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1.
Nat Commun ; 12(1): 5172, 2021 08 27.
Artigo em Inglês | MEDLINE | ID: mdl-34453055

RESUMO

Chromothripsis is detectable in 20-30% of newly diagnosed multiple myeloma (NDMM) patients and is emerging as a new independent adverse prognostic factor. In this study we interrogate 752 NDMM patients using whole genome sequencing (WGS) to investigate the relationship of copy number (CN) signatures to chromothripsis and show they are highly associated. CN signatures are highly predictive of the presence of chromothripsis (AUC = 0.90) and can be used identify its adverse prognostic impact. The ability of CN signatures to predict the presence of chromothripsis is confirmed in a validation series of WGS comprised of 235 hematological cancers (AUC = 0.97) and an independent series of 34 NDMM (AUC = 0.87). We show that CN signatures can also be derived from whole exome data (WES) and using 677 cases from the same series of NDMM, we are able to predict both the presence of chromothripsis (AUC = 0.82) and its adverse prognostic impact. CN signatures constitute a flexible tool to identify the presence of chromothripsis and is applicable to WES and WGS data.


Assuntos
Cromotripsia , Dosagem de Genes , Mieloma Múltiplo/genética , Humanos , Mieloma Múltiplo/diagnóstico , Mieloma Múltiplo/mortalidade , Prognóstico , Sequenciamento Completo do Exoma , Sequenciamento Completo do Genoma
3.
Cytogenet Genome Res ; 161(5): 236-242, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34274931

RESUMO

The use of new technologies in the routine diagnosis of constitutional abnormalities, such as high-resolution chromosomal microarray and next-generation sequencing, has unmasked new mechanisms for generating structural variation of the human genome. For example, complex chromosome rearrangements can originate by a chromosome catastrophe phenomenon in which numerous genomic rearrangements are apparently acquired in a single catastrophic event. This phenomenon is named chromoanagenesis (from the Greek "chromo" for chromosome and "anagenesis" for rebirth). Herein, we report 2 cases of genomic chaos detected at prenatal diagnosis. The terms "chromothripsis" and "chromoanasynthesis" and the challenge of genetic counseling are discussed.


Assuntos
Pontos de Quebra do Cromossomo , Cromotripsia , Rearranjo Gênico , Genoma Humano , Diagnóstico Pré-Natal/métodos , Aborto Eugênico , Adulto , Hibridização Genômica Comparativa , Variações do Número de Cópias de DNA , Feminino , Feto , Aconselhamento Genético/ética , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Cariotipagem/métodos , Masculino , Gravidez
4.
Cells ; 10(5)2021 05 04.
Artigo em Inglês | MEDLINE | ID: mdl-34064429

RESUMO

Chromothripsis has been defined as complex patterns of alternating genes copy number changes (normal, gain or loss) along the length of a chromosome or chromosome segment (International System for Human Cytogenomic Nomenclature 2020). The phenomenon of chromothripsis was discovered in 2011 and changed the concept of genome variability, mechanisms of oncogenic transformation, and hereditary diseases. This review describes the phenomenon of chromothripsis, its prevalence in genomes, the mechanisms underlying this phenomenon, and methods of its detection. Due to the fact that most often the phenomenon of chromothripsis occurs in cancer cells, in this review, we will separately discuss the issue of the contribution of chromothripsis to the process of oncogenesis.


Assuntos
Carcinogênese/genética , Cromotripsia , Animais , Humanos
6.
Nat Commun ; 12(1): 2093, 2021 04 07.
Artigo em Inglês | MEDLINE | ID: mdl-33828097

RESUMO

Telomere crisis contributes to cancer genome evolution, yet only a subset of cancers display breakage-fusion-bridge (BFB) cycles and chromothripsis, hallmarks of experimental telomere crisis identified in previous studies. We examine the spectrum of structural variants (SVs) instigated by natural telomere crisis. Eight spontaneous post-crisis clones did not show prominent patterns of BFB cycles or chromothripsis. Their crisis-induced genome rearrangements varied from infrequent simple SVs to more frequent and complex SVs. In contrast, BFB cycles and chromothripsis occurred in MRC5 fibroblast clones that escaped telomere crisis after CRISPR-controlled telomerase activation. This system revealed convergent evolutionary lineages altering one allele of chromosome 12p, where a short telomere likely predisposed to fusion. Remarkably, the 12p chromothripsis and BFB events were stabilized by independent fusions to chromosome 21. The data establish that telomere crisis can generate a wide spectrum of SVs implying that a lack of BFB patterns and chromothripsis in cancer genomes does not indicate absence of past telomere crisis.


