Abstract
Complex chromosome rearrangements, known as chromoanagenesis, are widespread in cancer. Based on large-scale DNA sequencing of human tumours, the most frequent type of complex chromosome rearrangement is chromothripsis, a massive, localized and clustered rearrangement of one (or a few) chromosomes seemingly acquired in a single event. Chromothripsis can be initiated by mitotic errors that produce a micronucleus encapsulating a single chromosome or chromosomal fragment. Rupture of the unstable micronuclear envelope exposes its chromatin to cytosolic nucleases and induces chromothriptic shattering. Found in up to half of tumours included in pan-cancer genomic analyses, chromothriptic rearrangements can contribute to tumorigenesis through inactivation of tumour suppressor genes, activation of proto-oncogenes, or gene amplification through the production of self-propagating extrachromosomal circular DNAs encoding oncogenes or genes conferring anticancer drug resistance. Here, we discuss what has been learned about the mechanisms that enable these complex genomic rearrangements and their consequences in cancer.
This is a preview of subscription content, access via your institution
Access options
Access Nature and 54 other Nature Portfolio journals
Get Nature+, our best-value online-access subscription
$29.99 / 30 days
cancel any time
Subscribe to this journal
Receive 12 print issues and online access
$189.00 per year
only $15.75 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Nowell, P. C. & Hungerford, D. A. Minute chromosome in human chronic granulocytic leukemia. Science 132, 1497–1497 (1960).
Kaung, D. T. & Swartzendruber, A. A. Effect of chemotherapeutic agents on chromosomes of patients with lung cancer. Dis. Chest 55, 98–100 (1969).
Van Steenis, H. Chromosomes and cancer. Nature 209, 819–821 (1966).
Ishihara, T., Kikuchi, Y. & Sandberg, A. A. Chromosomes of twenty cancer effusions: correlation of karyotypic, clinical, and pathologic aspects. J. Natl Cancer Inst. 30, 1303–1361 (1963).
Rowley, J. D. Letter: a new consistent chromosomal abnormality in chronic myelogenous leukaemia identified by quinacrine fluorescence and Giemsa staining. Nature 243, 290–293 (1973).
Thompson, S. L. & Compton, D. A. Chromosomes and cancer cells. Chromosome Res. 19, 433–444 (2011).
Frohling, S. & Dohner, H. Chromosomal abnormalities in cancer. N. Engl. J. Med. 359, 722–734 (2008).
Lander, E. S. et al. Initial sequencing and analysis of the human genome. Nature 409, 860–921 (2001).
Venter, J. C. et al. The sequence of the human genome. Science 291, 1304–1351 (2001).
Cibulskis, K. et al. Sensitive detection of somatic point mutations in impure and heterogeneous cancer samples. Nat. Biotechnol. 31, 213–219 (2013).
Tate, J. G. et al. COSMIC: the catalogue of somatic mutations in cancer. Nucleic Acids Res. 47, D941–D947 (2019).
Alexandrov, L. B. et al. Signatures of mutational processes in human cancer. Nature 500, 415–421 (2013).
Alexandrov, L. B. et al. The repertoire of mutational signatures in human cancer. Nature 578, 94–101 (2020).
Taylor, A. M. et al. Genomic and functional approaches to understanding cancer aneuploidy. Cancer Cell 33, 676–689.e3 (2018).
Drews, R. M. et al. A pan-cancer compendium of chromosomal instability. Nature 606, 976–983 (2022).
Ben-David, U. & Amon, A. Context is everything: aneuploidy in cancer. Nat. Rev. Genet. 21, 44–62 (2020).
Stratton, M. R., Campbell, P. J. & Futreal, P. A. The cancer genome. Nature 458, 719–724 (2009).
Yates, L. R. & Campbell, P. J. Evolution of the cancer genome. Nat. Rev. Genet. 13, 795–806 (2012).
Holland, A. J. & Cleveland, D. W. Chromoanagenesis and cancer: mechanisms and consequences of localized, complex chromosomal rearrangements. Nat. Med. 18, 1630–1638 (2012).
Stephens, P. J. et al. Massive genomic rearrangement acquired in a single catastrophic event during cancer development. Cell 144, 27–40 (2011). This study reported the discovery of chromothripsis and established potential mechanisms and consequences of massive chromosome rearrangements.
Liu, P. et al. Chromosome catastrophes involve replication mechanisms generating complex genomic rearrangements. Cell 146, 889–903 (2011).
