Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Perspective
  • Published:

OPINION

Extrachromosomal oncogene amplification in tumour pathogenesis and evolution

Nature Reviews Cancer volume 19, pages 283–288 (2019)Cite this article

Subjects

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.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

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.

Similar content being viewed by others

References

  1. Beroukhim, R. et al. The landscape of somatic copy-number alteration across human cancers. Nature 463, 899–905 (2010).

    Article  CAS  Google Scholar 

  2. Weischenfeldt, J. et al. Pan-cancer analysis of somatic copy-number alterations implicates IRS4 and IGF2 in enhancer hijacking. Nat. Genet. 49, 65–74 (2017).

    Article  CAS  Google Scholar 

  3. Menghi, F. et al. The tandem duplicator phenotype is a prevalent genome-wide cancer configuration driven by distinct gene mutations. Cancer Cell 34, 197–210 (2018).

    Article  CAS  Google Scholar 

  4. Gisselsson, D. et al. Generation of trisomies in cancer cells by multipolar mitosis and incomplete cytokinesis. Proc. Natl Acad. Sci. USA 107, 20489–20493 (2010).

    Article  CAS  Google Scholar 

  5. Korbel, J. O. & Campbell, P. J. Criteria for inference of chromothripsis in cancer genomes. Cell 152, 1226–1236 (2013).

    Article  CAS  Google Scholar 

  6. Solomon, E., Borrow, J. & Goddard, A. D. Chromosome aberrations and cancer. Science 254, 1153–1160 (1991).

    Article  CAS  Google Scholar 

  7. deCarvalho, A. C. et al. Discordant inheritance of chromosomal and extrachromosomal DNA elements contributes to dynamic disease evolution in glioblastoma. Nat. Genet. 50, 708–717 (2018).

    Article  CAS  Google Scholar 

  8. Turner, K. M. et al. Extrachromosomal oncogene amplification drives tumour evolution and genetic heterogeneity. Nature 543, 122–125 (2017).

    Article  CAS  Google Scholar 

  9. Garsed, D. W. et al. The architecture and evolution of cancer neochromosomes. Cancer Cell 26, 653–667 (2014).

    Article  CAS  Google Scholar 

  10. Macchia, G. et al. The hidden genomic and transcriptomic plasticity of giant marker chromosomes in cancer. Genetics 208, 951–961 (2018).

    Article  CAS  Google Scholar 

  11. Liehr, T., Claussen, U. & Starke, H. Small supernumerary marker chromosomes (sSMC) in humans. Cytogenet. Genome Res. 107, 55–67 (2004).

    Article  CAS  Google Scholar 

  12. Paulsen, T., Kumar, P., Koseoglu, M. M. & Dutta, A. Discoveries of extrachromosomal circles of DNA in normal and tumor cells. Trends Genet. 34, 270–278 (2018).

    Article  CAS  Google Scholar 

  13. Moller, H. D., Parsons, L., Jorgensen, T. S., Botstein, D. & Regenberg, B. Extrachromosomal circular DNA is common in yeast. Proc. Natl Acad. Sci. USA 112, E3114–E3122 (2015).

    Article  Google Scholar 

  14. Stanfield, S. W. & Lengyel, J. A. Small circular DNA of Drosophila melanogaster: chromosomal homology and kinetic complexity. Proc. Natl Acad. Sci. USA 76, 6142–6146 (1979).

    Article  CAS  Google Scholar 

  15. Shoura, M. J. et al. Intricate and cell type-specific populations of endogenous circular DNA (eccDNA) in Caenorhabditis elegans and Homo sapiens. G3 7, 3295–3303 (2017).

    Article  CAS  Google Scholar 

  16. Shibata, Y. et al. Extrachromosomal microDNAs and chromosomal microdeletions in normal tissues. Science 336, 82–86 (2012).

    Article  CAS  Google Scholar 

  17. Hotta, Y. & Bassel, A. Molecular size and circularity of DNA in cells of mammals and higher plants. Proc. Natl Acad. Sci. USA 53, 356–362 (1965).

