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Extrachromosomal oncogene amplification in tumour pathogenesis and evolution

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Abstract

Recent reports have demonstrated that oncogene amplification on extrachromosomal DNA (ecDNA) is a frequent event in cancer, providing new momentum to explore a phenomenon first discovered several decades ago. The direct consequence of ecDNA gains in these cases is an increase in DNA copy number of the oncogenes residing on the extrachromosomal element. A secondary effect, perhaps even more important, is that the unequal segregation of ecDNA from a parental tumour cell to offspring cells rapidly increases tumour heterogeneity, thus providing the tumour with an additional array of responses to microenvironment-induced and therapy-induced stress factors and perhaps providing an evolutionary advantage. This Perspectives article discusses the current knowledge and potential implications of oncogene amplification on ecDNA in cancer.

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Fig. 1: Reconstructing the architecture of ecDNA using short-read sequencing data.
Fig. 2: Inheritance of chromosomal versus ecDNA.
Fig. 3: Proposed sequence of ecDNA formation and propagation in tumours.

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Acknowledgements

The authors thank C. Beck (Jackson Laboratory for Genomic Medicine), S. Wu and K. M. Turner (Mischel laboratory) for feedback on the manuscript content and S. Cassidy (Jackson Laboratory for Genomic Medicine) for support in manuscript writing. R.G.W.V. is supported by grants from the US National Institutes of Health (NIH) (R01 CA190121), Cancer Center Support Grant P30CA034196 and grants from the Musella Foundation and the B*CURED Foundation. V.B. is supported in part by grants from the NIH (GM114362 and HG004962) and the US National Science Foundation (NSF) (DBI-1458557). P.S.M. is supported in part by grants from the NIH (NS73831), the Defeat GBM Program of the US National Brain Tumor Society, the Ben and Catherine Ivy Foundation, an award from the Sharpe–National Brain Tumor Society Research Program and a Compute for the Cure Award from the Nvidia Foundation.

Reviewer information

Nature Reviews Cancer thanks A. Dutta, W. Hahn and other anonymous reviewer(s) for their contribution to the peer review of this work.

Author information

The authors contributed equally to all aspects of the article.

Correspondence to Roel G. W. Verhaak or Vineet Bafna or Paul S. Mischel.

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Competing interests

R.G.W.V., V.B. and P.S.M. are co-founders of and have equity interest in Pretzel Therapeutics (PT). P.S.M. serves as a consultant to PT. V.B. is a co-founder of, has equity interest in and receives income from Digital Proteomics (DP). The terms of this arrangement have been reviewed and approved by the University of California, San Diego, in accordance with its conflict of interest policies. PT and DP were not involved in the research presented here.

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Glossary

Alternative lengthening of telomeres

One or more mechanisms that are frequently observed in tumours lacking telomerase activity and manifested by long but highly variable telomeres.

Breakage–fusion–bridge cycles

A mechanism of chromosomal instability initiated by a telomeric loss and multiple cycles of anaphase bridge formation followed by unequal breakage.

Chromothripsis

A phenomenon marked by shattering of a chromosome and re-ligation of some of the fragments, causing massive rearrangement in a single catastrophic event.

High-throughput short-read DNA sequencing

The term given to a variety of sequencing technologies that generate short (100–300 bp) reads in an unbiased and massively parallel manner, allowing for inexpensive and redundant sampling of a genome.

Homogeneously staining regions

(HSRs). Regions of a chromosome that have duplicated many times and show up as large regions that are homogeneously stained when painted with a fluorescence in situ hybridization (FISH) probe unique to the region. While tandem duplications are usually implicated in HSR formation, replication of ecDNA and their reintegration into the genome may also cause HSRs.

MicroDNAs

A form of short, extrachromosomal, circular DNA elements that are up to 400 bp long, non-repetitive and putatively formed owing to excision and replication of short DNA.

Optical map technologies

Genomic technologies that construct ordered maps of restriction site locations in large genomic fragments (150–400 kb). The maps serve as a unique fingerprint for the fragment and are useful in validating large structural variations, including insertions.

Supernumerary marker chromosomes

A phenomenon that occurs when cells have an additional and structurally abnormal copy of an autosomal chromosome. They are infrequently found in individuals.

Tandem duplication

Repeated segments of DNA inserted in the genome that disrupt expression of important tumour suppressor genes or amplify tumour promoter genes.

Telomeric circles

Structures based on circularization of telomeric tandem repeats that allow for rolling circle amplification and synthesis of longer repeat elements that help with lengthening of telomeres and stabilizing the chromosome.

Topologically associating domain

A region of the genome that is characterized by extensive interactions within owing to the spatial organization of the genome and reduced interactions with regions outside.

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Verhaak, R.G.W., Bafna, V. & Mischel, P.S. Extrachromosomal oncogene amplification in tumour pathogenesis and evolution. Nat Rev Cancer 19, 283–288 (2019) doi:10.1038/s41568-019-0128-6

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