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Review
. 2022 Dec;23(12):760-771.
doi: 10.1038/s41576-022-00521-5. Epub 2022 Aug 11.

Extrachromosomal DNA amplifications in cancer

Eunhee Yi #  1 , Rocío Chamorro González #  2   3   4 , Anton G Henssen  5   6   7   8   9 , Roel G W Verhaak  10   11
Affiliations
Review

Extrachromosomal DNA amplifications in cancer

Eunhee Yi et al. Nat Rev Genet. 2022 Dec.

Abstract

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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Conflict of interest statement

Competing interests

R.G.W.V. is a cofounder and/or advisor 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.

Figures

Figure 1.
Figure 1.. Oncogene amplification on ecDNA is a frequent event in cancer and promotes tumour heterogeneity.
a | The frequency of extrachromosomal DNA (ecDNA) amplification across newly diagnosed cancer–. b | EcDNA elements are replicated in S-phase and due to the absence of centromeres, segregate unevenly to daughter cells during mitosis. Clonal selection of tumour cells with an ecDNA-endowed proliferative advantage enables rapid intercellular diversification of ecDNA copy number and increases intratumoral heterogeneity.
Figure 2.
Figure 2.. EcDNA life cycle.
Following DNA breakage, extrachromosomal DNA (ecDNA) structures are formed through end-to-end ligation. Chromothripsis creates massive rearrangements and, like breakage-fusion-bridge (BFB) cycles, can result in complex ecDNA structures. EcDNA structures may evolve by acquiring new genome segments following additional breakage events, including through merging of co-existing ecDNAs. Selective pressure and linear DNA damage may cause ecDNA molecules to reintegrate into the linear genome and generate homogeneously staining regions (HSRs). Upon removal of selection pressure or changing circumstances, reintegrated ecDNAs may re-emerge.
Figure 3.
Figure 3.. EcDNA movement and location during the cell cycle.
During S-phase, extrachromosomal DNA (ecDNA) molecules relocate from the periphery to the centre of the nucleus. Replication occurs, resulting in double-minute shaped sister ecDNA chromatids, prior to the initiation of mitosis. During mitosis, ecDNAs randomly bind to chromosome ends and divide unequally to daughter cells. During anaphase, ecDNAs that are not tethered to chromosomal ends are clustered, are not carried into the newly forming daughter nuclei and remain in one daughter cell in micronuclei.
Figure 4.
Figure 4.. Chromatin organization on ecDNA.
a Extrachromosomal DNA (ecDNA) contains more accessible chromatin compared to linear chromosomal DNA, reflected by the increased read density and number of peaks in assay for transposase-accessible chromatin sequencing (ATAC-seq) profiles. b | The re-arrangement of distal chromosomal fragments into ecDNAs results in three-dimensional reorientation of chromatin elements and enables the ‘hijacking’ of distal enhancers.
Figure 5.
Figure 5.. The role of ecDNA and ecDNA hubs in transcriptional regulation.
a | Representative examples of extrachromosomal DNA (ecDNA) hubs. Example 1: an ecDNA hub comprising different ecDNA species containing cargo oncogene and cargo enhancers. Example 2: an ecDNA hub including some enhancer-only ecDNAs without cargo genes. EcDNAs are glued together by BRD4 and recruit RNA polymerase II (RNAPII). Co-amplified enhancer elements regulate gene transcription of ecDNA hub partners. b | EcDNAs that are in contact with chromosomes recruit RNAPII. Co-amplified enhancers regulate transcription of linear chromosome genes in proximity to contact regions.
Figure 6.
Figure 6.. Opportunities for development of ecDNA targeting therapeutic strategies.
New therapeutic approaches may be designed to target the amplification vehicle rather than amplified cargo genes, for improved outcomes of patients with extrachromosomal DNA (ecDNA)-containing cancer. At least five potential strategies for therapy are under consideration, including: blocking ecDNA replication (1); perturbing ecDNA segregation (2); disrupting ecDNA clustering into hubs (3); preventing new ecDNA formation (4); and promoting ecDNA expulsion in micronuclei (5).
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References

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    2. deCarvalho et al. (2018) and Turner et al. (2017) demonstrated that ecDNA is highly frequently observed in brain tumours, providing early suggestions that ecDNA incidence in cancer is much higher than previously thought.

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    2. deCarvalho et al. (2018) and Turner et al. (2017) demonstrated that ecDNA is highly frequently observed in brain tumours, providing early suggestions that ecDNA incidence in cancer is much higher than previously thought.

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