The Extrachromosomal DNA Fusion Factory: Extrachromosomal Genesis of Oncogenic Fusion Transcripts.

Fusion oncogenes are among the most potent and clinically actionable cancer drivers, contributing to approximately 15% to 20% of human malignancies. Traditionally viewed as stable consequences of chromosomal translocations, fusion oncogenesis has long been interpreted through a DNA-centric paradigm. However, this view is now challenged by the discovery of a vast and dynamic landscape of fusion RNAs. Recent integrative genomic studies suggest that extrachromosomal DNA (ecDNA) can serve as a platform for the formation, diversification, and amplification of oncogenic fusion transcripts in multiple cancer contexts. Here, we propose the "ecDNA fusion factory" as a unifying conceptual framework that integrates nonchromosomal genome architecture, structural instability, and RNA-level regulatory consequences to expand current understanding about the origin and adaptive evolution of some fusion drivers. In this model, fusion output can be dynamic and heterogeneous, shaped by ecDNA copy-number flux and context-dependent structural remodeling rather than exclusively by a single, fixed chromosomal breakpoint. This reframing suggests distinct therapeutic vulnerabilities, potentially motivating strategies that target both the fusion oncoprotein and the ecDNA platform that sustains it, and necessitates a revision of diagnostic paradigms to detect these structurally plastic and dynamically evolving oncogenic elements. Together, this perspective broadens current models of fusion-driven oncogenesis and highlights possible implications for precision oncology.