Assuntos
Cromotripsia , Neoplasias/genética , Telômero/química , Linhagem Celular , Instabilidade Cromossômica , Fibroblastos , Genoma , Instabilidade Genômica , Humanos , Pulmão , Metáfase , Modelos Biológicos , Telômero/ultraestrutura
7.
Nat Genet ; 53(6): 895-905, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33846636

RESUMO

Genome editing has therapeutic potential for treating genetic diseases and cancer. However, the currently most practicable approaches rely on the generation of DNA double-strand breaks (DSBs), which can give rise to a poorly characterized spectrum of chromosome structural abnormalities. Here, using model cells and single-cell whole-genome sequencing, as well as by editing at a clinically relevant locus in clinically relevant cells, we show that CRISPR-Cas9 editing generates structural defects of the nucleus, micronuclei and chromosome bridges, which initiate a mutational process called chromothripsis. Chromothripsis is extensive chromosome rearrangement restricted to one or a few chromosomes that can cause human congenital disease and cancer. These results demonstrate that chromothripsis is a previously unappreciated on-target consequence of CRISPR-Cas9-generated DSBs. As genome editing is implemented in the clinic, the potential for extensive chromosomal rearrangements should be considered and monitored.


Assuntos
Sistemas CRISPR-Cas/genética , Cromotripsia , Edição de Genes , Anemia Falciforme/genética , Antígenos CD34/metabolismo , Proteína 9 Associada à CRISPR/metabolismo , Divisão Celular , Cromossomos Humanos/genética , Clivagem do DNA , Genoma Humano , Humanos , Micronúcleo Germinativo/genética , Proteína Supressora de Tumor p53/metabolismo
8.
Prog Biophys Mol Biol ; 165: 19-28, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-33930405

RESUMO

Detecting and treating cancer effectively involves understanding the disease as one of somatic cell and tumor macroevolution. That understanding is key to avoid triggering an adverse reaction to therapy that generates an untreatable and deadly tumor population. Macroevolution differs from microevolution by karyotype changes rather than isolated localized mutations being the major source of hereditary variation. Cancer cells display major multi-site chromosome rearrangements that appear to have arisen in many different cases abruptly in the history of tumor evolution. These genome restructuring events help explain the punctuated macroevolutionary changes that mark major transitions in cancer progression. At least two different nonrandom patterns of rapid multisite genome restructuring - chromothripsis ("chromosome shattering") and chromoplexy ("chromosome weaving") - are clearly distinct in their distribution within the genome and in the cell biology of the stress-induced processes responsible for their occurrence. These observations tell us that eukaryotic cells have the capacity to reorganize their genomes rapidly in response to calamity. Since chromothripsis and chromoplexy have been identified in the human germline and in other eukaryotes, they provide a model for organismal macroevolution in response to the kinds of stresses that lead to mass extinctions.


Assuntos
Cromotripsia , Neoplasias , Biologia , Genoma , Humanos , Mutação , Neoplasias/genética
9.
Mol Cell ; 81(5): 901-904, 2021 03 04.
Artigo em Inglês | MEDLINE | ID: mdl-33667381

RESUMO

Combining live-cell imaging, cytogenetics, genome sequencing, and in vitro evolution, Shoshani et al. (2020) revealed deep connections between chromothripsis, the catastrophic shattering of a chromosome in abnormal nuclear structures, and gene amplification, a frequent culprit of oncogenic activation.