Baca, S. C. et al. Punctuated evolution of prostate cancer genomes. Cell 153, 666–677 (2013).
Korbel, J. O. & Campbell, P. J. Criteria for inference of chromothripsis in cancer genomes. Cell 152, 1226–1236 (2013). Korbel and Campbell proposed a set of criteria to distinguish chromothripsis from other rearrangements.
Crasta, K. et al. DNA breaks and chromosome pulverization from errors in mitosis. Nature 482, 53–58 (2012). This study identified cell division errors to be a main cause of chromothripsis.
Maciejowski, J., Li, Y., Bosco, N., Campbell, P. J. & de Lange, T. Chromothripsis and kataegis induced by telomere crisis. Cell 163, 1641–1654 (2015).
Zhang, C. Z. et al. Chromothripsis from DNA damage in micronuclei. Nature 522, 179–184 (2015). This study introduced single-cell genomic analysis combined with live-cell imaging (‘Look-Seq’) to follow genomic rearrangements, including chromothripsis, associated with micronuclei.
Shoshani, O. et al. Chromothripsis drives the evolution of gene amplification in cancer. Nature 591, 137–141 (2021). This study established chromothripsis as a key contributor to therapy-induced gene amplification in cancer, including the generation of ecDNAs.
Ly, P. et al. Selective Y centromere inactivation triggers chromosome shattering in micronuclei and repair by non-homologous end joining. Nat. Cell Biol. 19, 68–75 (2017).
Knudson, A. G. Jr. Mutation and cancer: statistical study of retinoblastoma. Proc. Natl Acad. Sci. USA 68, 820–823 (1971).
Rausch, T. et al. Genome sequencing of pediatric medulloblastoma links catastrophic DNA rearrangements with TP53 mutations. Cell 148, 59–71 (2012).
Molenaar, J. J. et al. Sequencing of neuroblastoma identifies chromothripsis and defects in neuritogenesis genes. Nature 483, 589–593 (2012).
Magrangeas, F., Avet-Loiseau, H., Munshi, N. C. & Minvielle, S. Chromothripsis identifies a rare and aggressive entity among newly diagnosed multiple myeloma patients. Blood 118, 675–678 (2011).
Cortes-Ciriano, I. et al. Comprehensive analysis of chromothripsis in 2,658 human cancers using whole-genome sequencing. Nat. Genet. 52, 331–341 (2020). This study (as a part of the PCAWG Consortium) performed a pan-cancer analysis of chromothripsis, establishing its very high prevalence in cancer.
The ICGC/TCGA Pan-Cancer Analysis of Whole Genomes Consortium. Pan-cancer analysis of whole genomes. Nature 578, 82–93 (2020).
Voronina, N. et al. The landscape of chromothripsis across adult cancer types. Nat. Commun. 11, 2320 (2020).
Rasnic, R. & Linial, M. Chromoanagenesis landscape in 10,000 TCGA patients. Cancers 13, 4197 (2021).
Steele, C. D. et al. Signatures of copy number alterations in human cancer. Nature 606, 984–991 (2022).
Bao, L., Zhong, X., Yang, Y. & Yang, L. Starfish infers signatures of complex genomic rearrangements across human cancers. Nat. Cancer 3, 1247–1259 (2022).
Hirsch, D. et al. Chromothripsis and focal copy number alterations determine poor outcome in malignant melanoma. Cancer Res. 73, 1454–1460 (2013).
Fontana, M. C. et al. Chromothripsis in acute myeloid leukemia: biological features and impact on survival. Leukemia 32, 1609–1620 (2018).
Rustad, E. H. et al. Revealing the impact of structural variants in multiple myeloma. Blood Cancer Discov. 1, 258–273 (2020).
Maclachlan, K. H. et al. Copy number signatures predict chromothripsis and clinical outcomes in newly diagnosed multiple myeloma. Nat. Commun. 12, 5172 (2021).
Rosswog, C. et al. Chromothripsis followed by circular recombination drives oncogene amplification in human cancer. Nat. Genet. 53, 1673–1685 (2021).
Turner, K. M. et al. Extrachromosomal oncogene amplification drives tumour evolution and genetic heterogeneity. Nature 543, 122–125 (2017).
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 performed a pan-cancer analysis of ecDNA prevalence, linking ecDNA to oncogene amplification and poor prognosis.
Kloosterman, W. P. et al. Chromothripsis is a common mechanism driving genomic rearrangements in primary and metastatic colorectal cancer. Genome Biol. 12, R103 (2011).
