Insights into Extrachromosomal DNA in Cancer: Biogenesis, Methodologies, Functions, and Therapeutic Potential

Abstract Originating from, but independent of, linear chromosomes, extrachromosomal DNA (ecDNA) exists in a more active state of transcription and autonomous replication. It plays a crucial role in the development of malignancies and therapy resistance. Since its discovery in eukaryotic cells more than half a century ago, the biological characteristics and functions of ecDNA have remained unclear due to limitations in detection methods. However, recent advancements in research tools have transformed ecDNA research. It is believed that ecDNA exhibits greater activity in the abnormal amplification of oncogenes, thereby driving cancer progression through their overexpression. Notably, compared to linear DNA, ecDNA can also function as a genomic element with regulatory roles, including both trans‐ and cis‐acting functions. Its critical roles in tumorigenesis, evolution, progression, and drug resistance in malignant tumors are increasingly recognized. This review provides a comprehensive summary of the evolutionary context of ecDNA and highlights significant progress in understanding its biological functions and potential applications as a therapeutic target in malignant tumors.