structural rearrangements Dotaz Zobrazit nápovědu
Východiska: Chromozomové přestavby hrají významnou roli v patofyziologii nádorů. Mezi mechanizmy vedoucí k jejich vzniku byla v nedávné době zařazena chromotripse. Ta způsobuje rozpad chromozomů a jejich opětovné seskupení s desítkami až stovkami přestaveb. Na rozdíl od klasického schématu nádorové transformace se při chromotripsi aberace nehromadí postupně, ale vznikají během jediné události. Vzniklé přestavby bývají rozsáhlé a často zapříčiňují aktivaci onkogenů či inaktivaci nádorových supresorů. Chromotripse je spojována s mnoha typy nádorů, především s nádory mozku a kostí. Byla však popsána nejen u nádorových onemocnění, ale i u vrozených poruch. Přesný mechanizmus vzniku nebyl dosud objasněn, existuje však několik modelů, z nichž nejpravděpodobnější se jeví vznik přestaveb následkem poškození DNA v tzv. mikrojádře. Stejně tak důsledky chromotripse pro průběh buněčných pochodů nejsou zatím plně pochopeny. U onkologických pacientů obecně je pozorována souvislost mezi chromotripsí a nepříznivou prognózou. Cíl: Záměrem tohoto článku je shrnout dosavadní poznatky o chromotripsi a předložit je čtenáři v přehledné podobě. Zaměřili jsme se na popsání základních rysů chromotripse, pravděpodobných mechanizmů jejího vzniku, důsledků na buněčné procesy a dále na poskytnutí přehledu onemocnění, u kterých se s ní můžeme setkat, přičemž pozornost je věnována zejména onkologickým onemocněním. Na závěr je uveden výhled pro využití dosavadních poznatků o chromotripsi při optimalizaci léčebných postupů u onkologických pacientů.
Background: Chromosome rearrangements play an important role in cancer pathophysiology. Recently, chromothripsis has been proposed among the mechanisms leading to their formation. Chromothripsis leads to fragmentation of chromosomes and their reconstitution with tens to hundreds of rearrangements clustered in small genome regions. In contrast to the traditional concept of malignant transformation, abnormalities caused by chromothripsis are not accumulated gradually but arise during a single event. The resulting structural variants are extensive and often cause oncogene activation or tumor suppressor inactivation. Chromothripsis is associated with many tumor types, especially with brain and bone tumors. Besides that, it has been described also in congenital disorders. The exact mechanism of chromothripsis origin has not been clarified yet; however, several hypotheses have been prosed, among which DNA damage in micronucleus seems to be most likely. Similarly, an impact of chromothripsis on cellular processes has not been fully understood, yet its association with unfavorable prognosis has been observed. Purpose: The purpose of this article is to summarize the current knowledge about chromothripsis and to present gathered pieces of information in a structured way. We focused on describing the basic features of chromothripsis, potential mechanisms of its origin, its impact on cellular processes and providing an overview of diseases where chromothripsis has been noted, with particular attention to cancer. Finally, we suggest a potential use of current knowledge about chromothripsis in the optimization of personalized treatment. Supported by Ministry of Health of the Czech Republic, grant no. 15-31834A. All rights reserved. The authors declare they have no potential conflicts of interest concerning drugs, products, or services used in the study. The Editorial Board declares that the manuscript met the ICMJE recommendation for biomedical papers. Submitted: 31. 12. 2018 Accepted: 19. 3. 2019
- MeSH
- chromothripsis * MeSH
- chromozomy MeSH
- DNA MeSH
- lidé MeSH
- mutace MeSH
- nádory * etiologie genetika terapie MeSH
- oprava DNA MeSH
- strukturální variace genomu MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- práce podpořená grantem MeSH
- přehledy MeSH
BACKGROUND: We investigated the features of the genomic rearrangements in a cohort of 50 male individuals with proteolipid protein 1 (PLP1) copy number gain events who were ascertained with Pelizaeus-Merzbacher disease (PMD; MIM: 312080). We then compared our new data to previous structural variant mutagenesis studies involving the Xq22 region of the human genome. The aggregate data from 159 sequenced join-points (discontinuous sequences in the reference genome that are joined during the rearrangement process) were studied. Analysis of these data from 150 individuals enabled the spectrum and relative distribution of the underlying genomic mutational signatures to be delineated. METHODS: Genomic rearrangements in PMD individuals with PLP1 copy number gain events were investigated by high-density customized array or clinical chromosomal microarray analysis and breakpoint junction sequence analysis. RESULTS: High-density customized array showed that the majority of cases (33/50; ~ 66%) present with single duplications, although complex genomic rearrangements (CGRs) are also frequent (17/50; ~ 34%). Breakpoint mapping to nucleotide resolution revealed further previously unknown structural and sequence complexities, even in single duplications. Meta-analysis of all studied rearrangements that occur at the PLP1 locus showed that single duplications were found in ~ 54% of individuals and that, among all CGR cases, triplication flanked by duplications is the most frequent CGR array CGH pattern observed. Importantly, in ~ 32% of join-points, there is evidence for a mutational signature of microhomeology (highly similar yet imperfect sequence matches). CONCLUSIONS: These data reveal a high frequency of CGRs at the PLP1 locus and support the assertion that replication-based mechanisms are prominent contributors to the formation of CGRs at Xq22. We propose that microhomeology can facilitate template switching, by stabilizing strand annealing of the primer using W-C base complementarity, and is a mutational signature for replicative repair.