Sakamoto, Y. et al. Phasing analysis of lung cancer genomes using a long read sequencer. Nat. Commun. 13, 3464 (2022).
Nurk, S. et al. The complete sequence of a human genome. Science 376, 44–53 (2022).
Lei, M. et al. Long-read DNA sequencing fully characterized chromothripsis in a patient with Langer-Giedion syndrome and Cornelia de Lange syndrome-4. J. Hum. Genet. 65, 667–674 (2020).
Schopflin, R. et al. Integration of Hi-C with short and long-read genome sequencing reveals the structure of germline rearranged genomes. Nat. Commun. 13, 6470 (2022).
Rausch, T. et al. Long-read sequencing of diagnosis and post-therapy medulloblastoma reveals complex rearrangement patterns and epigenetic signatures. Cell Genom. 3, 100281 (2023).
Przybytkowski, E. et al. Chromosome-breakage genomic instability and chromothripsis in breast cancer. BMC Genom. 15, 579 (2014).
Berry, N. K., Dixon-McIver, A., Scott, R. J., Rowlings, P. & Enjeti, A. K. Detection of complex genomic signatures associated with risk in plasma cell disorders. Cancer Genet. 218-219, 1–9 (2017).
Ortega, V., Mendiola, C. & Velagaleti, G. V. N. Identification of chromothripsis in biopsy using SNP-based microarray. Methods Mol. Biol. 1769, 85–117 (2018).
Chan, E. K. F. et al. Optical mapping reveals a higher level of genomic architecture of chained fusions in cancer. Genome Res. 28, 726–738 (2018).
Yang, H. et al. High-resolution structural variant profiling of myelodysplastic syndromes by optical genome mapping uncovers cryptic aberrations of prognostic and therapeutic significance. Leukemia 36, 2306–2316 (2022).
Ramos-Campoy, S. et al. TP53 abnormalities are underlying the poor outcome associated with chromothripsis in chronic lymphocytic leukemia patients with complex karyotype. Cancers 14, 3715 (2022).
Francis, J. M. et al. EGFR variant heterogeneity in glioblastoma resolved through single-nucleus sequencing. Cancer Discov. 4, 956–971 (2014).
Jeong, H. et al. Functional analysis of structural variants in single cells using Strand-seq. Nat. Biotechnol. 41, 832–844 (2022).
Sanders, A. D. et al. Single-cell analysis of structural variations and complex rearrangements with tri-channel processing. Nat. Biotechnol. 38, 343–354 (2020).
Parra, G. R. et al. Single cell multi-omics analysis of chromothriptic medulloblastoma highlights genomic and transcriptomic consequences of genome instability. Preprint at bioRxiv https://doi.org/10.1101/2021.06.25.449944 (2021).
Shiau, C. K. et al. High throughput single cell long-read sequencing analyses of same-cell genotypes and phenotypes in human tumors. Nat. Commun. 14, 4124 (2023).
Payne, A. C. et al. In situ genome sequencing resolves DNA sequence and structure in intact biological samples. Science 371, eaay3446 (2021).
Mackinnon, R. N. & Campbell, L. J. Chromothripsis under the microscope: a cytogenetic perspective of two cases of AML with catastrophic chromosome rearrangement. Cancer Genet. 206, 238–251 (2013).
Chen, K. H., Boettiger, A. N., Moffitt, J. R., Wang, S. & Zhuang, X. RNA imaging. Spatially resolved, highly multiplexed RNA profiling in single cells. Science 348, aaa6090 (2015).
Su, J. H., Zheng, P., Kinrot, S. S., Bintu, B. & Zhuang, X. Genome-scale imaging of the 3D organization and transcriptional activity of chromatin. Cell 182, 1641–1659.e26 (2020).
Yang, J., Deng, G. & Cai, H. ChromothripsisDB: a curated database of chromothripsis. Bioinformatics 32, 1433–1435 (2016).
Gao, J. et al. Integrative analysis of complex cancer genomics and clinical profiles using the cBioPortal. Sci. Signal. 6, pl1 (2013).
International Cancer Genome Consortium et al. International network of cancer genome projects. Nature 464, 993–998 (2010).
Bamford, S. et al. The COSMIC (Catalogue of Somatic Mutations in Cancer) database and website. Br. J. Cancer 91, 355–358 (2004).
Heath, A. P. et al. The NCI genomic data commons. Nat. Genet. 53, 257–262 (2021).
