Cox, D., Yuncken, C. & Spriggs, A. Minute chromatin bodies in malignant tumours of childhood. Lancet 286, 55–58 (1965).

Article  Google Scholar 

Spriggs, A. I., Boddington, M. M. & Clarke, C. M. Chromosomes of human cancer cells. Br. Med. J. 2, 1431 (1962).

Article  CAS  PubMed  PubMed Central  Google Scholar 

Hoff, D. D. V., Needham-VanDevanter, D. R., Yucel, J., Windle, B. E. & Wahl, G. M. Amplified human MYC oncogenes localized to replicating submicroscopic circular DNA molecules. Proc. Natl Acad. Sci. USA 85, 4804–4808 (1988).

Article  Google Scholar 

Wu, S. et al. Circular ecDNA promotes accessible chromatin and high oncogene expression. Nature 575, 699–703 (2019). This study utilize a multidisciplinary approach combining ultrastructural imaging, long-range optical mapping and computational analysis of whole-genome sequencing to reveal that oncogenes carried on ecDNA in cancer have high expression, owing to the enhanced accessibility of ecDNA and ultra-long-range active chromatin contacts.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Kim, H. et al. Extrachromosomal DNA is associated with oncogene amplification and poor outcome across multiple cancers. Nat. Genet. 52, 891–897 (2020). This study, based on computational analysis of WGS data from 3,212 patients with cancer, reveals that ecDNA amplification is a common phenomenon in various cancer types that results in enhanced oncogene transcription, chromatin accessibility and poor patient survival.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Yi, E. et al. Live-cell imaging shows uneven segregation of extrachromosomal DNA elements and transcriptionally active extrachromosomal DNA hubs in cancer. Cancer Discov. 12, 468–483 (2022).

Article  CAS  PubMed  Google Scholar 

Lange, J. T. et al. The evolutionary dynamics of extrachromosomal DNA in human cancers. Nat. Genet. 54, 1527–1533 (2022). This study demonstrates that the random inheritance of ecDNA in cancer leads to significant intra-tumoural ecDNA copy number diversity, enabling rapid adaptation to metabolic stresses and targeted therapies, thereby contributing to the aggressive behaviour of ecDNA-containing cancers and underscoring the clinical impact of non-chromosomal oncogene inheritance.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Kaufman, R. J., Brown, P. C. & Schimke, R. T. Amplified dihydrofolate reductase genes in unstably methotrexate-resistant cells are associated with double minute chromosomes. Proc. Natl Acad. Sci. USA 76, 5669–5673 (1979).

Article  CAS  PubMed  PubMed Central  Google Scholar 

Takayama, S. & Uwaike, Y. Analysis of the replication mode of double minutes using the PCC technique combined with BrdUrd labeling. Chromosoma 97, 198–203 (1988).

Article  CAS  PubMed  Google Scholar 

Barker, P. E. & Hsu, T. C. Are double minutes chromosomes? Exp. Cell Res. 113, 457–458 (1978).

Article  Google Scholar 

de Salum, S. B. & Larripa, I. Brief communication: minute chromatin bodies in a murine in vitro cell line. J. Natl Cancer Inst. 55, 717–720 (1975).

Article  PubMed  Google Scholar 

Ruiz, J. C., Choi, K. H., Hoff, D. D., von, 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).

CAS  PubMed  PubMed Central  Google Scholar 

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).

CAS  PubMed  PubMed Central  Google Scholar 

Turner, K. M. et al. Extrachromosomal oncogene amplification drives tumour evolution and genetic heterogeneity. Nature 543, 122–125 (2017). Through WGS and cytogenic analyses of thousands of samples from 17 different cancer types, this paper reveals the wide prevalence of ecDNA in cancer and hints that ecDNA-mediated oncogene amplification is a driving force underlying tumour heterogeneity.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Levan, A. & Levan, G. Have double minutes functioning centromeres? Hereditas 88, 81–92 (1978).

Article  CAS  PubMed  Google Scholar 

Hung, K. L. et al. Targeted profiling of human extrachromosomal DNA by CRISPR-CATCH. Nat. Genet. 54, 1746–1754 (2022).

