Extrachromosomal DNA amplifications in cancer.
Nature reviews. Genetics
JGM, Humans, Oncogenes, Neoplasms, Chromosomes, DNA
Nat Rev Genet. 2022;23(12):760-71
The authors thank K. Seburn for providing constructive feedback while writing the manuscript (The Jackson Laboratory (JAX), Research Program Development). They thank C.-l. Wei (JAX) and R. Koche (Memorial Sloan–Kettering Cancer Center) for helpful discussions. This work was sup- ported by grants from the US National Institutes of Health (NIH) (R01 CA237208, R21 NS114873, R21 CA256575, R33 CA236681, OT2 CA278649 and Cancer Center Support Grant P30 CA034196 (R.G.W.V.)), Cancer Research UK (reference 270422-0523 to R.G.W.V.) and a grant from the Brain Tumour Charity (R.G.W.V.). E.Y. is supported by a basic research fellowship from the American Brain Tumour Association (BRF1800014). A.G.H. is supported by the Deutsche Forschungsgemeinschaft (DFG; German Research Foundation) (398299703, the eDynamic Cancer Grand Challenge) and the European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation programme (grant agreement No. 949172). R.C.G. is sup- ported by a fellowship from the ‘la Caixa’ Foundation (ID 100010434). The fellowship code is LCF/BQ/ EU20/11810051.
Extrachromosomal DNA (ecDNA) amplification is an important driver alteration in cancer. It has been observed in most cancer types and is associated with worse patient outcome. The functional impact of ecDNA has been linked to its unique properties, such as its circular structure that is associated with altered chromatinization and epigenetic regulatory landscape, as well as its ability to randomly segregate during cell division, which fuels intercellular copy number heterogeneity. Recent investigations suggest that ecDNA is structurally more complex than previously anticipated and that it localizes to specialized nuclear bodies (hubs) and can act in trans as an enhancer for genes on other ecDNAs or chromosomes. In this Review, we synthesize what is currently known about how ecDNA is generated and how its genetic and epigenetic architecture affects proto-oncogene deregulation in cancer. We discuss how recently identified ecDNA functions may impact oncogenesis but also serve as new therapeutic vulnerabilities in cancer.
Chamorro González R,
Extrachromosomal DNA amplifications in cancer. Nat Rev Genet. 2022;23(12):760-71