Fenech, M. et al. Micronuclei as biomarkers of DNA damage, aneuploidy, inducers of chromosomal hypermutation and as sources of pro-inflammatory DNA in humans. Mutat. Res. Rev. Mutat. Res. 786, 108342 (2020).
Krupina, K., Goginashvili, A. & Cleveland, D. W. Causes and consequences of micronuclei. Curr. Opin. Cell Biol. 70, 91–99 (2021).
Kato, H. & Sandberg, A. A. Chromosome pulverization in human cells with micronuclei. J. Natl Cancer Inst. 40, 165–179 (1968).
Liu, S. et al. Nuclear envelope assembly defects link mitotic errors to chromothripsis. Nature 561, 551–555 (2018).
Xia, Y. et al. Nuclear rupture at sites of high curvature compromises retention of DNA repair factors. J. Cell Biol. 217, 3796–3808 (2018).
Hatch, E. M., Fischer, A. H., Deerinck, T. J. & Hetzer, M. W. Catastrophic nuclear envelope collapse in cancer cell micronuclei. Cell 154, 47–60 (2013). This study identified the collapse of the nuclear envelope surrounding a micronucleus to be a common feature of cancer cells.
Vargas, J. D., Hatch, E. M., Anderson, D. J. & Hetzer, M. W. Transient nuclear envelope rupturing during interphase in human cancer cells. Nucleus 3, 88–100 (2012).
Willan, J. et al. ESCRT-III is necessary for the integrity of the nuclear envelope in micronuclei but is aberrant at ruptured micronuclear envelopes generating damage. Oncogenesis 8, 29 (2019).
Vietri, M. et al. Unrestrained ESCRT-III drives micronuclear catastrophe and chromosome fragmentation. Nat. Cell Biol. 22, 856–867 (2020).
Ly, P. et al. Chromosome segregation errors generate a diverse spectrum of simple and complex genomic rearrangements. Nat. Genet. 51, 705–715 (2019). This study used a cellular model of missegregation of the Y chromosome bearing a selective marker to demostrate that chromosome micronucleation can initiate a broad spectrum of genome rearrangements (including chromothripsis) found in human cancer.
Bochtler, T. et al. Micronucleus formation in human cancer cells is biased by chromosome size. Genes Chromosomes Cancer 58, 392–395 (2019).
Klaasen, S. J. et al. Nuclear chromosome locations dictate segregation error frequencies. Nature 607, 604–609 (2022).
Mammel, A. E., Huang, H. Z., Gunn, A. L., Choo, E. & Hatch, E. M. Chromosome length and gene density contribute to micronuclear membrane stability. Life Sci. Alliance 5, e202101210 (2022).
Schutze, D. M. et al. Immortalization capacity of HPV types is inversely related to chromosomal instability. Oncotarget 7, 37608–37621 (2016).
Dacus, D. et al. Beta human papillomavirus 8 E6 induces micronucleus formation and promotes chromothripsis. J. Virol. 96, e0101522 (2022).
Li, J. S. Z. et al. Chromosomal fragile site breakage by EBV-encoded EBNA1 at clustered repeats. Nature 616, 504–509 (2023).
Barra, V. & Fachinetti, D. The dark side of centromeres: types, causes and consequences of structural abnormalities implicating centromeric DNA. Nat. Commun. 9, 4340 (2018).
McClintock, B. The stability of broken ends of chromosomes in zea mays. Genetics 26, 234–282 (1941).
Maciejowski, J. & de Lange, T. Telomeres in cancer: tumour suppression and genome instability. Nat. Rev. Mol. Cell Biol. 18, 175–186 (2017).
Hoffelder, D. R. et al. Resolution of anaphase bridges in cancer cells. Chromosoma 112, 389–397 (2004).
Pampalona, J., Soler, D., Genesca, A. & Tusell, L. Telomere dysfunction and chromosome structure modulate the contribution of individual chromosomes in abnormal nuclear morphologies. Mutat. Res. 683, 16–22 (2010).
Li, Y. et al. Constitutional and somatic rearrangement of chromosome 21 in acute lymphoblastic leukaemia. Nature 508, 98–102 (2014).
Mardin, B. R. et al. A cell-based model system links chromothripsis with hyperploidy. Mol. Syst. Biol. 11, 828 (2015).
Umbreit, N. T. et al. Mechanisms generating cancer genome complexity from a single cell division error. Science 368, eaba0712 (2020).