- MeSH
- body zlomu chromozomu MeSH
- duplikace genu MeSH
- genetická predispozice k nemoci MeSH
- genetické asociační studie MeSH
- genom lidský MeSH
- genomika metody MeSH
- genová přestavba * MeSH
- jednonukleotidový polymorfismus MeSH
- lidé MeSH
- mutace * MeSH
- myelinový proteolipidový protein genetika MeSH
- nestabilita genomu MeSH
- srovnávací genomová hybridizace MeSH
- variabilita počtu kopií segmentů DNA * MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Research Support, N.I.H., Extramural MeSH
Myelodysplastic syndromes (MDS) represent a clinically and genetically heterogeneous group of clonal haematopoietic diseases characterized by a short survival and high rate of transformation to acute myeloid leukaemia (AML). In spite of this variability, MDS is associated with typical recurrent non-random cytogenetic defects. Chromosomal abnormalities are detected in the malignant bone-marrow cells of approximately 40-80 % of patients with primary or secondary MDS. The most frequent chromosomal rearrangements involve chromosomes 5, 7 and 8. MDS often shows presence of unbalanced chromosomal changes, especially large deletions [del(5), del(7q), del(12p), del(18q), del(20q)] or losses of whole chromosomes (7 and Y). The most typical cytogenetic abnormality is a partial or complete deletion of 5q- that occurs in roughly 30 % of all MDS cases either as the sole abnormality or in combination with other aberrations as a part of frequently complex karyotypes. The mechanisms responsible for the formation of MDS-associated recurrent translocations and complex karyotypes are unknown. Since some of the mentioned aberrations are characteristic for several haematological malignancies, more general cellular conditions could be expected to play a role. In this article, we introduce the most common rearrangements linked to MDS and discuss the potential role of the non-random higher-order chromatin structure in their formation. A contribution of the chromothripsis - a catastrophic event discovered only recently - is considered to explain how complex karyotypes may occur (during a single event).
- MeSH
- chromatin metabolismus MeSH
- chromozomální aberace * MeSH
- genová přestavba * MeSH
- lidé MeSH
- myelodysplastické syndromy genetika MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- přehledy MeSH
- MeSH
- akutní lymfatická leukemie genetika klasifikace mortalita MeSH
- buněčné klony MeSH
- chromozomální aberace MeSH
- dítě MeSH
- DNA nádorová analýza MeSH
- finanční podpora výzkumu jako téma MeSH
- lidé MeSH
- mladiství MeSH
- prognóza MeSH
- průtoková cytometrie MeSH
- Check Tag
- dítě MeSH
- lidé MeSH
- mladiství MeSH
- Publikační typ
- srovnávací studie MeSH
We analyzed complex chromosomal aberrations in 37 adult patients with myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) using classical cytogenetic method, FISH with locus-specific probes, multicolor FISH (mFISH) and multicolor banding (mBAND). Unbalanced structural aberrations, leading to a gain or loss of chromosomal material, were frequently observed in bone marrow cells. In 30 patients (81.1%) loss or rearrangement of chromosome 5, 7 and/or 11 was found. The most frequent numerical change was trisomy 8 as expected (detected in six patients-16.2%) and the most frequent breakpoints 5q13, 5q33, 7q31, 10p12, 11q23, 12p13, 17p11 and 21q22 were determined.
- MeSH
- akutní erytroblastická leukemie genetika patologie MeSH
- buňky kostní dřeně fyziologie patologie MeSH
- chromozomální aberace MeSH
- dějiny 16. století MeSH
- dospělí MeSH
- financování organizované MeSH
- genová přestavba genetika MeSH
- hybridizace in situ fluorescenční MeSH
- karyotypizace MeSH
- lidé středního věku MeSH
- lidé MeSH
- lidské chromozomy genetika MeSH
- myelodysplastické syndromy genetika patologie MeSH
- senioři MeSH
- Check Tag
- dějiny 16. století MeSH
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- historické články MeSH
Inverted repeats (IRs) can facilitate structural variation as crucibles of genomic rearrangement. Complex duplication-inverted triplication-duplication (DUP-TRP/INV-DUP) rearrangements that contain breakpoint junctions within IRs have been recently associated with both MECP2 duplication syndrome (MIM#300260) and Pelizaeus-Merzbacher disease (PMD, MIM#312080). We investigated 17 unrelated PMD subjects with copy number gains at the PLP1 locus including triplication and quadruplication of specific genomic intervals-16/17 were found to have a DUP-TRP/INV-DUP rearrangement product. An IR distal to PLP1 facilitates DUP-TRP/INV-DUP formation as well as an inversion structural variation found frequently amongst normal individuals. We show that a homology-or homeology-driven replicative mechanism of DNA repair can apparently mediate template switches within stretches of microhomology. Moreover, we provide evidence that quadruplication and potentially higher order amplification of a genomic interval can occur in a manner consistent with rolling circle amplification as predicted by the microhomology-mediated break induced replication (MMBIR) model.
- MeSH
- body zlomu chromozomu MeSH
- chromozomální inverze MeSH
- duplikace genu * MeSH
- genová dávka MeSH
- lidé MeSH
- myelinový proteolipidový protein genetika MeSH
- Pelizaeusova-Merzbacherova nemoc genetika MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Research Support, N.I.H., Extramural MeSH
