Targeting Extrachromosomal DNA in Cancer: A New Frontier in Precision Oncology

Extrachromosomal DNA (ecDNA) has recently been recognized as a key driver of cancer biology, contributing to oncogene amplification, transcriptional reprogramming, intratumoral heterogeneity, and therapeutic resistance. Unlike chromosomal DNA, ecDNA exists as circular, acentromeric elements that undergo dynamic segregation, cluster into hubs, and engage in enhancer hijacking, thereby maintaining aggressive tumor phenotypes. This narrative review synthesizes current evidence on the molecular mechanisms underlying ecDNA formation, including Chromothripsis, breakage–fusion–bridge (BFB) cycles, and replication stress, and highlights how these events reform cancer genome architecture. We further discuss the rapid advances in detection methods, ranging from next-generation and single-cell sequencing to CRISPR-based capture techniques and liquid biopsy approaches, which have improved the identification and characterization of ecDNA in clinical samples. Increasing evidence links ecDNA to poor prognosis and therapy failure, underscoring its value as a prognostic biomarker and therapeutic target. Finally, we explore emerging strategies to disrupt ecDNA maintenance and function, which may open new avenues in precision oncology. Overall, ecDNA research is redefining our understanding of cancer evolution and offers promising translational opportunities.