Gisselsson, D. et al. Telomere dysfunction triggers extensive DNA fragmentation and evolution of complex chromosome abnormalities in human malignant tumors. Proc. Natl Acad. Sci. USA 98, 12683–12688 (2001).
Yang, Y. G., Lindahl, T. & Barnes, D. E. Trex1 exonuclease degrades ssDNA to prevent chronic checkpoint activation and autoimmune disease. Cell 131, 873–886 (2007).
Christmann, M., Tomicic, M. T., Aasland, D., Berdelle, N. & Kaina, B. Three prime exonuclease I (TREX1) is Fos/AP-1 regulated by genotoxic stress and protects against ultraviolet light and benzo(a)pyrene-induced DNA damage. Nucleic Acids Res. 38, 6418–6432 (2010).
Maciejowski, J. et al. APOBEC3-dependent kataegis and TREX1-driven chromothripsis during telomere crisis. Nat. Genet. 52, 884–890 (2020).
Nader, G. P. F. et al. Compromised nuclear envelope integrity drives TREX1-dependent DNA damage and tumor cell invasion. Cell 184, 5230–5246.e22 (2021).
Xia, Y. et al. Rescue of DNA damage after constricted migration reveals a mechano-regulated threshold for cell cycle. J. Cell Biol. 218, 2545–2563 (2019).
Hong, Y. et al. LEM-3 is a midbody-tethered DNA nuclease that resolves chromatin bridges during late mitosis. Nat. Commun. 9, 728 (2018).
Song, J., Freeman, A. D. J., Knebel, A., Gartner, A. & Lilley, D. M. J. Human ANKLE1 is a nuclease specific for branched DNA. J. Mol. Biol. 432, 5825–5834 (2020).
Jiang, H., Kong, N., Liu, Z., West, S. C. & Chan, Y. W. Human endonuclease ANKLE1 localizes at the midbody and processes chromatin bridges to prevent DNA damage and cGAS-STING activation. Adv. Sci. 10, e2204388 (2023).
Tang, S., Stokasimov, E., Cui, Y. & Pellman, D. Breakage of cytoplasmic chromosomes by pathological DNA base excision repair. Nature 606, 930–936 (2022).
Terzoudi, G. I. et al. Stress induced by premature chromatin condensation triggers chromosome shattering and chromothripsis at DNA sites still replicating in micronuclei or multinucleate cells when primary nuclei enter mitosis. Mutat. Res. Genet. Toxicol. Env. Mutagen. 793, 185–198 (2015).
Tang, H. L. et al. Cell survival, DNA damage, and oncogenic transformation after a transient and reversible apoptotic response. Mol. Biol. Cell 23, 2240–2252 (2012).
Tubio, J. M. & Estivill, X. Cancer: when catastrophe strikes a cell. Nature 470, 476–477 (2011).
Rello-Varona, S. et al. Autophagic removal of micronuclei. Cell Cycle 11, 170–176 (2012).
Nassour, J. et al. Autophagic cell death restricts chromosomal instability during replicative crisis. Nature 565, 659–663 (2019).
Zhao, M. et al. CGAS is a micronucleophagy receptor for the clearance of micronuclei. Autophagy 17, 3976–3991 (2021).
Wang, J. et al. Comprehensive chromosome end remodeling during programmed DNA elimination. Curr. Biol. 30, 3397–3413.e4 (2020).
Morishita, M. et al. Chromothripsis-like chromosomal rearrangements induced by ionizing radiation using proton microbeam irradiation system. Oncotarget 7, 10182–10192 (2016).
Doudna, J. A. & Charpentier, E. Genome editing. The new frontier of genome engineering with CRISPR-Cas9. Science 346, 1258096 (2014).
Hsu, P. D., Lander, E. S. & Zhang, F. Development and applications of CRISPR-Cas9 for genome engineering. Cell 157, 1262–1278 (2014).
Leibowitz, M. L. et al. Chromothripsis as an on-target consequence of CRISPR-Cas9 genome editing. Nat. Genet. 53, 895–905 (2021).
Geng, K. et al. Target-enriched nanopore sequencing and de novo assembly reveals co-occurrences of complex on-target genomic rearrangements induced by CRISPR-Cas9 in human cells. Genome Res. 32, 1876–1891 (2022).
Trivedi, P., Steele, C. D., Au, F. K. C., Alexandrov, L. B. & Cleveland, D. W. Mitotic tethering enables inheritance of shattered micronuclear chromosomes. Nature 618, 1049–1056 (2023).
