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.
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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 supported 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 supported by a fellowship from the ‘la Caixa’ Foundation (ID 100010434). The fellowship code is LCF/BQ/EU20/11810051.
R.G.W.V. is a co-founder and/or adviser of Boundless Bio and Stellanova Therapeutics. There is no commercial interest or intellectual property associated with this work. The remaining authors declare no competing interests.
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Genes involved in normal cell growth that, when abnormally activated, lead or contribute to cancer development.
- Focal amplification
A DNA region that only spans a sub-chromosomal arm proportion of the chromosome and is amplified at a high level; that is, more than eight copies.
- Intratumoural heterogeneity
The differences among cancer cells within the same tumour.
- Cargo gene
Any gene (or genes) harboured on the sequence of an extrachromosomal DNA (ecDNA) element.
- Homogeneously staining regions
(HSRs). Chromosomal regions with DNA amplification presenting a uniformed staining pattern with Giemsa nucleic acid stain.
- Enhancer hijacking
A process in which a somatic structural genomic rearrangement brings an enhancer into physical proximity of a gene it does not normally interact with, and activates it ectopically.
The type of zygosity in which only one allele contains a gene or mutation.
The process of inferring haplotype information of a sequence from genomic data.
A massive chromosomal rearrangement resulting from a chromosome shattering event, characterized by more than 20 DNA fragments stitched together in an abnormal order.
- Breakage–fusion–bridge cycles
(BFBs). A mechanism of chromosomal instability caused by a cycle of telomere breaks and dicentric chromosome formation.
A cellular process in which replicated genetic information in a single cell is divided into two identical nuclei.
The small nuclear structures that reside in the cytoplasm and contain damaged DNA fragments which were not incorporated into the main nucleus after mitosis.
- ecDNA concatenation
(Extrachromosomal DNA concatenation). A structure in which two or more closed circular DNAs are interlinked.
- Chromatin accessibility
The extent to which proteins are able to interact with chromatinized DNA, which is regulated through nucleosome occupancy and other factors occluding access to DNA.
- Transcription factories
Molecular complexes consisting of extrachromosomal DNAs (ecDNAs) and transcription machinery components, with high transcriptional activity of ecDNA sequences.
- Synthetic aneuploidy effect
Increased transcriptional activity of regions of the genome where extrachromosomal DNAs (ecDNAs) make a physical connection, similar to the effect of aneuploidy.
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Yi, E., Chamorro González, R., Henssen, A.G. et al. Extrachromosomal DNA amplifications in cancer. Nat Rev Genet (2022). https://doi.org/10.1038/s41576-022-00521-5