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Chromoanagenesis: Cataclysms Behind Complex Chromosomal Rearrangements Franck Pellestor1,2

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Chromoanagenesis: Cataclysms Behind Complex Chromosomal Rearrangements Franck Pellestor1,2 Pellestor Molecular Cytogenetics (2019) 12:6 https://doi.org/10.1186/s13039-019-0415-7 REVIEW Open Access Chromoanagenesis: cataclysms behind complex chromosomal rearrangements Franck Pellestor1,2 Abstract Background: During the last decade, genome sequencing projects in cancer genomes as well as in patients with congenital diseases and healthy individuals have led to the identification of new types of massive chromosomal rearrangements arising during single chaotic cellular events. These unanticipated catastrophic phenomenon are termed chromothripsis, chromoanasynthesis and chromoplexis., and are grouped under the name of “chromoanagenesis”. Results: For each process, several specific features have been described, allowing each phenomenon to be distinguished from each other and to understand its mechanism of formation and to better understand its aetiology. Thus, chromothripsis derives from chromosome shattering followed by the random restitching of chromosomal fragments with low copy-number change whereas chromoanasynthesis results from erroneous DNA replication of a chromosome through serial fork stalling and template switching with variable copy-number gains, and chromoplexy refers to the occurrence of multiple inter-and intra-chromosomal translocations and deletions with little or no copy- number alterations in prostate cancer. Cumulating data and experimental models have shown that chromothripsis and chromoanasynthesis may essentially result from lagging chromosome encapsulated in micronuclei or telomere attrition andend-to-endtelomerefusion. Conclusion: The concept of chromanagenesis has provided new insight into the aetiology of complex structural rearrangements, the connection between defective cell cycle progression and genomic instability, and the complexity of cancer evolution. Increasing reported chromoanagenesis events suggest that these chaotic mechanisms are probably much more frequent than anticipated. Keywords: Chromoanagenesis, Chromothripsis, Chromoanasynthesis, Chromoplexy, Cancer, Evolution, Genome instability, Micronucleus, Double-strand breaks, Telomeres, Replication Background chromothripsis, the chromoanasynthesis and the chromo- Over the past decade, genome sequencing effort combin- plexy [1]. ing new generation DNA sequencing technologies and ef- The concept of chromoanagenesis provides new ficient bioinformatics tools have lead to the discovery of insight into the nature of complex chromosomal rear- new types of complex and massive chromosomal and gen- rangements. Both the complexity and the diversity of omic alterations characterized by the simultaneous occur- chromoanagenesis-related rearrangements raise important rence of multiple structural rearrangements confined to questions concerning the cellular mechanisms driving chro- one or a few chromosomal segments through a single moanagenesis events, the aetiology of these chaotic pro- catastrophic event. Grouped under the term of chromoa- cesses and their impact in human pathology. Experimental nagenesis (for chromosome rebirth), this new class of models allowed to validate the existence of these cata- genomic alterations involve 3 distinct phenomenons: the strophic phenomenon, and to evidence some of the causa- tive mechanisms. In this review, are summarized exciting Correspondence: [email protected] data and recent progress on understanding the formation 1Unit of Chromosomal Genetics, Department of Medical Genetics, Arnaud de Villeneuve Hospital, Montpellier CHRU, 371, avenue du Doyen Gaston Giraud, and the consequences of these complex genomic alterations. 34295 Montpellier cedex 5, France 2INSERM 1183 Unit «Genome and Stem Cell Plasticity in Development and Aging », Institute of Regenerative Medicine and Biotherapies, St Eloi Hospital, Montpellier, France © The Author(s). 