Extrachromosomal DNA as a dynamic engine of cancer evolution: structure, plasticity and therapeutic resistance

Extrachromosomal DNA (ecDNA) has become recognized as a common and influential form of oncogene and regulatory element amplification in human cancers. EcDNA consists of large, acentric circular DNA molecules that replicate autonomously. They frequently carry oncogenes, immune modulatory genes and enhancers, and they segregate in a non-Mendelian manner during mitosis. These properties support high transcriptional output, marked intratumoral heterogeneity and rapid adaptation. EcDNA has been proved that is associated with immune evasion, treatment resistance and poor prognosis. In this review, we bring together recent work to argue that ecDNA is better understood as a dynamic and selectable genomic subsystem rather than a static amplification artifact. First, we summarize current models of ecDNA formation, maintenance and structural plasticity. We then outline key functional features of ecDNA, such as oncogene amplification, enhancer hijacking, three-dimensional clustering into transcriptional hubs and epigenetic remodeling of cell states. Drawing on multi-region and longitudinal analyses, we distinguish between tumor lineage and circle lineage and describe how ecDNA architectures can define parallel evolutionary trajectories within and across lesions. We next consider how ecDNA behaves under therapeutic pressure and contributes to different cancer therapy through reversible copy number changes, pathway rewiring and non-genetic state transitions. Finally, we discuss recent advances in ecDNA detection from diverse data sources, potent clinical applications and early attempts to exploit ecDNA-specific vulnerabilities. Viewing ecDNA in this dynamic framework emphasizes its central role in cancer evolution and points to concrete opportunities to refine patient stratification and to develop strategies that selectively eliminate ecDNA-driven tumors.