    Article  CAS  Google Scholar 

  18. Moller, H. D. et al. Circular DNA elements of chromosomal origin are common in healthy human somatic tissue. Nat. Commun. 9, 1069 (2018).

    Article  Google Scholar 

  19. Henson, J. D. et al. DNA C-circles are specific and quantifiable markers of alternative-lengthening-of-telomeres activity. Nat. Biotechnol. 27, 1181–1185 (2009).

    Article  CAS  Google Scholar 

  20. Cohen, S., Regev, A. & Lavi, S. Small polydispersed circular DNA (spcDNA) in human cells: association with genomic instability. Oncogene 14, 977–985 (1997).

    Article  CAS  Google Scholar 

  21. Cox, D., Yuncken, C. & Spriggs, A. I. Minute chromatin bodies in malignant tumours of childhood. Lancet 1, 55–58 (1965).

    Article  CAS  Google Scholar 

  22. Fan, Y. et al. Frequency of double minute chromosomes and combined cytogenetic abnormalities and their characteristics. J. Appl. Genet. 52, 53–59 (2011).

    Article  Google Scholar 

  23. Stark, G. R., Debatisse, M., Giulotto, E. & Wahl, G. M. Recent progress in understanding mechanisms of mammalian DNA amplification. Cell 57, 901–908 (1989).

    Article  CAS  Google Scholar 

  24. Schimke, R. T. Gene amplification in cultured animal cells. Cell 37, 705–713 (1984).

    Article  CAS  Google Scholar 

  25. Alt, F. W., Kellems, R. E., Bertino, J. R. & Schimke, R. T. Selective multiplication of dihydrofolate reductase genes in methotrexate-resistant variants of cultured murine cells. J. Biol. Chem. 253, 1357–1370 (1978).

    CAS  PubMed  Google Scholar 

  26. Haber, D. A., Beverley, S. M., Kiely, M. L. & Schimke, R. T. Properties of an altered dihydrofolate reductase encoded by amplified genes in cultured mouse fibroblasts. J. Biol. Chem. 256, 9501–9510 (1981).

    CAS  PubMed  Google Scholar 

  27. Haber, D. A. & Schimke, R. T. Unstable amplification of an altered dihydrofolate reductase gene associated with double-minute chromosomes. Cell 26, 355–362 (1981).

    Article  CAS  Google Scholar 

  28. Beverley, S. M., Coderre, J. A., Santi, D. V. & Schimke, R. T. Unstable DNA amplifications in methotrexate-resistant Leishmania consist of extrachromosomal circles which relocalize during stabilization. Cell 38, 431–439 (1984).

    Article  CAS  Google Scholar 

  29. Kohl, N. E. et al. Transposition and amplification of oncogene-related sequences in human neuroblastomas. Cell 35, 359–367 (1983).

    Article  CAS  Google Scholar 

  30. Alitalo, K., Schwab, M., Lin, C. C., Varmus, H. E. & Bishop, J. M. Homogeneously staining chromosomal regions contain amplified copies of an abundantly expressed cellular oncogene (c-myc) in malignant neuroendocrine cells from a human colon carcinoma. Proc. Natl Acad. Sci. USA 80, 1707–1711 (1983).

    Article  CAS  Google Scholar 

  31. Von Hoff, D. D. et al. Elimination of extrachromosomally amplified MYC genes from human tumor cells reduces their tumorigenicity. Proc. Natl Acad. Sci. USA 89, 8165–8169 (1992).

    Article  Google Scholar 

  32. Von Hoff, D. D. et al. Hydroxyurea accelerates loss of extrachromosomally amplified genes from tumor cells. Cancer Res. 51, 6273–6279 (1991).

    Google Scholar 

  33. Carroll, S. M. et al. Double minute chromosomes can be produced from precursors derived from a chromosomal deletion. Mol. Cell. Biol. 8, 1525–1533 (1988).

    Article  CAS  Google Scholar 

  34. Ruiz, J. C., Choi, K. H., von Hoff, D. D., Roninson, I. B. & Wahl, G. M. Autonomously replicating episomes contain mdr1 genes in a multidrug-resistant human cell line. Mol. Cell. Biol. 9, 109–115 (1989).

