Abstract
Extrachromosomal DNA (ecDNA) has recently been recognized as a major contributor to cancer pathogenesis that is identified in most cancer types and is associated with poor outcomes. When it was discovered over 60 years ago, ecDNA was considered to be rare, and its impact on tumour biology was not well understood. The application of modern imaging and computational techniques has yielded powerful new insights into the importance of ecDNA in cancer. The non-chromosomal inheritance of ecDNA during cell division results in high oncogene copy number, intra-tumoural genetic heterogeneity and rapid tumour evolution that contributes to treatment resistance and shorter patient survival. In addition, the circular architecture of ecDNA results in altered patterns of gene regulation that drive elevated oncogene expression, potentially enabling the remodelling of tumour genomes. The generation of clusters of ecDNAs, termed ecDNA hubs, results in interactions between enhancers and promoters in trans, yielding a new paradigm in oncogenic transcription. In this Review, we highlight the rapid advancements in ecDNA research, providing new insights into ecDNA biogenesis, maintenance and transcription and its role in promoting tumour heterogeneity. To conclude, we delve into a set of unanswered questions whose answers will pave the way for the development of ecDNA targeted therapeutic approaches.
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Acknowledgements
This work was delivered as part of the eDyNAmiC team supported by the Cancer Grand Challenges partnership funded by Cancer Research UK (CRUK) (P.M. and H.C., CGCATF-2021/100012) and the National Cancer Institute (P.M. and H.C., OT2CA278688). This study was also supported by a grant from the National Brain Tumour Society (P.S.M.) and National Institutes of Health (NIH) R01-CA238379 (P.S.M.). X.Y. is a Damon Runyon Fellow supported by the Damon Runyon Cancer Research Foundation (DRG-2474-22). In addition, we thank members of Chang and Mischel labs for helpful discussions.
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H.C. is a co-founder of Accent Therapeutics, Boundless Bio, Cartography Biosciences and Orbital Therapeutics, and is an adviser to 10x Genomics, Arsenal Biosciences, Chroma Medicine and Spring Discovery. P.M. is a co-founder of, chairs the scientific advisory board (SAB) of and has equity interest in Boundless Bio. P.M. is also an adviser with equity for Asteroid Therapeutics. X.Y declares no competing interests.
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Glossary
- Breakage–fusion–bridge (BFB) cycle
-
A mechanism of chromosomal instability wherein broken ends of different chromatids or chromosomes fuse.
- ChIA-Drop
-
A chromatin conformation capture technique that combines chromatin immunoprecipitation with droplet-based single-cell sequencing, allowing the investigation of chromatin interactions at the single-cell level.
- Chromatin interaction analysis with paired-end-tag sequencing
-
(ChIA-PET). A genomic technique that enables the identification and mapping of long-range chromatin interactions by combining chromatin immunoprecipitation with paired-end high-throughput sequencing.
- Chromosome territories
-
The specific region of the nucleus that a certain chromosome tends to occupy.
- CRISPR-C
-
A technique that allows in vitro ecDNA generation in cells by inducing double-strand breaks flanking the region of interest upon the delivery of pairs of CRISPR–Cas9 guide RNAs.
- Double minutes
-
(DM). A traditional term for ecDNA that is still indicated in names of most ecDNA-containing cell lines, for example Colo 320DM.
- Gene amplification
-
A process by which the copy number of a specific gene is increased in a cell, leading to heightened expression and contributing to the development and progression of cancer when oncogene is amplified.
- Genetic identity by descent
-
A genetic term indicating the sharing of a specific DNA segment between two or more individuals owing to inheritance from a common ancestor.
- Homogeneously staining region
-
(HSR). A large repetitive region in a chromosome that displays a homogeneous staining pattern when targeted with probes; in this Review, HSR is used to mostly refer to oncogene amplification regions in chromosomes.
- Microhomology
-
The presence of short, identical or nearly identical sequences (typically 2 to 20 base pairs) at or near the ends of two DNA fragments, typically arising during DNA repair or rearrangment to facilitate precise alignment.
- Micronuclei
-
Small, additional nuclei that can form during cell division and contain fragments of chromosomes or entire chromosomes that were not incorporated into the main nucleus.
- Non-homologous end joining
-
(NHEJ). DNA repair mechanism whereby double-stand breaks are ligated without the need for a homologous template.
- Nucleosomes
-
Basic structural units of eukaryotic DNA packaging, consisting of a segment of coiled DNA around eight core histone proteins.
- Repli-seq
-
A genomic technique that involves sequencing the DNA obtained from cells at different stages of the S phase to map DNA replication patterns and identify regions undergoing replication.
- Topologically associated domain
-
(TAD). A genomic region that spatially interacts with itself.
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Yan, X., Mischel, P. & Chang, H. Extrachromosomal DNA in cancer. Nat Rev Cancer 24, 261–273 (2024). https://doi.org/10.1038/s41568-024-00669-8
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DOI: https://doi.org/10.1038/s41568-024-00669-8