Massive Genomic Rearrangement Acquired in a Single Catastrophic Event during Cancer Development

Stephens, Philip J.; Greenman, Chris; Fu, Beiyuan; Yang, Fengtang; Bignell, Graham R.; Mudie, Laura; Pleasance, Erin; Lau, King Wai; Beare, David; Stebbings, Lucy; McLaren, Stuart; Lin, Meng-Lay; McBride, David J.; Varela, Ignacio; Nik-Zainal, Serena; Leroy, Catherine; Jia, Mingming; Menzies, Andrew; Butler, Adam; Teague, Jon W.; Quail, Michael A.; Burton, John H.; Swerdlow, Harold; Carter, Nigel P.; Morsberger, Laura; Iacobuzio‐Donahue, Christine A.; Follows, George; Green, Andrew; Flanagan, Adrienne M.; Stratton, Michael R.; Futreal, P. Andrew; Campbell, Peter J.

doi:10.1016/j.cell.2010.11.055

Cited by 2,132 publications

(2,421 citation statements)

References 36 publications

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“…[38][39][40][41] On the basis of copy number profiling, chromothripsis was present in an estimated 1-3% of human cancers. 18,42 By contrast, 19% (3/16) of cases (and 38% of the 'S' group) in the current series presented copy number profiles suggesting chromothripsis, a phenomenon unprecedented in adenosarcoma. All the three tumors belonged to the 'S' group, which is consistent with previous observations that chromothripsis is generally correlated with poor prognosis.…”

Section: Discussioncontrasting

confidence: 69%

“…35,36 Chromothripsis has been described as a cellular catastrophe that causes pulverization of one or a few chromosomes, typically with massive rearrangements of the affected chromosome regions accompanied by numerous copy number losses and gains. 18,37 To infer chromothripsis with array-based copy number profiling data, various criteria have been applied, the central common part of which is to identify oscillating copy number states on a single chromosome. [38][39][40][41] On the basis of copy number profiling, chromothripsis was present in an estimated 1-3% of human cancers.…”

Section: Discussionmentioning

confidence: 99%

“…This highly fragmented status involving single chromosomes indicated the phenomenon of chromothripsis. 18,19 Both cases S1 and S6 also harbored amplifications involving chromosome 12 (including CDK4 and MDM2 genes), implying that chromothripsis might be the mechanism accounting Chromosomal instability in adenosarcomas for amplification of these loci. In comparison, cases N1, N2, and S3 also had amplifications of these loci despite no evidence of chromothripsis (Figure 4), thus implying a different mechanism of amplification.…”

Section: Identification Of Chromothripsis-like Copy Number Profiles Wmentioning

confidence: 99%

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Genomewide copy number analysis of Müllerian adenosarcoma identified chromosomal instability in the aggressive subgroup

Lee

Changou

et al. 2016

Modern Pathology

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Müllerian adenosarcomas are malignant gynecologic neoplasms. Advanced staging and sarcomatous overgrowth predict poor prognosis. Because the genomic landscape remains poorly understood, we conducted this study to characterize the genomewide copy number variations in adenosarcomas. Sixteen tumors, including eight with and eight without sarcomatous overgrowth, were subjected to a molecular inversion probe array analysis. Copy number variations, particularly losses, were significantly higher in cases with sarcomatous overgrowth. Frequent gains of chromosomal 12q were noted, often involving cancer-associated genes CDK4 (six cases), MDM2, CPM, YEATS4, DDIT3, GLI1 (five each), HMGA2 and STAT6 (four), without association with sarcomatous overgrowth status. The most frequent losses involved chromosomes 13q (five cases), 9p, 16q and 17q (four cases each) and were almost limited to cases with sarcomatous overgrowth. MDM2 and CDK4 amplification, as well as losses of RB1 (observed in two cases) and CDKN2A/B (one case), was verified by FISH. By immunohistochemistry, all MDM2/CDK4-coamplified cases were confirmed to overexpress both encoded proteins, whereas all four cases with (plus an additional four without) gain of HMGA2 overexpressed the HMGA2 protein. Both cases with RB1 loss were negative for the immunostaining of the encoded protein. Chromothripsis-like copy number profiles involving chromosome 12 or 14 were observed in three fatal cases, all of which harbored sarcomatous overgrowth. With whole chromosome painting and deconvolution fluorescent microscopy, dividing tumor cells in all three cases were shown to have scattered extrachromosomal materials derived from chromosomes involved by chromothripsis, suggesting that this phenomenon may serve as visual evidence for chromothripsis in paraffin

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Section: Discussioncontrasting

confidence: 69%

Section: Discussionmentioning

confidence: 99%

Section: Identification Of Chromothripsis-like Copy Number Profiles Wmentioning

confidence: 99%

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Genomewide copy number analysis of Müllerian adenosarcoma identified chromosomal instability in the aggressive subgroup

Lee

Changou

et al. 2016

Modern Pathology

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“…It has also been proposed that, as a consequence of premature compaction, limited chromosome pulverization can occur if a micronucleated cell enters mitosis with an under-replicated micronucleus (Crasta et al, 2012). These findings are relevant for human health since they provide insights into the phenomenon of chromothripsis (Liu et al, 2011;Stephens et al, 2011).…”