    Article  CAS  Google Scholar 

  35. Storlazzi, C. T. et al. MYC-containing double minutes in hematologic malignancies: evidence in favor of the episome model and exclusion of MYC as the target gene. Hum. Mol. Genet. 15, 933–942 (2006).

    Article  CAS  Google Scholar 

  36. Storlazzi, C. T. et al. Gene amplification as double minutes or homogeneously staining regions in solid tumors: origin and structure. Genome Res. 20, 1198–1206 (2010).

    Article  CAS  Google Scholar 

  37. Garraway, L. A. & Lander, E. S. Lessons from the cancer genome. Cell 153, 17–37 (2013).

    Article  CAS  Google Scholar 

  38. Vogelstein, B. et al. Cancer genome landscapes. Science 339, 1546–1558 (2013).

    Article  CAS  Google Scholar 

  39. Mitelman, F., Johansson, B. & Mertens, F. The impact of translocations and gene fusions on cancer causation. Nat. Rev. Cancer 7, 233–245 (2007).

    Article  CAS  Google Scholar 

  40. Nathanson, D. A. et al. Targeted therapy resistance mediated by dynamic regulation of extrachromosomal mutant EGFR DNA. Science 343, 72–76 (2014).

    Article  CAS  Google Scholar 

  41. Snuderl, M. et al. Mosaic amplification of multiple receptor tyrosine kinase genes in glioblastoma. Cancer Cell 20, 810–817 (2011).

    Article  CAS  Google Scholar 

  42. Szerlip, N. J. et al. Intratumoral heterogeneity of receptor tyrosine kinases EGFR and PDGFRA amplification in glioblastoma defines subpopulations with distinct growth factor response. Proc. Natl Acad. Sci. USA 109, 3041–3046 (2012).

    Article  CAS  Google Scholar 

  43. Vogt, N. et al. Molecular structure of double-minute chromosomes bearing amplified copies of the epidermal growth factor receptor gene in gliomas. Proc. Natl Acad. Sci. USA 101, 11368–11373 (2004).

    Article  CAS  Google Scholar 

  44. Bigner, S. H. et al. Relationship between gene amplification and chromosomal deviations in malignant human gliomas. Cancer Genet. Cytogenet. 29, 165–170 (1987).

    Article  CAS  Google Scholar 

  45. Deshpande, V. et al. Exploring the landscape of focal amplifications in cancer using AmpliconArchitect. Nat. Commun. 10, 392 (2019).

    Article  Google Scholar 

  46. L’Abbate, A. et al. Genomic organization and evolution of double minutes/homogeneously staining regions with MYC amplification in human cancer. Nucleic Acids Res. 42, 9131–9145 (2014).

    Article  Google Scholar 

  47. Ly, P. & Cleveland, D. W. Rebuilding chromosomes after catastrophe: emerging mechanisms of chromothripsis. Trends Cell Biol. 27, 917–930 (2017).

    Article  CAS  Google Scholar 

  48. Zheng, S. et al. A survey of intragenic breakpoints in glioblastoma identifies a distinct subset associated with poor survival. Genes Dev. 27, 1462–1472 (2013).

    Article  CAS  Google Scholar 

  49. Malhotra, A. et al. Breakpoint profiling of 64 cancer genomes reveals numerous complex rearrangements spawned by homology-independent mechanisms. Genome Res. 23, 762–776 (2013).

    Article  CAS  Google Scholar 

  50. Xu, K. et al. Structure and evolution of double minutes in diagnosis and relapse brain tumors. Acta Neuropathol. 137, 123–137 (2018).

    Article  Google Scholar 

  51. Nikolaev, S. et al. Extrachromosomal driver mutations in glioblastoma and low-grade glioma. Nat. Commun. 5, 5690 (2014).

    Article  CAS  Google Scholar 

  52. Yost, S. E. et al. High-resolution mutational profiling suggests the genetic validity of glioblastoma patient-derived pre-clinical models. PLOS ONE 8, e56185 (2013).

    Article  CAS  Google Scholar 

  53. Xue, Y. et al. An approach to suppress the evolution of resistance in BRAF(V600E)-mutant cancer. Nat. Med. 23, 929–937 (2017).