Lin, Y. F. et al. Mitotic clustering of pulverized chromosomes from micronuclei. Nature 618, 1041–1048 (2023). Trivedi et al. and Lin et al. showed that tethering of micronuclei-derived chromosome fragments in mitosis enables their inheritance.
Paull, T. T. et al. A critical role for histone H2AX in recruitment of repair factors to nuclear foci after DNA damage. Curr. Biol. 10, 886–895 (2000).
Lupski, J. R. Genomic disorders: structural features of the genome can lead to DNA rearrangements and human disease traits. Trends Genet. 14, 417–422 (1998).
Hastings, P. J., Lupski, J. R., Rosenberg, S. M. & Ira, G. Mechanisms of change in gene copy number. Nat. Rev. Genet. 10, 551–564 (2009).
Kloosterman, W. P. et al. Constitutional chromothripsis rearrangements involve clustered double-stranded DNA breaks and nonhomologous repair mechanisms. Cell Rep. 1, 648–655 (2012).
Ratnaparkhe, M. et al. Defective DNA damage repair leads to frequent catastrophic genomic events in murine and human tumors. Nat. Commun. 9, 4760 (2018).
Schipler, A. et al. Chromosome thripsis by DNA double strand break clusters causes enhanced cell lethality, chromosomal translocations and 53BP1-recruitment. Nucleic Acids Res. 44, 7673–7690 (2016).
Cleal, K., Jones, R. E., Grimstead, J. W., Hendrickson, E. A. & Baird, D. M. Chromothripsis during telomere crisis is independent of NHEJ, and consistent with a replicative origin. Genome Res. 29, 737–749 (2019).
Nigg, E. A. Mitotic kinases as regulators of cell division and its checkpoints. Nat. Rev. Mol. Cell Biol. 2, 21–32 (2001).
Northcott, P. A. et al. Subgroup-specific structural variation across 1,000 medulloblastoma genomes. Nature 488, 49–56 (2012).
Rucker, F. G. et al. Chromothripsis is linked to TP53 alteration, cell cycle impairment, and dismal outcome in acute myeloid leukemia with complex karyotype. Haematologica 103, e17–e20 (2018).
Mehine, M., Kaasinen, E. & Aaltonen, L. A. Chromothripsis in uterine leiomyomas. N. Engl. J. Med. 369, 2160–2161 (2013).
Holzmann, C. et al. Cytogenetically normal uterine leiomyomas without MED12-mutations-a source to identify unknown mechanisms of the development of uterine smooth muscle tumors. Mol. Cytogenet. 7, 88 (2014).
Mehine, M., Makinen, N., Heinonen, H. R., Aaltonen, L. A. & Vahteristo, P. Genomics of uterine leiomyomas: insights from high-throughput sequencing. Fertil. Steril. 102, 621–629 (2014).
Pendina, A. A. et al. Case of chromothripsis in a large solitary non-recurrent uterine leiomyoma. Eur. J. Obstet. Gynecol. Reprod. Biol. 219, 134–136 (2017).
McEvoy, J. et al. RB1 gene inactivation by chromothripsis in human retinoblastoma. Oncotarget 5, 438–450 (2014).
Mitchell, T. J. et al. Timing the landmark events in the evolution of clear cell renal cell cancer: TRACERx renal. Cell 173, 611–623.e7 (2018).
Nones, K. et al. Genomic catastrophes frequently arise in esophageal adenocarcinoma and drive tumorigenesis. Nat. Commun. 5, 5224 (2014).
Notta, F. et al. A renewed model of pancreatic cancer evolution based on genomic rearrangement patterns. Nature 538, 378–382 (2016).
Parker, M. et al. C11orf95-RELA fusions drive oncogenic NF-kappaB signalling in ependymoma. Nature 506, 451–455 (2014).
Kodama, T. et al. A novel mechanism of EML4-ALK rearrangement mediated by chromothripsis in a patient-derived cell line. J. Thorac. Oncol. 9, 1638–1646 (2014).
Singh, Z. N. et al. Cryptic ETV6-PDGFRB fusion in a highly complex rearrangement of chromosomes 1, 5, and 12 due to a chromothripsis-like event in a myelodysplastic syndrome/myeloproliferative neoplasm. Leuk. Lymphoma 60, 1304–1307 (2019).
Anderson, N. D. et al. Rearrangement bursts generate canonical gene fusions in bone and soft tissue tumors. Science 361, eaam8419 (2018).
