Chromothripsis and Human Genetic Disease

Abstract

Chromothripsis (CTH) is a newly discovered mutational mechanism, which in a single catastrophic event results in localised complex structural rearrangements confined to one or a few chromosomes. After an initial shattering or clustered fragmentation of a chromosomal region, the fragments join together in random order and orientation. During this process some of the generated fragments may be lost. It is not entirely clear which factors trigger the localised fragmentation; however, several mechanisms have been proposed, such as ionising radiation, aborted apoptosis, isolation of chromosome(s) in micronuclei, LINE1‐endonucleases, etc. CTH may disrupt multiple genes and/or regulatory regions. When it is incompatible with cell survival, the result should be apoptosis. However, if a cell escapes apoptosis, the extensive genomic rearrangements may have different phenotypic outcomes: cancer (somatic), congenital and developmental disorders (germline), neutral or even beneficial effects.

Key Concepts

  • Chromothripsis is a phenomenon where multiple localised double‐stranded DNA breaks result in complex genomic rearrangements.
  • Chromothripsis occurs within a single cell cycle.
  • Ionising radiation, aborted apoptosis, isolation of chromosome(s) in micronuclei and LINE1‐endonucleases are proposed to have a role in chromothripsis.
  • Chromothripsis in somatic cells may trigger cancer development.
  • Chromothripsis in the germline may result in congenital and developmental disorders.

Keywords: chromothripsis; clustered mutations; single‐step event; structural rearrangements; repair mechanisms; micronuclei; chromosome pulverisation; LINE‐1 endonuclease; cancer; congenital and developmental disorders

Figure 1. Schematic mechanism of chromothripsis. The first step of chromothripsis is the generation of clustered DNA (deoxyribonucleic acid) double‐strand breaks. Chromothripsis may involve one or few chromosomes, a chromosomal arm (both p and q arms) or an entire chromosome. This results in multiple fragments, which are stitched together in random order, and orientation by DNA repair machineries. During this process some of the fragments may be lost. The derivative chromosome(s) will contain complex structural rearrangements. By piecing together all the structural variants detected by paired‐end or mate‐pair sequencing, it should be possible to delineate the derivative chromosomes.
Figure 2. Proposed mechanisms for chromosome shattering. (a) Localised ionising irradiation within the nucleus may induce localised DNA double‐strand breaks, resulting in complex chromosomal alterations typical of chromothripsis. (b) Some stress factors may induce apoptosis (programmed cell death) triggering DNA fragmentation. However, if the damage is not too severe, abortion of apoptosis could occur, and incorrect repair of DNA fragments could lead to complex chromosomal rearrangements. (c) During cell division lagging chromosomes or fragments may be isolated within micronuclei, where they undergo defective DNA replication and repair, resulting in extensive DNA fragmentation. (d) LINE1‐endonuclease may cleave DNA on its target sites at multiple places owing to spatial organisation of the interphase DNA and occasionally facilitate insertion of retrotransposons at the breakpoints.
Figure 3. Schematic illustration of phenotypic consequences of chromothripsis.
close

References

Anderson SE, Kamath A, Pilz DT and Morgan SM (2016) A rare example of germ‐line chromothripsis resulting in large genomic imbalance. Clinical Dysmorphology 25 (2): 58–62.

Ballarati L, Recalcati MP, Bedeschi MF, et al. (2009) Cytogenetic, FISH and array‐CGH characterization of a complex chromosomal rearrangement carried by a mentally and language impaired patient. European Journal of Medical Genetics 52 (4): 218–223.

Bertelsen B, Nazaryan‐Petersen L, Sun W, et al. (2016) A germline chromothripsis event stably segregating in 11 individuals through three generations. Genetics in Medicine 18 (5): 494–500.

van Binsbergen E, Hochstenbach R, Giltay J and Swinkels M (2012) Unstable transmission of a familial complex chromosome rearrangement. American Journal of Medical Genetics. Part A 158A (11): 2888–2893.

Chiang C, Jacobsen JC, Ernst C, et al. (2012) Complex reorganization and predominant non‐homologous repair following chromosomal breakage in karyotypically balanced germline rearrangements and transgenic integration. Nature Genetics 44 (4): 390–397, S1.

Crasta K, Ganem NJ, Dagher R, et al. (2012) DNA breaks and chromosome pulverization from errors in mitosis. Nature 482 (7383): 53–58.

Cremer T and Cremer C (2001) Chromosome territories, nuclear architecture and gene regulation in mammalian cells. Nature Reviews. Genetics 2 (4): 292–301.

Fontana P, Genesio R, Casertano A, et al. (2014) Loeys‐Dietz syndrome type 4, caused by chromothripsis, involving the TGFB2 gene. Gene 538 (1): 69–73.

