Of Simple and Complex Genome Rearrangements, Chromothripsis, Chromoanasynthesis, and Chromosome Chaos

Poot, Martin

doi:10.1159/000454964

Cited by 15 publications

(8 citation statements)

References 28 publications

(40 reference statements)

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“…The utilization in genome-wide profiling in MM patients with the use of array-CGH technique showed that similarly to other hematological malignancies, malignant PCs can harbor a complex chromosomal aberration known as chromothripsis with incidence of 2% [ 31 ]. While the incidence of chromothripsis seems to be rare event in blood cancer diseases, it is only a portion of all types of genomic chaos, which is considered to be one the major contributors to cancer development and progression [ 32 , 33 ]. The study of French Myeloma Group also showed that incidence of this catastrophic event detected by microarray techniques in genome of PCs is associated with very poor prognosis and aggressive course of the disease [ 20 ].…”

Section: Discussionmentioning

confidence: 99%

Chromothripsis 18 in multiple myeloma patient with rapid extramedullary relapse

et al. 2018

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BackgroundCatastrophic chromosomal event known as chromothripsis was proven to be a significant hallmark of poor prognosis in several cancer diseases. While this phenomenon is very rare in among multiple myeloma (MM) patients, its presence in karyotype is associated with very poor prognosis.Case presentationIn our case, we report a 62 year female patient with rapid progression of multiple myeloma (MM) into extramedullary disease and short overall survival (OS = 23 months). I-FISH investigation revealed presence of gain 1q21 and hyperdiploidy (+ 5,+ 9,+ 15) in 82% and 86%, respectively, while IgH rearrangements, del(17)(p13) and del(13)(q14) were evaluated as negative.Whole-genome profiling using array-CGH showed complex genomic changes including hyperdiploidy (+ 3,+ 5,+ 9,+ 11, + 15,+ 19), monosomy X, structural gains (1q21-1q23.1, 1q32-1q44, 16p13.13-16p11.2) and losses (1q23.1-1q32.1; 8p23.3-8p11.21) of genetic material and chromothripsis in chromosome 18 with 6 breakpoint areas. Next-generation sequencing showed a total of 338 variants with 1.8% (6/338) of pathological mutations in NRAS (c.181C > A; p.Gln61Lys) or variants of unknown significance in TP53, CUX1 and POU4F1.ConclusionsOur findings suggest that presence of chromothripsis should be considered as another important genetic hallmark of poor prognosis in MM patients and utilization of genome-wide screening techniques such as array-CGH and NGS improves the clinical diagnostics of the disease.Electronic supplementary materialThe online version of this article (10.1186/s13039-018-0357-5) contains supplementary material, which is available to authorized users.

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Section: Discussionmentioning

confidence: 99%

Chromothripsis 18 in multiple myeloma patient with rapid extramedullary relapse

et al. 2018

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“…Molecular characterization of the mutations in these kataegic showers indicates that they result from the action of the AID/APOBEC family of cytosine deaminases on exposed single-stranded domains [ 596 ]: mutations are predominantly (>70%) C-to-T transitions, as expected for C-to-U deamination products [ 597 , 598 ], and are largely fixed in the same DNA strand, a sign of catalytic processivity [ 599 ]. Chromothripsis means “chromosome shattering”, and indicates cases where multiple chromosome fragments, usually from a single chromosome, are ligated together in a new arrangement with multiple transpositions, inversions, deletions, and duplications [ 600 , 601 , 602 ]. A variety of processes are thought to lead to the underlying multiple chromosome breakage and DS break repair events that are producing each chromothripsis occurence (see Supplementary Table S15 for references), but we know that chromothripsis usually occurs with a single chromosome because breakage and repair processes can be seen to occur on individual chromosomes that are isolated in micronuclei compartments [ 603 ].…”

Section: Ecological Disruption and Read-write Genome Modificationsmentioning

confidence: 99%

“…A form of kataegis occurs in the yeast genome at highly transcribed loci [ 607 , 608 ] and also at tRNA loci [ 609 ]. Chromothripsis affects multiple protein-coding loci in healthy individuals [ 604 ], and has been found to arise more frequently than previously thought in both gametogenesis and early human embryogenesis [ 601 , 610 , 611 , 612 ]. Obviously, germline episodes of either kataegis, chromothripsis, or both can contribute to major genome changes in evolutionary diversification and innovation [ 613 , 614 ].…”