Article  CAS  PubMed  PubMed Central  Google Scholar 

Luebeck, J. et al. Extrachromosomal DNA in the cancerous transformation of Barrett’s oesophagus. Nature 616, 798–805 (2023). This study, based on WGS data from patients with oesophageal adenocarcinoma and Barrett’s oesophagus, reveals that ecDNA can develop at early stages in the transition from dysplasia to cancer and that the frequency of ecDNA increases as the disease progresses.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Hung, K. L. et al. ecDNA hubs drive cooperative intermolecular oncogene expression. Nature 600, 731–736 (2021). This study demonstrates that ecDNA forms hubs within the nucleus, facilitating intermolecular enhancer–gene interactions that drive oncogene overexpression in various cancer cell types and primary tumours.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Helmsauer, K. et al. Enhancer hijacking determines extrachromosomal circular MYCN amplicon architecture in neuroblastoma. Nat. Commun. 11, 5823 (2020).

Article  CAS  PubMed  PubMed Central  Google Scholar 

Brown, P. C., Beverley, S. M. & Schimke, R. T. Relationship of amplified dihydrofolate reductase genes to double minute chromosomes in unstably resistant mouse fibroblast cell lines. Mol. Cell. Biol. 1, 1077–1083 (1981).

CAS  PubMed  PubMed Central  Google Scholar 

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  PubMed  Google Scholar 

Kaufman, R. J., Brown, P. C. & Schimke, R. T. Loss and stabilization of amplified dihydrofolate reductase genes in mouse sarcoma s-180 cell lines. Mol. Cell. Biol. 1, 1084–1093 (1981).

CAS  PubMed  PubMed Central  Google Scholar 

Wahl, G. M. The importance of circular DNA in mammalian gene amplification. Cancer Res. 49, 1333–1340 (1989).

CAS  PubMed  Google Scholar 

Ruiz, J. C. & Wahl, G. M. Chromosomal destabilization during gene amplification. Mol. Cell. Biol. 10, 3056–3066 (1990).

CAS  PubMed  PubMed Central  Google Scholar 

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  PubMed  PubMed Central  Google Scholar 

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

Article  CAS  PubMed  Google Scholar 

Hung, K. L., Mischel, P. S. & Chang, H. Y. Gene regulation on extrachromosomal DNA. Nat. Struct. Mol. Biol. 29, 736–744 (2022).

Article  CAS  PubMed  PubMed Central  Google Scholar 

Li, Z., Wang, B., Liang, H. & Han, L. Pioneering insights of extrachromosomal DNA (ecDNA) generation, action and its implications for cancer therapy. Int. J. Biol. Sci. 18, 4006–4025 (2022).

Article  CAS  PubMed  PubMed Central  Google Scholar 

Abeysinghe, H. R., Cedrone, E., Tyan, T., Xu, J. & Wang, N. Amplification of C-MYC as the origin of the homogeneous staining region in ovarian carcinoma detected by micro-FISH. Cancer Genet. Cytogenet. 114, 136–143 (1999).

Article  CAS  PubMed  Google Scholar 

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  PubMed  PubMed Central  Google Scholar 

Benner, S. E., Wahl, G. M. & Hoff, D. D. V. Double minute chromosomes and homogeneously staining regions in tumors taken directly from patients versus in human tumor cell lines. Anti-Cancer Drugs 2, 11–26 (1991).

Article  CAS  PubMed  Google Scholar 

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

Article  CAS  PubMed  Google Scholar 

Bigner, S. H., Mark, J. & Bigner, D. D. Cytogenetics of human brain tumors. Cancer Genet. Cytogenet. 47, 141–154 (1990).

Article  CAS  PubMed  Google Scholar 

Yoshimoto, M. et al. MYCN gene amplification identification of cell populations containing double minutes and homogeneously staining regions in neuroblastoma tumors. Am. J. Pathol. 155, 1439–1443 (1999).

Article  CAS  PubMed  PubMed Central  Google Scholar 

Vicario, R. et al. Patterns of HER2 gene amplification and response to anti-HER2 therapies. PloS ONE 10, e0129876 (2015).

Article  PubMed  PubMed Central  Google Scholar 

McGill, J. R. et al. Double minutes are frequently found in ovarian carcinomas. Cancer Genet. Cytogenet. 71, 125–131 (1993).

Article  CAS  PubMed