Genesio R, Ronga V, Castelluccio P, et al. (2013) Pure 16q21q22.1 deletion in a complex rearrangement possibly caused by a chromothripsis event. Molecular Cytogenetics 6 (1): 29.

Genesio R, Fontana P, Mormile A, et al. (2015) Constitutional chromothripsis involving the critical region of 9q21.13 microdeletion syndrome. Molecular Cytogenetics 8: 96.

Giardino D, Corti C, Ballarati L, et al. (2006) Prenatal diagnosis of a de novo complex chromosome rearrangement (CCR) mediated by six breakpoints, and a review of 20 prenatally ascertained CCRs. Prenatal Diagnosis 26 (6): 565–570.

Govind SK, Zia A, Hennings‐Yeomans PH, et al. (2014) ShatterProof: operational detection and quantification of chromothripsis. BMC Bioinformatics 15: 78.

Gu H, Jiang JH, Li JY, et al. (2013) A familial Cri‐du‐Chat/5p deletion syndrome resulted from rare maternal complex chromosomal rearrangements (CCRs) and/or possible chromosome 5p chromothripsis. PLoS One 8 (10).

Halgren C, Bache I, Bak M, et al. (2012) Haploinsufficiency of CELF4 at 18q12.2 is associated with developmental and behavioral disorders, seizures, eye manifestations, and obesity. European Journal of Human Genetics: EJHG 20 (12): 1315–1319.

Hirsch D, Kemmerling R, Davis S, et al. (2013) Chromothripsis and focal copy number alterations determine poor outcome in malignant melanoma. Cancer Research 73 (5): 1454–1459.

Holland AJ and Cleveland DW (2012) Chromoanagenesis and cancer: mechanisms and consequences of localized, complex chromosomal rearrangements. Nature Medicine 18 (11): 1630–1638.

Kloosterman WP, Guryev V, van Roosmalen M, et al. (2011a) Chromothripsis as a mechanism driving complex de novo structural rearrangements in the germline. Human Molecular Genetics 20 (10): 1916–1924.

Kloosterman WP, Hoogstraat M, Paling O, et al. (2011b) Chromothripsis is a common mechanism driving genomic rearrangements in primary and metastatic colorectal cancer. Genome Biology 12 (10): R103.

Kloosterman WP, Tavakoli‐Yaraki M, Van Roosmalen MJ, et al. (2012) Constitutional chromothripsis rearrangements involve clustered double‐stranded DNA breaks and nonhomologous repair mechanisms. Cell Reports 1 (6): 648–655.

Kloosterman WP and Cuppen E (2013) Chromothripsis in congenital disorders and cancer: similarities and differences. Current Opinion in Cell Biology 25 (3): 341–348.

Korbel JO, Urban AE, Affourtit JP, et al. (2007) Paired‐end mapping reveals extensive structural variation in the human genome. Science (New York, N.Y.) 318 (5849): 420–426.

Korbel JO and Campbell PJ (2013) Criteria for inference of chromothripsis in cancer genomes. Cell 152 (6): 1226–1236.

Liu P, Erez A, Nagamani SCS, et al. (2011) Chromosome catastrophes involve replication mechanisms generating complex genomic rearrangements. Cell 146 (6): 889–903.

Macera MJ, Sobrino A, Levy B, et al. (2015) Prenatal diagnosis of chromothripsis, with nine breaks characterized by karyotyping, FISH, microarray and whole‐genome sequencing. Prenatal Diagnosis 35 (3): 299–301.

Magrangeas F, Avet‐Loiseau H, Munshi NC and Minvielle S (2011) Chromothripsis identifies a rare and aggressive entity among newly diagnosed multiple myeloma patients. Blood 118 (3): 675–678.

Malhotra A, Lindberg M, Faust GG, et al. (2013) Breakpoint profiling of 64 cancer genomes reveals numerous complex rearrangements spawned by homology‐independent mechanisms. Genome Research 23 (5): 762–776.

Masset H, Hestand MS, Van Esch H, et al. (2016) A distinct class of chromoanagenesis events characterized by focal copy number gains. Human Mutation 37 (7): 661–668.

McDermott DH, Gao JL, Liu Q, et al. (2015) Chromothriptic cure of WHIM syndrome. Cell 160 (4): 686–699.

McEvoy J, Nagahawatte P, Finkelstein D, et al. (2014) RB1 gene inactivation by chromothripsis in human retinoblastoma. Oncotarget 5 (2): 438–450.

Mehine M, Makinen N, Heinonen H‐R, Aaltonen LA and Vahteristo P (2014) Genomics of uterine leiomyomas: insights from high‐throughput sequencing. Fertility and Sterility 102 (3): 621–629.

Mitelman F, Johansson B and Mertens F (2007) The impact of translocations and gene fusions on cancer causation. Nature reviews. Cancer 7 (4): 233–245.

