1932

Abstract

Human genes are arranged on 23 pairs of chromosomes, but in cancer, tumor-promoting genes and regulatory elements can free themselves from chromosomes and relocate to circular, extrachromosomal pieces of DNA (ecDNA). ecDNA, because of its nonchromosomal inheritance, drives high-copy-number oncogene amplification and enables tumors to evolve their genomes rapidly. Furthermore, the circular ecDNA architecture fundamentally alters gene regulation and transcription, and the higher-order organization of ecDNA contributes to tumor pathogenesis. Consequently, patients whose cancers harbor ecDNA have significantly shorter survival. Although ecDNA was first observed more than 50 years ago, its critical importance has only recently come to light. In this review, we discuss the current state of understanding of how ecDNAs form and function as well as how they contribute to drug resistance and accelerated cancer evolution.

Loading

Article metrics loading...

/content/journals/10.1146/annurev-pathmechdis-051821-114223
2022-01-24
2024-12-08
Loading full text...

Full text loading...

/deliver/fulltext/pathmechdis/17/1/annurev-pathmechdis-051821-114223.html?itemId=/content/journals/10.1146/annurev-pathmechdis-051821-114223&mimeType=html&fmt=ahah

Literature Cited

  1. 1. 
    Lubs HA, Salmon JH. 1965. The chromosomal complement of human solid tumors. J. Neurosurg. 22:2160–68
    [Google Scholar]
  2. 2. 
    Cox D, Yuncken C, Spriggs A 1965. Minute chromatin bodies in malignant tumours of childhood. Lancet 286:740255–58
    [Google Scholar]
  3. 3. 
    Levan A, Levan G. 1978. Have double minutes functioning centromeres?. Hereditas 88:181–92
    [Google Scholar]
  4. 4. 
    Turner KM, Deshpande V, Beyter D, Koga T, Rusert J et al. 2017. Extrachromosomal oncogene amplification drives tumour evolution and genetic heterogeneity. Nature 543:7643122–25
    [Google Scholar]
  5. 5. 
    Alt FW, Kellems RE, Bertino JR, Schimke RT. 1978. Selective multiplication of dihydrofolate reductase genes in methotrexate-resistant variants of cultured murine cells. J. Biol. Chem. 253:51357–70
    [Google Scholar]
  6. 6. 
    Kaufman RJ, Brown PC, Schimke RT. 1979. Amplified dihydrofolate reductase genes in unstably methotrexate-resistant cells are associated with double minute chromosomes. PNAS 76:115669–73
    [Google Scholar]
  7. 7. 
    Haber DA, Schimke RT. 1981. Unstable amplification of an altered dihydrofolate reductase gene associated with double-minute chromosomes. Cell 26:3 Part 1355–62
    [Google Scholar]
  8. 8. 
    Kaufman RJ, Brown PC, Schimke RT. 1981. Loss and stabilization of amplified dihydrofolate reductase genes in mouse sarcoma S-180 cell lines. Mol. Cell. Biol. 1:121084–93
    [Google Scholar]
  9. 9. 
    Beverley SM, Coderre JA, Santi DV, Schimke RT. 1984. Unstable DNA amplifications in methotrexate-resistant Leishmania consist of extrachromosomal circles which relocalize during stabilization. Cell 38:2431–39
    [Google Scholar]
  10. 10. 
    Kohl NE, Kanda N, Schreck RR, Bruns G, Latt SA et al. 1983. Transposition and amplification of oncogene-related sequences in human neuroblastomas. Cell 35:2 Part 1359–67
    [Google Scholar]
  11. 11. 
    Von Hoff DD, Needham-VanDevanter DR, Yucel J, Windle BE, Wahl GM. 1988. Amplified human MYC oncogenes localized to replicating submicroscopic circular DNA molecules. PNAS 85:134804–8
    [Google Scholar]
  12. 12. 