Arniani, S. et al. Chromothripsis is a frequent event and underlies typical genetic changes in early T-cell precursor lymphoblastic leukemia in adults. Leukemia 36, 2577–2585 (2022).
Cox, D., Yuncken, C. & Spriggs, A. I. Minute chromatin bodies in malignant tumours of childhood. Lancet 1, 55–58 (1965).
Ilic, M., Zaalberg, I. C., Raaijmakers, J. A. & Medema, R. H. Life of double minutes: generation, maintenance, and elimination. Chromosoma 131, 107–125 (2022).
Pecorino, L. T., Verhaak, R. G. W., Henssen, A. & Mischel, P. S. Extrachromosomal DNA (ecDNA): an origin of tumor heterogeneity, genomic remodeling, and drug resistance. Biochem. Soc. Trans. 50, 1911–1920 (2022).
van Leen, E., Bruckner, L. & Henssen, A. G. The genomic and spatial mobility of extrachromosomal DNA and its implications for cancer therapy. Nat. Genet. 54, 107–114 (2022).
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).
Fakharzadeh, S. S., Trusko, S. P. & George, D. L. Tumorigenic potential associated with enhanced expression of a gene that is amplified in a mouse tumor cell line. EMBO J. 10, 1565–1569 (1991).
Mansfield, A. S. et al. Neoantigenic potential of complex chromosomal rearrangements in mesothelioma. J. Thorac. Oncol. 14, 276–287 (2019).
Mackenzie, K. J. et al. cGAS surveillance of micronuclei links genome instability to innate immunity. Nature 548, 461–465 (2017). This study demonstrated that DNA in ruptured micronuclei is recognized by the innate immunity DNA sensor cGAS.
Harding, S. M. et al. Mitotic progression following DNA damage enables pattern recognition within micronuclei. Nature 548, 466–470 (2017).
Bartsch, K. et al. Absence of RNase H2 triggers generation of immunogenic micronuclei removed by autophagy. Hum. Mol. Genet. 26, 3960–3972 (2017).
Bakhoum, S. F. et al. Chromosomal instability drives metastasis through a cytosolic DNA response. Nature 553, 467–472 (2018).
Gratia, M. et al. Bloom syndrome protein restrains innate immune sensing of micronuclei by cGAS. J. Exp. Med. 216, 1199–1213 (2019).
Ku, J. W. K. et al. Bacterial-induced cell fusion is a danger signal triggering cGAS-STING pathway via micronuclei formation. Proc. Natl Acad. Sci. USA 117, 15923–15934 (2020).
Lohard, S. et al. STING-dependent paracriny shapes apoptotic priming of breast tumors in response to anti-mitotic treatment. Nat. Commun. 11, 259 (2020).
Flynn, P. J., Koch, P. D. & Mitchison, T. J. Chromatin bridges, not micronuclei, activate cGAS after drug-induced mitotic errors in human cells. Proc. Natl Acad. Sci. USA 118, e2103585118 (2021).
Heijink, A. M. et al. BRCA2 deficiency instigates cGAS-mediated inflammatory signaling and confers sensitivity to tumor necrosis factor-alpha-mediated cytotoxicity. Nat. Commun. 10, 100 (2019).
Sun, L., Wu, J., Du, F., Chen, X. & Chen, Z. J. Cyclic GMP-AMP synthase is a cytosolic DNA sensor that activates the type I interferon pathway. Science 339, 786–791 (2013).
Wu, J. et al. Cyclic GMP-AMP is an endogenous second messenger in innate immune signaling by cytosolic DNA. Science 339, 826–830 (2013).
Ablasser, A. et al. cGAS produces a 2’-5’-linked cyclic dinucleotide second messenger that activates STING. Nature 498, 380–384 (2013).
Liu, H. et al. Nuclear cGAS suppresses DNA repair and promotes tumorigenesis. Nature 563, 131–136 (2018).
Jiang, H. et al. Chromatin-bound cGAS is an inhibitor of DNA repair and hence accelerates genome destabilization and cell death. EMBO J. 38, e102718 (2019).
Banerjee, D. et al. A non-canonical, interferon-independent signaling activity of cGAMP triggers DNA damage response signaling. Nat. Commun. 12, 6207 (2021).
Cramer, S. F. & Patel, A. The frequency of uterine leiomyomas. Am. J. Clin. Pathol. 94, 435–438 (1990).
McDermott, D. H. et al. Chromothriptic cure of WHIM syndrome. Cell 160, 686–699 (2015).
