Extrachromosomal DNA in Cancer

In cancer, complex genome rearrangements and other structural alterations, including the amplification of oncogenes on circular extrachromosomal DNA (ecDNA) elements, drive the formation and progression of tumors. ecDNA is a particularly challenging structural alteration. By untethering oncogenes from chromosomal constraints, it elevates oncogene copy number, drives intratumoral genetic heterogeneity, promotes rapid tumor evolution, and results in treatment resistance. The profound changes in DNA shape and nuclear architecture generated by ecDNA alter the transcriptional landscape of tumors by catalyzing new types of regulatory interactions that do not occur on chromosomes. The current suite of tools for interrogating cancer genomes is well suited for deciphering sequence but has limited ability to resolve the complex changes in DNA structure and dynamics that ecDNA generates. Here, we review the challenges of resolving ecDNA form and function and discuss the emerging tool kit for deciphering ecDNA architecture and spatial organization, including what has been learned to date about how this dramatic change in shape alters tumor development, progression, and drug resistance.

Automated summary

In cancer, the amplification of oncogenes on circular extrachromosomal DNA (ecDNA) elements drives tumor formation and progression. ecDNA increases oncogene copy number, promotes genetic heterogeneity, and results in treatment resistance. It also alters the transcriptional landscape of tumors. Current tools are limited in resolving the complex changes in DNA structure and dynamics caused by ecDNA, but new tools are emerging.