    Fan Y, Mao R, Lv H, Xu J, Yan L et al. 2011. Frequency of double minute chromosomes and combined cytogenetic abnormalities and their characteristics. J. Appl. Genet. 52:153–59
    [Google Scholar]
  13. 13. 
    Takayama S, Uwaike Y. 1988. Analysis of the replication mode of double minutes using the PCC technique combined with BrdUrd labeling. Chromosoma 97:3198–203
    [Google Scholar]
  14. 14. 
    Deng X, Zhang L, Zhang Y, Yan Y, Xu Z et al. 2006. Double minute chromosomes in mouse methotrexate-resistant cells studied by atomic force microscopy. Biochem. Biophys. Res. Commun. 346:41228–33
    [Google Scholar]
  15. 15. 
    Kim H, Nguyen N-PP, Turner K, Wu S, Gujar AD et al. 2020. Extrachromosomal DNA is associated with oncogene amplification and poor outcome across multiple cancers. Nat. Genet. 52:9891–97
    [Google Scholar]
  16. 16. 
    Mitra AB, Murty VVVS, Luthra UK. 1983. Double-minute chromosomes in the leukocytes of a patient with a previous history of cervical carcinoma. Cancer Genet. Cytogenet. 8:2117–22
    [Google Scholar]
  17. 17. 
    Madhavi R, Guntur M, Ghosh R, Ghosh PK 1990. Double minute chromosomes in the leukocytes of a young girl with breast carcinoma. Cancer Genet. Cytogenet. 44:2203–7
    [Google Scholar]
  18. 18. 
    Scappaticci S, Fossati GS, Valenti L, Scabini M, Tateo S et al. 1995. A search for double minute chromosomes in cultured lymphocytes from different types of tumors. Cancer Genet. Cytogenet. 82:150–53
    [Google Scholar]
  19. 19. 
    Dal Cin P, Wanschura S, Kazmierczak B, Tallini G, Dei Tos A et al. 1998. Amplification and expression of the HMGIC gene in a benign endometrial polyp. Genes Chromosomes Cancer 22:295–99
    [Google Scholar]
  20. 20. 
    Brothman AR, Cram LS, Brothman LJ, Kraemer PM. 1987. Cultured Bloom's syndrome substrains: a relationship between growth in low serum and the expression of double minute chromosomes. Cancer Genet. Cytogenet. 26:2287–97
    [Google Scholar]
  21. 21. 
    Bahr G, Gilbert F, Balaban G, Engler W. 1983. Homogeneously staining regions and double minutes in a human cell line: chromatin organization and DNA content. J. Natl. Cancer Inst. 71:4657–61
    [Google Scholar]
  22. 22. 
    Rattner JB, Lin CC. 1984. Ultrastructural organization of double minute chromosomes and HSR regions in human colon carcinoma cells. Cytogenet. Cell Genet. 38:3176–81
    [Google Scholar]
  23. 23. 
    Hamkalo BA, Farnham PJ, Johnston R, Schimke RT. 1985. Ultrastructural features of minute chromosomes in a methotrexate-resistant mouse 3T3 cell line. PNAS 82:41126–30
    [Google Scholar]
  24. 24. 
    Schneider SS, Hiemstra JL, Zehnbauer BA, Taillon-Miller P, Le Paslier DL et al. 1992. Isolation and structural analysis of a 1.2-megabase N-myc amplicon from a human neuroblastoma. Mol. Cell. Biol. 12:125563–70
    [Google Scholar]
  25. 25. 
    Schoenlein PV, Barrett JT, Welter D. 1999. The degradation profile of extrachromosomal circular DNA during cisplatin-induced apoptosis is consistent with preferential cleavage at matrix attachment regions. Chromosoma 108:2121–31
    [Google Scholar]
  26. 26. 
    Smith G, Taylor-Kashton C, Dushnicky L, Symons S, Wright J, Mai S 2003. c-Myc-induced extrachromosomal elements carry active chromatin. Neoplasia 5:2110–20
    [Google Scholar]
  27. 27. 
    Wu S, Turner KM, Nguyen N, Raviram R, Erb M et al. 2019. Circular ecDNA promotes accessible chromatin and high oncogene expression. Nature 575:7784699–703