Kloosterman, W. P. et al. Chromothripsis as a mechanism driving complex de novo structural rearrangements in the germline. Hum. Mol. Genet. 20, 1916–1924 (2011).
de Pagter, M. S. et al. Chromothripsis in healthy individuals affects multiple protein-coding genes and can result in severe congenital abnormalities in offspring. Am. J. Hum. Genet. 96, 651–656 (2015).
Chiang, C. et al. Complex reorganization and predominant non-homologous repair following chromosomal breakage in karyotypically balanced germline rearrangements and transgenic integration. Nat. Genet. 44, 390–397, S1 (2012).
Nazaryan, L. et al. The strength of combined cytogenetic and mate-pair sequencing techniques illustrated by a germline chromothripsis rearrangement involving FOXP2. Eur. J. Hum. Genet. 22, 338–343 (2014).
Redin, C. et al. The genomic landscape of balanced cytogenetic abnormalities associated with human congenital anomalies. Nat. Genet. 49, 36–45 (2017).
Weckselblatt, B., Hermetz, K. E. & Rudd, M. K. Unbalanced translocations arise from diverse mutational mechanisms including chromothripsis. Genome Res. 25, 937–947 (2015).
Gamba, B. F., Richieri-Costa, A., Costa, S., Rosenberg, C. & Ribeiro-Bicudo, L. A. Chromothripsis with at least 12 breaks at 1p36.33-p35.3 in a boy with multiple congenital anomalies. Mol. Genet. Genom. 290, 2213–2216 (2015).
Meier, B. et al. C. elegans whole-genome sequencing reveals mutational signatures related to carcinogens and DNA repair deficiency. Genome Res. 24, 1624–1636 (2014).
Lee, J. K. et al. Complex chromosomal rearrangements by single catastrophic pathogenesis in NUT midline carcinoma. Ann. Oncol. 28, 890–897 (2017).
Lee, J. J. et al. Tracing oncogene rearrangements in the mutational history of lung adenocarcinoma. Cell 177, 1842–1857.e21 (2019).
Tan, E. H. et al. Catastrophic chromosomal restructuring during genome elimination in plants. eLife 4, e06516 (2015).
Guo, W., Comai, L. & Henry, I. M. Chromoanagenesis from radiation-induced genome damage in Populus. PLoS Genet. 17, e1009735 (2021).
Guo, W., Comai, L. & Henry, I. M. Chromoanagenesis in plants: triggers, mechanisms, and potential impact. Trends Genet. 39, 34–45 (2023).
Liu, J. et al. Genome-scale sequence disruption following biolistic transformation in rice and maize. Plant Cell 31, 368–383 (2019).
Fossi, M., Amundson, K., Kuppu, S., Britt, A. & Comai, L. Regeneration of solanum tuberosum plants from protoplasts induces widespread genome instability. Plant Physiol. 180, 78–86 (2019).
Carbonell-Bejerano, P. et al. Catastrophic unbalanced genome rearrangements cause somatic loss of berry color in grapevine. Plant Physiol. 175, 786–801 (2017).
Acknowledgements
The authors apologize to all colleagues whose work was not included due to space and format constraints. The authors received salary support from NIH grant R35 GM122476.
Author information
Authors and Affiliations
Contributions
The authors contributed equally to all aspects of the manuscript.
Corresponding author
Ethics declarations
Competing interests
The authors declare no competing interests.
Peer review
Peer review information
Nature Reviews Genetics thanks Jan O. Korbel, who co-reviewed with Marco R. Cosenza, and David S. Pellman, who co-reviewed with Shangming Tang and Tajinder Ubhi, and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.
Additional information
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Related links
cBioPortal: https://www.cbioportal.org/
ChromothripsisDB: http://cailab.labshare.cn/chromothripsisdb
Chromothripsis Explorer: http://compbio.med.harvard.edu/chromothripsis/
COSMIC: https://cancer.sanger.ac.uk/cosmic
GDC: https://portal.gdc.cancer.gov/
ICGC: https://dcc.icgc.org/
Rights and permissions
Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.
About this article
Cite this article
Krupina, K., Goginashvili, A. & Cleveland, D.W. Scrambling the genome in cancer: causes and consequences of complex chromosome rearrangements. Nat Rev Genet 25, 196–210 (2024). https://doi.org/10.1038/s41576-023-00663-0
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/s41576-023-00663-0
This article is cited by
-
Aspects and outcomes of surveillance for individuals at high-risk of pancreatic cancer
Familial Cancer (2024)