Section: Ecological Disruption and Read-write Genome Modificationsmentioning

confidence: 99%

Living Organisms Author Their Read-Write Genomes in Evolution

Shapiro

2017

Biology

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Evolutionary variations generating phenotypic adaptations and novel taxa resulted from complex cellular activities altering genome content and expression: (i) Symbiogenetic cell mergers producing the mitochondrion-bearing ancestor of eukaryotes and chloroplast-bearing ancestors of photosynthetic eukaryotes; (ii) interspecific hybridizations and genome doublings generating new species and adaptive radiations of higher plants and animals; and, (iii) interspecific horizontal DNA transfer encoding virtually all of the cellular functions between organisms and their viruses in all domains of life. Consequently, assuming that evolutionary processes occur in isolated genomes of individual species has become an unrealistic abstraction. Adaptive variations also involved natural genetic engineering of mobile DNA elements to rewire regulatory networks. In the most highly evolved organisms, biological complexity scales with “non-coding” DNA content more closely than with protein-coding capacity. Coincidentally, we have learned how so-called “non-coding” RNAs that are rich in repetitive mobile DNA sequences are key regulators of complex phenotypes. Both biotic and abiotic ecological challenges serve as triggers for episodes of elevated genome change. The intersections of cell activities, biosphere interactions, horizontal DNA transfers, and non-random Read-Write genome modifications by natural genetic engineering provide a rich molecular and biological foundation for understanding how ecological disruptions can stimulate productive, often abrupt, evolutionary transformations.

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“…(2) The large number of DSBs induced by the anticancer treatment must be repaired by homologous recombination, which is error-free and acts only in the postsynthetic phases of late-S and G2; this repair allows a proportion of the cells to repair the DSBs without generating karyotypic changes, although they can carry point mutations. However, an important repair mechanism for these lesions acting throughout the cell cycle is the nonhomologous recombination or NHEJ, both classical or alternative route, and other similar mechanisms, involving abnormal replication [81], that can generate a random rejoining of the chromosomal fragments, producing a karyotypically heterogeneous cell population, with large CIN, leading the formation of highly rearranged genomes and genomic chaos.…”

Section: Discussionmentioning

confidence: 99%

Nonclonal Chromosome Aberrations and Genome Chaos in Somatic and Germ Cells from Patients and Survivors of Hodgkin Lymphoma

Frias

Ramos

Salas-Labadía

et al. 2019

Genes

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Anticancer regimens for Hodgkin lymphoma (HL) patients include highly genotoxic drugs that have been very successful in killing tumor cells and providing a 90% disease-free survival at five years. However, some of these treatments do not have a specific cell target, damaging both cancerous and normal cells. Thus, HL survivors have a high risk of developing new primary cancers, both hematologic and solid tumors, which have been related to treatment. Several studies have shown that after treatment, HL patients and survivors present persistent chromosomal instability, including nonclonal chromosomal aberrations. The frequency and type of chromosomal abnormalities appear to depend on the type of therapy and the cell type examined. For example, MOPP chemotherapy affects hematopoietic and germ stem cells leading to long-term genotoxic effects and azoospermia, while ABVD chemotherapy affects transiently sperm cells, with most of the patients showing recovery of spermatogenesis. Both regimens have long-term effects in somatic cells, presenting nonclonal chromosomal aberrations and genomic chaos in a fraction of noncancerous cells. This is a source of karyotypic heterogeneity that could eventually generate a more stable population acquiring clonal chromosomal aberrations and leading towards the development of a new cancer.

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Of Simple and Complex Genome Rearrangements, Chromothripsis, Chromoanasynthesis, and Chromosome Chaos

Cited by 15 publications

References 28 publications

Chromothripsis 18 in multiple myeloma patient with rapid extramedullary relapse

Chromothripsis 18 in multiple myeloma patient with rapid extramedullary relapse

Living Organisms Author Their Read-Write Genomes in Evolution

Nonclonal Chromosome Aberrations and Genome Chaos in Somatic and Germ Cells from Patients and Survivors of Hodgkin Lymphoma

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