    [Google Scholar]
  28. 28. 
    Dixon JR, Gorkin DU, Ren B. 2016. Chromatin domains: the unit of chromosome organization. Mol. Cell 62:5668–80
    [Google Scholar]
  29. 29. 
    Morton AR, Dogan-Artun N, Faber ZJ, MacLeod G, Bartels CF et al. 2019. Functional enhancers shape extrachromosomal oncogene amplifications. Cell 179:61330–41.e13
    [Google Scholar]
  30. 30. 
    Helmsauer K, Valieva ME, Ali S, Chamorro González R, Schöpflin R et al. 2020. Enhancer hijacking determines extrachromosomal circular MYCN amplicon architecture in neuroblastoma. Nat. Commun. 11:5823
    [Google Scholar]
  31. 31. 
    Koche RP, Rodriguez-Fos E, Helmsauer K, Burkert M, MacArthur IC et al. 2020. Extrachromosomal circular DNA drives oncogenic genome remodeling in neuroblastoma. Nat. Genet. 52:29–34
    [Google Scholar]
  32. 32. 
    Cremer T, Cremer M. 2010. Chromosome territories. Cold Spring Harb. Perspect. Biol. 2:3a003889
    [Google Scholar]
  33. 33. 
    Maass PG, Barutcu AR, Rinn JL. 2019. Interchromosomal interactions: a genomic love story of kissing chromosomes. J. Cell Biol. 218:127–38
    [Google Scholar]
  34. 34. 
    Zhu Y, Gujar AD, Wong C-H, Tjong H, Ngan CY et al. 2021. Oncogenic extrachromosomal DNA functions as mobile enhancers to globally amplify chromosomal transcription. Cancer Cell 6:19–15
    [Google Scholar]
  35. 35. 
    Hung KL, Yost KE, Xie L, Shi Q, Helmsauer K et al. 2021. ecDNA hubs drive cooperative intermolecular oncogene expression. Nature. https://doi.org/10.1038/s41586-021-04116-8
    [Crossref]
  36. 36. 
    Carroll SM, DeRose ML, Gaudray P, Moore CM, Needham-VanDevanter DR et al. 1988. Double minute chromosomes can be produced from precursors derived from a chromosomal deletion. Mol. Cell. Biol. 8:41525–33
    [Google Scholar]
  37. 37. 
    Hahn PJ, Nevaldine B, Longo JA 1992. Molecular structure and evolution of double-minute chromosomes in methotrexate-resistant cultured mouse cells. Mol. Cell. Biol. 12:72911–18
    [Google Scholar]
  38. 38. 
    Storlazzi CT, Lonoce A, Guastadisegni MC, Trombetta D, D'Addabbo P et al. 2010. Gene amplification as double minutes or homogeneously staining regions in solid tumors: origin and structure. Genome Res 20:91198–206
    [Google Scholar]
  39. 39. 
    L'Abbate A, Macchia G, D'Addabbo P, Lonoce A, Tolomeo D et al. 2014. Genomic organization and evolution of double minutes/homogeneously staining regions with MYC amplification in human cancer. Nucleic Acids Res. 42:149131–45
    [Google Scholar]
  40. 40. 
    Vogt N, Gibaud A, Lemoine F, de la Grange P, Debatisse M, Malfoy B 2014. Amplicon rearrangements during the extrachromosomal and intrachromosomal amplification process in a glioma. Nucleic Acids Res. 42:2113194–205
    [Google Scholar]
  41. 41. 
    Nathanson DA, Gini B, Mottahedeh J, Visnyei K, Koga T et al. 2014. Targeted therapy resistance mediated by dynamic regulation of extrachromosomal mutant EGFR DNA. Science 343:616672–76
    [Google Scholar]
  42. 42. 
    Shoshani O, Brunner SF, Yaeger R, Ly P, Nechemia-Arbely Y et al. 2021. Chromothripsis drives the evolution of gene amplification in cancer. Nature 591:7848137–41
    [Google Scholar]
  43. 43. 
    Xue Y, Martelotto L, Baslan T, Vides A, Solomon M et al. 2017. An approach to suppress the evolution of resistance in BRAFV600E-mutant cancer. Nat. Med. 23:8929–37
    [Google Scholar]
  44. 44. 