Section: A Mechanism For Chromosome Pulverization and Chromothripsis?mentioning

confidence: 99%

A Mechanism for Controlled Breakage of Under-replicated Chromosomes during Mitosis

et al. 2016

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While DNA replication and mitosis occur in a sequential manner, precisely how cells maintain their temporal separation and order remains elusive. Here, we unveil a double-negative feedback loop between replication intermediates and an M-phase-specific structure-selective endonuclease, MUS81-SLX4, which renders DNA replication and mitosis mutually exclusive. MUS81 nuclease is constitutively active throughout the cell cycle but requires association with SLX4 for efficient substrate targeting. To preclude toxic processing of replicating chromosomes, WEE1 kinase restrains CDK1 and PLK1-mediated MUS81-SLX4 assembly during S phase. Accordingly, WEE1 inhibition triggers widespread nucleolytic breakage of replication intermediates, halting DNA replication and leading to chromosome pulverization. Unexpectedly, premature entry into mitosis-licensed by unrestrained CDK1 activity during S phaserequires MUS81-SLX4, which inhibits DNA replication. This suggests that ongoing replication assists WEE1 in delaying entry into M phase and, indirectly, in preventing MUS81-SLX4 assembly. Conversely, MUS81-SLX4 activation during mitosis promotes targeted resolution of persistent replication intermediates, which safeguards chromosome segregation. Unexpectedly, premature entry into mitosis -licensed by unrestrained CDK1 activity during S-phase-requires MUS81-SLX4, which inhibits DNA replication. This suggests that ongoing replication assists WEE1 in delaying entry into M-phase and, indirectly, in preventing MUS81-SLX4 assembly. Conversely, MUS81-SLX4 activation during mitosis promotes targeted resolution of persistent replication intermediates, which safeguards chromosome segregation.3

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“…As a result, it is impossible to split the assembled genome of A. vaga into haploid sets: the apparent ploidy level of A. vaga is scale-dependent, with a tetraploid structure at gene scale versus chromosome-scale haploidy. Such relaxation of constraints on genome structure is reminiscent of other mitotic lineages such as cancer cells 10 and somatic tissues 11 .…”

mentioning

confidence: 99%

Genomic evidence for ameiotic evolution in the bdelloid rotifer Adineta vaga

Flot

Hespeels

et al. 2013

Nature

362

624

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Loss of sexual reproduction is considered an evolutionary dead end for metazoans, but bdelloid rotifers challenge this view as they appear to have persisted asexually for millions of years 1 . Neither male sex organs nor meiosis have ever been observed in these microscopic animals: oocytes are formed through mitotic divisions, with no reduction of chromosome number and no indication of chromosome pairing 2 . However, current evidence does not exclude that they may engage in sex on rare, cryptic occasions. Here we report the genome of a bdelloid rotifer, Adineta vaga (Davis, 1873) 3 , and show that its structure is incompatible with conventional meiosis. At gene scale, the genome of A. vaga is tetraploid and comprises both anciently duplicated segments and less divergent allelic regions. However, in contrast to sexual species, the allelic regions are rearranged and sometimes even found on the same chromosome. Such structure does not allow meiotic pairing; instead, we find abundant evidence of gene conversion, which may limit the accumulation of deleterious mutations in the absence of meiosis. Gene families involved in resistance to oxidation, carbohydrate metabolism and defence against transposons are significantly expanded, which may explain why transposable elements cover only 3% of the assembled sequence. Furthermore, 8% of the genes are likely to be of non-metazoan origin and were probably acquired horizontally. This apparent convergence between bdelloids and prokaryotes sheds new light on the evolutionary significance of sex.With more than 460 described species 4 , bdelloid rotifers ( Fig. 1) represent the highest metazoan taxonomic rank in which males, hermaphrodites and meiosis are unknown. Such persistence and diversification of an ameiotic clade of animals are in contradiction with the supposed long-term disadvantages of asexuality, making bdelloids an 'evolutionary scandal' 5 . Another unusual feature of bdelloid rotifers is their extreme resistance to desiccation at any stage of their life cycle 6 , enabling these microscopic animals to dwell in ephemeral freshwater habitats such as mosses, lichens and forest litter; this ability is presumably the source of their extreme resistance to ionizing radiation 7 .We assembled the genome of a clonal A. vaga lineage into separate haplotypes with a N 50 of 260 kilobases (kb) (that is, half of the assembly was composed of fragments longer than 260 kb). Assembly size was 218 megabases (Mb) but 26 Mb of the sequence had twice the average sequencing coverage, suggesting that some nearly identical regions were not resolved during assembly ( Supplementary Fig. 3); hence, the total genome size is likely to be 244 Mb, which corresponds to the estimate obtained independently using fluorometry (Supplementary Note C2). Annotation of the complete assembly (including all haplotypes) yielded 49,300 genes. Intragenomic sequence comparisons revealed numerous homologous blocks with conserved gene order (colinear regions). For each such block we computed the per-site synonymous d...

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Massive Genomic Rearrangement Acquired in a Single Catastrophic Event during Cancer Development

Cited by 2,132 publications

References 36 publications

Genomewide copy number analysis of Müllerian adenosarcoma identified chromosomal instability in the aggressive subgroup

Genomewide copy number analysis of Müllerian adenosarcoma identified chromosomal instability in the aggressive subgroup

A Mechanism for Controlled Breakage of Under-replicated Chromosomes during Mitosis

Genomic evidence for ameiotic evolution in the bdelloid rotifer Adineta vaga

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