Extrachromosomal DNA (ecDNA) in cancer pathogenesis.

In cancer, oncogenes and surrounding regulatory regions can untether themselves from chromosomes, forming extrachromosomal DNA particles (ecDNAs). Because of their non-chromosomal inheritance, ecDNA drives high oncogene copy number and intratumoral genetic heterogeneity, endowing tumors with the ability to rapidly change their genomes, accelerating tumor evolution, and contributing to therapeutic resistance. Further, the circular topology of ecDNA leads to enhanced chromatin accessibility, altered gene regulation, and massive oncogene transcription, driving tumor growth and progression, and placing ecDNA at the interface of cancer genomics and epigenetics. Recent studies show that ecDNA is a common event in many of the most aggressive forms of cancer, potentially challenging our current precision oncology approaches. In this review, we discuss what is known about ecDNA and its biological and clinical impact, highlighting new research and suggesting the promise, and some of the challenges ahead for the field.