    Kanda T, Sullivan KF, Wahl GM. 1998. Histone-GFP fusion protein enables sensitive analysis of chromosome dynamics in living mammalian cells. Curr. Biol. 8:7377–85
    [Google Scholar]
  45. 45. 
    Kanda T, Otter M, Wahl GM. 2001. Mitotic segregation of viral and cellular acentric extrachromosomal molecules by chromosome tethering. J. Cell Sci. 114:149–58
    [Google Scholar]
  46. 46. 
    Lundberg G, Rosengren AH, Håkanson U, Stewénius H, Jin Y et al. 2008. Binomial mitotic segregation of MYCN-carrying double minutes in neuroblastoma illustrates the role of randomness in oncogene amplification. PLOS ONE 3:8e3099
    [Google Scholar]
  47. 47. 
    Verhaak RGW, Bafna V, Mischel PS. 2019. Extrachromosomal oncogene amplification in tumour pathogenesis and evolution. Nat. Rev. Cancer 19:5283–88
    [Google Scholar]
  48. 48. 
    Lange JT, Chen CY, Pichugin Y, Xie L, Tang J et al. 2021. Principles of ecDNA random inheritance drive rapid genome change and therapy resistance in human cancers. bioRxiv 2021.06.11.447968. https://doi.org/10.1101/2021.06.11.447968
    [Crossref]
  49. 49. 
    Lederberg J. 1952. Cell genetics and hereditary symbiosis. Physiol. Rev. 32:4403–30
    [Google Scholar]
  50. 50. 
    Leibowitz ML, Zhang C-Z, Pellman D. 2015. Chromothripsis: a new mechanism for rapid karyotype evolution. Annu. Rev. Genet. 49:183–211
    [Google Scholar]
  51. 51. 
    Zhang C-Z, Spektor A, Cornils H, Francis JM, Jackson EK et al. 2015. Chromothripsis from DNA damage in micronuclei. Nature 522:7555179–84
    [Google Scholar]
  52. 52. 
    Ly P, Brunner SF, Shoshani O, Kim DH, Lan W et al. 2019. Chromosome segregation errors generate a diverse spectrum of simple and complex genomic rearrangements. Nat. Genet. 51:4705–15
    [Google Scholar]
  53. 53. 
    Stephens PJ, Greenman CD, Fu B, Yang F, Bignell GR et al. 2011. Massive genomic rearrangement acquired in a single catastrophic event during cancer development. Cell 144:127–40
    [Google Scholar]
  54. 54. 
    Rausch T, Jones DTW, Zapatka M, Stütz AM, Zichner T et al. 2012. Genome sequencing of pediatric medulloblastoma links catastrophic DNA rearrangements with TP53 mutations. Cell 148:1/259–71
    [Google Scholar]
  55. 55. 
    Francis JM, Zhang C-Z, Maire CL, Jung J, Manzo VE et al. 2014. EGFR variant heterogeneity in glioblastoma resolved through single-nucleus sequencing. Cancer Discov 4:8956–71
    [Google Scholar]
  56. 56. 
    Møller HD, Lin L, Xiang X, Petersen TS, Huang J et al. 2018. CRISPR-C: circularization of genes and chromosome by CRISPR in human cells. Nucleic Acids Res 46:22e131
    [Google Scholar]
  57. 57. 
    Zuberi L, Adeyinka A, Kuriakose P 2010. Rapid response to induction in a case of acute promyelocytic leukemia with MYC amplification on double minutes at diagnosis. Cancer Genet. Cytogenet. 198:2170–72
    [Google Scholar]
  58. 58. 
    Gibaud A, Vogt N, Hadj-Hamou NS, Meyniel JP, Hupé P et al. 2010. Extrachromosomal amplification mechanisms in a glioma with amplified sequences from multiple chromosome loci. Hum. Mol. Genet. 19:71276–85
    [Google Scholar]
  59. 59. 
    Vogt N, Lefèvre S-H, Apiou F, Dutrillaux A-M, Cör A et al. 2004. Molecular structure of double-minute chromosomes bearing amplified copies of the epidermal growth factor receptor gene in gliomas. PNAS 101:3111368–73
    [Google Scholar]
  60. 60. 
    Yang L, Luquette LJ, Gehlenborg N, Xi R, Haseley PS et al. 2013. Diverse mechanisms of somatic structural variations in human cancer genomes. Cell 153:4919–29