    Article  CAS  Google Scholar 

  54. Gatenby, R. A. & Gillies, R. J. A microenvironmental model of carcinogenesis. Nat. Rev. Cancer 8, 56–61 (2008).

    Article  CAS  Google Scholar 

  55. Zhang, A. W. et al. Interfaces of malignant and immunologic clonal dynamics in ovarian cancer. Cell 173, 1755–1769 (2018).

    Article  CAS  Google Scholar 

  56. Grasso, C. S. et al. Genetic mechanisms of immune evasion in colorectal cancer. Cancer Discov. 8, 730–749 (2018).

    Article  CAS  Google Scholar 

  57. McGranahan, N. et al. Allele-specific HLA loss and immune escape in lung cancer evolution. Cell 171, 1259–1271 (2017).

    Article  CAS  Google Scholar 

  58. Whyte, W. A. et al. Master transcription factors and mediator establish super-enhancers at key cell identity genes. Cell 153, 307–319 (2013).

    Article  CAS  Google Scholar 

  59. Dixon, J. R. et al. Topological domains in mammalian genomes identified by analysis of chromatin interactions. Nature 485, 376–380 (2012).

    Article  CAS  Google Scholar 

  60. Shachar, S., Voss, T. C., Pegoraro, G., Sciascia, N. & Misteli, T. Identification of gene positioning factors using high-throughput imaging mapping. Cell 162, 911–923 (2015).

    Article  CAS  Google Scholar 

  61. Hnisz, D. et al. Activation of proto-oncogenes by disruption of chromosome neighborhoods. Science 351, 1454–1458 (2016).

    Article  CAS  Google Scholar 

  62. Flavahan, W. A. et al. Insulator dysfunction and oncogene activation in IDH mutant gliomas. Nature 529, 110–114 (2016).

    Article  CAS  Google Scholar 

  63. Corces, M. R. et al. The chromatin accessibility landscape of primary human cancers. Science 362, eaav1898 (2018).

    Article  Google Scholar 

  64. Moller, H. D. et al. CRISPR-C: circularization of genes and chromosome by CRISPR in human cells. Nucleic Acids Res. 46, e131 (2018).

    PubMed  PubMed Central  Google Scholar 

  65. Grohmann, E., Muth, G. & Espinosa, M. Conjugative plasmid transfer in gram-positive bacteria. Microbiol. Mol. Biol. Rev. 67, 277–301 (2003).

    Article  CAS  Google Scholar 

  66. Figurski, D. H. & Helinski, D. R. Replication of an origin-containing derivative of plasmid RK2 dependent on a plasmid function provided in trans. Proc. Natl Acad. Sci. USA 76, 1648–1652 (1979).

    Article  CAS  Google Scholar 

  67. Bennett, P. M. Plasmid encoded antibiotic resistance: acquisition and transfer of antibiotic resistance genes in bacteria. Br. J. Pharmacol. 153 (Suppl. 1), 347–357 (2008).

    Google Scholar 

Download references

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

Authors and Affiliations

  1. The Jackson Laboratory for Genomic Medicine, Farmington, CT, USA

    Roel G. W. Verhaak

  2. Computer Science and Engineering, University of California San Diego, La Jolla, CA, USA

    Vineet Bafna

  3. Ludwig Institute for Cancer Research, San Diego, La Jolla, CA, USA

    Paul S. Mischel

  4. UCSD School of Medicine, La Jolla, CA, USA

    Paul S. Mischel

Authors
  1. Roel G. W. Verhaak
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Vineet Bafna
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Paul S. Mischel
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

The authors contributed equally to all aspects of the article.

Corresponding authors

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

Ethics declarations

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.

Additional information

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

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.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

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

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41568-019-0128-6

This article is cited by

Search

Advanced search

Quick links

Nature Briefing: Cancer

Sign up for the Nature Briefing: Cancer newsletter — what matters in cancer research, free to your inbox weekly.

Get what matters in cancer research, free to your inbox weekly. Sign up for Nature Briefing: Cancer