Gnanasekar","orcid":"0000-0002-8303-8674","position":3,"is_corresponding":false},{"id":1452801,"name":"Alexander M. 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