    [Google Scholar]
  61. 61. 
    Lee JA, Carvalho CMB, Lupski JR. 2007. A DNA replication mechanism for generating nonrecurrent rearrangements associated with genomic disorders. Cell 131:71235–47
    [Google Scholar]
  62. 62. 
    Smolen GA, Muir B, Mohapatra G, Barmettler A, Kim WJ et al. 2006. Frequent Met oncogene amplification in a Brca1/Trp53 mouse model of mammary tumorigenesis. Cancer Res 66:73452–55
    [Google Scholar]
  63. 63. 
    Tang D-J, Hu L, Xie D, Wu Q-L, Fang Y et al. 2005. Oncogenic transformation by SEI-1 is associated with chromosomal instability. Cancer Res 65:156504–8
    [Google Scholar]
  64. 64. 
    Bao Y, Liu J, You J, Wu D, Yu Y et al. 2016. Met promotes the formation of double minute chromosomes induced by Sei-1 in NIH-3T3 murine fibroblasts. Oncotarget 7:3556664–75
    [Google Scholar]
  65. 65. 
    Utani K, Fu H, Jang S-M, Marks AB, Smith OK et al. 2017. Phosphorylated SIRT1 associates with replication origins to prevent excess replication initiation and preserve genomic stability. Nucleic Acids Res 45:137807–24
    [Google Scholar]
  66. 66. 
    Xu K, Ding L, Chang T-C, Shao Y, Chiang J et al. 2019. Structure and evolution of double minutes in diagnosis and relapse brain tumors. Acta Neuropathol 137:1123–37
    [Google Scholar]
  67. 67. 
    Pandita A, Aldape KD, Zadeh G, Guha A, James CD 2004. Contrasting in vivo and in vitro fates of glioblastoma cell subpopulations with amplified EGFR. Genes Chromosomes Cancer 39:129–36
    [Google Scholar]
  68. 68. 
    Schulte A, Günther HS, Martens T, Zapf S, Riethdorf S et al. 2012. Glioblastoma stem-like cell lines with either maintenance or loss of high-level EGFR amplification, generated via modulation of ligand concentration. Clin. Cancer Res. 18:71901–13
    [Google Scholar]
  69. 69. 
    Giannini C, Sarkaria JN, Saito A, Uhm JH, Galanis E et al. 2005. Patient tumor EGFR and PDGFRA gene amplifications retained in an invasive intracranial xenograft model of glioblastoma multiforme. Neuro-Oncology 7:2164–76
    [Google Scholar]
  70. 70. 
    deCarvalho AC, Kim H, Poisson LM, Winn ME, Mueller C et al. 2018. Discordant inheritance of chromosomal and extrachromosomal DNA elements contributes to dynamic disease evolution in glioblastoma. Nat. Genet. 50:5708–17
    [Google Scholar]
  71. 71. 
    Pauletti G, Lai E, Attardi G 1990. Early appearance and long-term persistence of the submicroscopic extrachromosomal elements (amplisomes) containing the amplified DHFR genes in human cell lines. PNAS 87:82955–59
    [Google Scholar]
  72. 72. 
    Snapka RM, Varshavsky A. 1983. Loss of unstably amplified dihydrofolate reductase genes from mouse cells is greatly accelerated by hydroxyurea. PNAS 80:247533–37
    [Google Scholar]
  73. 73. 
    Von Hoff DD, Waddelow T, Forseth B, Davidson K, Scott J, Wahl G 1991. Hydroxyurea accelerates loss of extrachromosomally amplified genes from tumor cells. Cancer Res 51:23 Part 16273–79
    [Google Scholar]
  74. 74. 
    Von Hoff DD, McGill JR, Forseth BJ, Davidson KK, Bradley TP et al. 1992. Elimination of extrachromosomally amplified MYC genes from human tumor cells reduces their tumorigenicity. PNAS 89:178165–69
    [Google Scholar]
  75. 75. 
    Raymond E, Faivre S, Weiss G, McGill J, Davidson K et al. 2001. Effects of hydroxyurea on extrachromosomal DNA in patients with advanced ovarian carcinomas. Clin. Cancer Res. 7:51171–80
    [Google Scholar]
