Micronuclear ecDNA constrains tumor cell fitness and is associated with favorable patient survival

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+ MNs display impaired proliferative capacity and are more likely to undergo cell death. In patients with MYCN-amplified neuroblastoma, higher frequencies of ecDNA+ MNs at diagnosis are associated with improved overall survival. Together, these findings identify ecDNA mis-segregation as a mechanism that limits tumor fitness, highlighting mitotic ecDNA retention as a potential therapeutic vulnerability. Single-micronucleus sequencing and live-cell imaging of cancer cells, as well as analyses of biopsies from patients with neuroblastoma, reveal that ecDNA in micronuclei limits tumor cell fitness and is associated with patient survival.

The authors' abstract, as published at the source. Nature Genetics, 2026 · DOI ↗