2019 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Pellestor Molecular Cytogenetics (2019) 12:6 Page 2 of 12 Chromothripsis chromothripsis might be caused by abortive apoptosis. Chromothripsis is the first of these new catastrophic Whereas apoptosis was considered as an irreversible process (mechanism) described in 2011 [2]. The cascade of extensive chromatin fragmentations leading phenomenon is currently defined as a mutational event to cell death, a small subset of cells could undergo a driven by multiple double-strand breaks (DSBs) occurring restricted form of apoptosis and thus survive. The partial in a single catastrophic event between a limited numbers DNA fragmentation could be restricted to regions of of chromosomal segments, and followed by the reassem- high chromatin accessibility. The subsequent DNA re- bly of the DNA fragments in random order and orienta- pair might be accomplished through a fast and incorrect tion to form complex derivative chromosomes (Fig. 1). repair process, promoting the emergence of chaotic Several factors common to all chromothripsis events, chromosomal rearrangement [16, 25]. such as the generation of numerous clustered chromo- Since many examples of chromothripsis rearrangements somal breakpoints, the low DNA copy number changes affect chromosome ends, it has been proposed that chro- and the preservation of heterozygosity in the rearranged mothripsis could also arise via telomere attriction [2, 26]. segments, allow to distinguish chromothripsis from Indeed, uncapped chromosome-ends are prone to fusion, other complex chromosomal rearrangements and define leading to the formation of dicentric chromosomes [27]. its molecular signature [3, 4]. During mitosis, this telomere crisis can yield complex re- Initially described in cancers [1], the phenomenon was arrangements through breakage-fusion-bridge (BFB) cy- rapidly evidenced in patients with congenital abnormal- cles [28]. Several studies have suggested the association ities [5–7]. Notably, even some translocations and inver- between chromothripsis and the occurrence of BFBs [26, sions classified as simple balanced rearrangements were 29]. By examining the fate of dicentric human chromo- identified as more complex than previously appreciated somes, Maciejowski et al. [30] evidenced the formation of [8]. In the same way, extreme balanced germline chromo- chromatin bridges connecting daughter cells. These brid- thripsis were identified in patients with autism spectrum ges can undergo nuclear envelope rupture and nucleolytic disorders and other developmental abnormalities [9, 10]. attack by cytoplasmic TREX1 exonuclease, causing in the Also, chromothripsis was observed in healthy subjects [11, restricted area of the bridge, chromothripsis-like rear- 12]aswellasinprenataldiagnosis[13]. Some studies rangements frequently associated with local hypermuta- reported the possible reversibility of chromothripsis [14] tions known as kataegis [30, 31]. and its potential curative effect [15]. Accumulating data Other proposed models suggest that replication stress on familial chromothripsis validated the notion of the and mitotic error could synergize to induce chromosomal heritability of some chromothripsis rearrangements. instability and chromothripsis occurrence [16, 32, 33]or Precise analysis of breakpoint junction sequences have that premature chromosome condensation (PCC) induced indicated that the re-assembly of DNA fragments was by the fusion of an interphasic cell with a metaphasic cell driven by recombination-based mechanism such as clas- could initiate chromothripsis, leading to incomplete repli- sical non-homologous end joining (c-NHEJ) or alternative cation and subsequent partial pulverization of chromo- form of end joining (alt-EJ), operating in all phases of the somes [34]. cell cycles and working independently of micro-homologies The emergence of chromothripsis has also been but potentially error-prone [16–19]. Since the end-joining strongly associated with dysregulation or loss of p53 process mediates the formation of reciprocal translocations tumour suppressor genes. Known as the guardian of the and complex three-way translocations, Kloosterman et al. genome, p53 plays a major role in maintaining genome [20] suggested that a similar cascade mechanism could stability by mediating cell cycle arrest, apoptosis and cell operate in the creation of the derivative complex chro- senescence in response to DNA damages [35, 36]. The mosomes found in constitutional chromothripsis. potential implication of p53 pathways in chromothripsis Concerning the shattering of chromosome segments, occurrence was postulated by Rausch et al. [37] after the multiple DBSs can arise from various exogenous sources discovery of a striking correlation between germline p53 such as ionizing radiation, free radicals, environmental mutations (Li-Fraumeni syndrome) and chromothripsis toxins or chemotherapeutic drugs [21]. Even cannabis patterns in patients with Sonic-Hedgehog medulloblas- exposure has been associated with chromothripsis oc- toma brain tumors. These findings led the authors to currence [22]. Other exogenous causal factors might be propose that germline p53 mutations could
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