Assuntos
Cromotripsia , Neoplasias , Cromossomos/genética , Análise Citogenética , Amplificação de Genes , Humanos , Neoplasias/genética
10.
Curr Opin Cell Biol ; 70: 91-99, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33610905

RESUMO

Micronuclei are small membrane-bounded compartments with a DNA content encapsulated by a nuclear envelope and spatially separated from the primary nucleus. Micronuclei have long been linked to chromosome instability, genome rearrangements, and mutagenesis. They are frequently found in cancers, during senescence, and after genotoxic stress. Compromised integrity of the micronuclear envelope delays or disrupts DNA replication, inhibits DNA repair, and exposes micronuclear DNA directly to cytoplasm. Micronuclei play a central role in tumorigenesis, with micronuclear DNA being a source of complex genome rearrangements (including chromothripsis) and promoting a cyclic GMP-AMP synthase (cGAS)-mediated cellular immune response that may contribute to cancer metastasis. Here, we discuss recent findings on how micronuclei are generated, what the consequences are, and what cellular mechanisms can be applied to protect against micronucleation.


Assuntos
Cromotripsia , Micronúcleos com Defeito Cromossômico , Dano ao DNA , Instabilidade Genômica , Humanos , Membrana Nuclear
11.
Int J Cancer ; 148(4): 812-824, 2021 02 15.
Artigo em Inglês | MEDLINE | ID: mdl-32949152

RESUMO

Micronuclei, small spatially-separated, nucleus-like structures, are a common feature of human cancer cells. There are considerable heterogeneities in the sources, structures and genetic activities of micronuclei. Accumulating evidence suggests that micronuclei and main nuclei represent separate entities with respect to DNA replication, DNA damage sensing and repairing capacity because micronuclei are not monitored by the same checkpoints nor covered by the same nuclear envelope as the main nuclei. Thus, micronuclei are spatially restricted "mutation factories." Several large-scale DNA sequencing and bioinformatics studies over the last few years have revealed that most micronuclei display a mutational signature of chromothripsis immediately after their generation and the underlying molecular mechanisms have been dissected extensively. Clonal expansion of the micronucleated cells is context-dependent and is associated with chromothripsis and several other mutational signatures including extrachromosomal circular DNA, kataegis and chromoanasynthesis. These results suggest what was once thought to be merely a passive indicator of chromosomal instability is now being recognized as a strong mutator phenotype that may drive intratumoral genetic heterogeneity. Herein, we revisit the actionable determinants that contribute to the bursts of mutagenesis in micronuclei and present the growing number of evidence which suggests that micronuclei have distinct short- and long-term mutational and functional effects to cancer genomes. We also pose challenges for studying the long-term effects of micronucleation in the upcoming years.


Assuntos
Núcleo Celular/genética , Dano ao DNA , Instabilidade Genômica/genética , Micronúcleos com Defeito Cromossômico , Mutação , Neoplasias/genética , Cromotripsia , Humanos , Mitose/genética , Neoplasias/patologia , Proteína Supressora de Tumor p53/genética
13.
Nature ; 591(7848): 137-141, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33361815

RESUMO

Focal chromosomal amplification contributes to the initiation of cancer by mediating overexpression of oncogenes1-3, and to the development of cancer therapy resistance by increasing the expression of genes whose action diminishes the efficacy of anti-cancer drugs. Here we used whole-genome sequencing of clonal cell isolates that developed chemotherapeutic resistance to show that chromothripsis is a major driver of circular extrachromosomal DNA (ecDNA) amplification (also known as double minutes) through mechanisms that depend on poly(ADP-ribose) polymerases (PARP) and the catalytic subunit of DNA-dependent protein kinase (DNA-PKcs). Longitudinal analyses revealed that a further increase in drug tolerance is achieved by structural evolution of ecDNAs through additional rounds of chromothripsis. In situ Hi-C sequencing showed that ecDNAs preferentially tether near chromosome ends, where they re-integrate when DNA damage is present. Intrachromosomal amplifications that formed initially under low-level drug selection underwent continuing breakage-fusion-bridge cycles, generating amplicons more than 100 megabases in length that became trapped within interphase bridges and then shattered, thereby producing micronuclei whose encapsulated ecDNAs are substrates for chromothripsis. We identified similar genome rearrangement profiles linked to localized gene amplification in human cancers with acquired drug resistance or oncogene amplifications. We propose that chromothripsis is a primary mechanism that accelerates genomic DNA rearrangement and amplification into ecDNA and enables rapid acquisition of tolerance to altered growth conditions.