Morishita M, Muramatsu T, Suto Y, et al. (2016) Chromothripsis‐like chromosomal rearrangements induced by ionizing radiation using proton microbeam irradiation system. Oncotarget 7 (9): 10182–10192.

Nazaryan L, Stefanou EG, Hansen C, et al. (2014) The strength of combined cytogenetic and mate‐pair sequencing techniques illustrated by a germline chromothripsis rearrangement involving FOXP2. European Journal of Human Genetics: EJHG 22 (3): 338–343.

Nazaryan‐Petersen L, Bertelsen B, Bak M, et al. (2016) Germline chromothripsis driven by L1‐mediated retrotransposition and Alu/Alu homologous recombination. Human Mutation 37 (4): 385–395.

de Pagter MS, Van Roosmalen MJ, Baas AF, et al. (2015) Chromothripsis in healthy individuals affects multiple protein‐coding genes and can result in severe congenital abnormalities in offspring. American Journal of Human Genetics 96 (4): 651–656.

de Pater JM, Ippel PF, van Dam WM, Loneus WH and Engelen JJM (2002) Characterization of partial trisomy 9p due to insertional translocation by chromosomal (micro)FISH. Clinical Genetics 62 (6): 482–487.

Poot M, van't Slot R, Leupert R, et al. (2009) Three de novo losses and one insertion within a pericentric inversion of chromosome 6 in a patient with complete absence of expressive speech and reduced pain perception. European Journal of Medical Genetics 52 (1): 27–30.

Rausch T, Jones DTW, Zapatka M, et al. (2012) Genome sequencing of pediatric medulloblastoma links catastrophic DNA rearrangements with TP53 mutations. Cell 148 (1–2): 59–71.

Rode A, Maass KK, Willmund KV, Lichter P and Ernst A (2016) Chromothripsis in cancer cells: an update. International Journal of Cancer 138 (10): 2322–2333.

Stephens PJ, Greenman CD, Fu B, et al. (2011) Massive genomic rearrangement acquired in a single catastrophic event during cancer development. Cell 144 (1): 27–40.

Talkowski ME, Ernst C, Heilbut A, et al. (2011) Next‐generation sequencing strategies enable routine detection of balanced chromosome rearrangements for clinical diagnostics and genetic research. American Journal of Human Genetics 88 (4): 469–481.

Teles Alves I, Hiltemann S, Hartjes T, et al. (2013) Gene fusions by chromothripsis of chromosome 5q in the VCaP prostate cancer cell line. Human Genetics 132 (6): 709–713.

Tubio JMC and Estivill X (2011) Cancer: when catastrophe strikes a cell. Nature 470 (7335): 476–477.

Voet T, Vanneste E and Vermeesch J (2011) The human cleavage stage embryo is a cradle of chromosomal rearrangements. Cytogenetic and Genome Research 133 (2–4): 160–168.

Wang J‐C, Fisker T and Sahoo T (2015) Constitutional chromothripsis involving chromosome 19 in a child with subtle dysmorphic features. American Journal of Medical Genetics. Part A 167A (4): 910–913.

Wu C, Wyatt AW, Mcpherson A, et al. (2012) Poly‐gene fusion transcripts and chromothripsis in prostate cancer. Genes, Chromosomes and Cancer 51 (12): 1144–1153.

Zhang CZ, Leibowitz ML and Pellman D (2013) Chromothripsis and beyond: rapid genome evolution from complex chromosomal rearrangements. Genes and Development 27 (23): 2513–2530.

Zhang C‐Z, Spektor A, Cornils H, et al. (2015) Chromothripsis from DNA damage in micronuclei. Nature 522 (7555): 179–184.

Further Reading

Chen JM, Férec C and Cooper DN (2012) Transient hypermutability, chromothripsis and replication‐based mechanisms in the generation of concurrent clustered mutations. Mutation Research 750 (1): 52–59.

Forment JV, Kaidi A and Jackson SP (2012) Chromothripsis and cancer: causes and consequences of chromosome shattering. Nature Reviews. Cancer 12 (10): 663–670.

Hart L and O'Driscoll M (2001) Causes and Consequences of Structural Genomic Alterations in the Human Genome (In: eLS). John Wiley & Sons, Ltd. DOI: 10.1002/9780470015902.a0024976.

Storchova Z and Kloosterman WP (2016) The genomic characteristics and cellular origin of chromothripsis. Current Opinion in Cell Biology 40: 106–113.

Contact Editor close
Submit a note to the editor about this article by filling in the form below.

* Required Field

How to Cite close
Nazaryan‐Petersen, Lusine, and Tommerup, Niels(Sep 2016) Chromothripsis and Human Genetic Disease. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0024627]