  76. 76. 
    Shimizu N, Misaka N, Utani K. 2007. Nonselective DNA damage induced by a replication inhibitor results in the selective elimination of extrachromosomal double minutes from human cancer cells. Genes Chromosomes Cancer 46:10865–74
    [Google Scholar]
  77. 77. 
    Oobatake Y, Shimizu N. 2020. Double-strand breakage in the extrachromosomal double minutes triggers their aggregation in the nucleus, micronucleation, and morphological transformation. Genes Chromosomes Cancer 59:3133–43
    [Google Scholar]
  78. 78. 
    Schoenlein PV, Barrett JT, Kulharya A, Dohn MR, Sanchez A et al. 2003. Radiation therapy depletes extrachromosomally amplified drug resistance genes and oncogenes from tumor cells via micronuclear capture of episomes and double minute chromosomes. Int. J. Radiat. Oncol. Biol. Phys. 55:41051–65
    [Google Scholar]
  79. 79. 
    Cai M, Zhang H, Hou L, Gao W, Song Y et al. 2019. Inhibiting homologous recombination decreases extrachromosomal amplification but has no effect on intrachromosomal amplification in methotrexate-resistant colon cancer cells. Int. J. Cancer 144:51037–48
    [Google Scholar]
  80. 80. 
    Taniguchi R, Utani K, Thakur B, Ishine K, Aladjem MI, Shimizu N. 2021. SIRT1 stabilizes extrachromosomal gene amplification and contributes to repeat-induced gene silencing. J. Biol. Chem. 296:100356
    [Google Scholar]
  81. 81. 
    Rajkumar U, Turner K, Luebeck J, Deshpande V, Chandraker M et al. 2019. ecSeg: semantic segmentation of metaphase images containing extrachromosomal DNA. iScience 21:428–35
    [Google Scholar]
  82. 82. 
    Deshpande V, Luebeck J, Nguyen N-PD, Bakhtiari M, Turner KM et al. 2019. Exploring the landscape of focal amplifications in cancer using AmpliconArchitect. Nat. Commun. 10:392
    [Google Scholar]
  83. 83. 
    Luebeck J, Coruh C, Dehkordi SR, Lange JT, Turner KM et al. 2020. AmpliconReconstructor integrates NGS and optical mapping to resolve the complex structures of focal amplifications. Nat. Commun. 11:4374
    [Google Scholar]
  84. 84. 
    Kumar P, Kiran S, Saha S, Su Z, Paulsen T et al. 2020. ATAC-seq identifies thousands of extrachromosomal circular DNA in cancer and cell lines. Sci. Adv. 6:20eaba2489
    [Google Scholar]
  85. 85. 
    Møller HD, Bojsen RK, Tachibana C, Parsons L, Botstein D, Regenberg B. 2016. Genome-wide purification of extrachromosomal circular DNA from eukaryotic cells. J. Vis. Exp. 2016:110e54239
    [Google Scholar]
  86. 86. 
    Cohen S, Lavi S. 1996. Induction of circles of heterogeneous sizes in carcinogen-treated cells: two-dimensional gel analysis of circular DNA molecules. Mol. Cell. Biol. 16:52002–14
    [Google Scholar]
  87. 87. 
    Paulsen T, Kumar P, Koseoglu MM, Dutta A. 2018. Discoveries of extrachromosomal circles of DNA in normal and tumor cells. Trends Genet 34:4270–78
    [Google Scholar]
  88. 88. 
    Verhaak RGW, Bafna V, Mischel PS. 2019. Extrachromosomal oncogene amplification in tumour pathogenesis and evolution. Nat. Rev. Cancer 19:5283–88
    [Google Scholar]
  89. 89. 
    Foulkes I, Sharpless NE. 2020. Cancer grand challenges: embarking on a new era of discovery. Cancer Discov. 11:123–27
    [Google Scholar]
/content/journals/10.1146/annurev-pathmechdis-051821-114223
Loading
/content/journals/10.1146/annurev-pathmechdis-051821-114223
Loading

Data & Media loading...

  • Article Type: Review Article
This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error