Assuntos
Cromotripsia , Evolução Molecular , Amplificação de Genes/genética , Neoplasias/genética , Oncogenes/genética , Dano ao DNA , Reparo do DNA por Junção de Extremidades , DNA Circular/química , DNA Circular/metabolismo , DNA de Neoplasias/química , DNA de Neoplasias/metabolismo , Proteína Quinase Ativada por DNA , Resistencia a Medicamentos Antineoplásicos , Células HEK293 , Células HeLa , Humanos , Micronúcleos com Defeito Cromossômico , Neoplasias/tratamento farmacológico , Neoplasias/enzimologia , Neoplasias/patologia , Poli(ADP-Ribose) Polimerases/metabolismo , Seleção Genética , Sequenciamento Completo do Genoma
14.
Mutat Res Rev Mutat Res ; 786: 108335, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33339583

RESUMO

Auto-immune diseases (AUD) are characterized by an immune response to antigenic components of the host itself. The etiology of AUD is not well understood. The available evidence points to an interaction between genetic, epigenetic, environmental, infectious and life-style factors. AUD are more prevalent in women than in men; sex hormones play a crucial role in this sex bias. Micronuclei (MN) emerged as a new player in the induction of AUD, based on the capacity of DNA-sensors to detect self-DNA that leaks into the cytoplasm from disrupted MN and induce the cGAS-STING pathway triggering an innate auto-immune response and chronic inflammation. It was found that inflammation can induce MN and MN can induce inflammation, leading to a vicious inflammation-oxidative-DNA damage-MN-formation-chromothripsis cycle. MN originating from sex chromosome-loss may induce inflammation and AUD. We performed a systematic review of studies reporting MN in patients with systemic or organ-specific AUD. A meta-analysis was performed on lymphocyte MN in diabetes mellitus (10 studies, 457 patients/290 controls) and Behcet's disease (3 studies, 100 patients/70 controls) and for buccal MN in diabetes mellitus (11 studies, 507 patients/427 controls). A statistically significant increase in patients compared to controls was found in the meta-analyses providing an indication of an association between MN and AUD. A 36%-higher mean-MRi in buccal cells (3.8+/-0.7) was found compared to lymphocytes (2.8+/-0.7)(P = 0.01). The meta-MRi in lymphocytes and buccal cells (1.7 and 3.0 respectively) suggest that buccal cells may be more sensitive. To assess their relative sensitivity, studies with measurements from the same subjects would be desirable. It is important that future studies (i) investigate, in well-designed powered studies, the prospective association of MN-formation with AUD and (ii) explore the molecular mechanisms by which chromosome shattering in MN and the release of chromatin fragments from MN lead to the formation of auto-antibodies.


Assuntos
Doenças Autoimunes/genética , Cromotripsia , Inflamação/genética , Micronúcleos com Defeito Cromossômico , Doenças Autoimunes/complicações , Doenças Autoimunes/patologia , Feminino , Humanos , Inflamação/complicações , Inflamação/patologia , Linfócitos/patologia , Masculino , Testes para Micronúcleos
15.
Acta Neuropathol Commun ; 8(1): 203, 2020 11 23.
Artigo em Inglês | MEDLINE | ID: mdl-33228790

RESUMO

Recurrent RELA and YAP1 fusions are intimately associated with tumorigenesis in supratentorial ependymomas. Chromothripsis and focal copy number alterations involving 11q are hallmarks of these tumors. However, it is unknown whether the chromosomal alterations are a direct causal event resulting in fusion transcripts. In addition, the biological significance of the RELA fusion variants and YAP1 fusions is not yet fully characterized. In this study, we generated gene rearrangements on 11q with the CRISPR/Cas9 system and investigated the formation of oncogenic ependymoma fusion genes. Further, we examined the oncogenic potential of RELA fusion variants and YAP1 fusions in a lentiviral gene transfer model. We observed that endogenous RELA fusion events were successfully induced by CRISPR/Cas9-mediated genome rearrangement in cultured cells. In vivo genome editing in mouse brain resulted in the development of ependymoma-like brain tumors that harbored the Rela fusion gene. All RELA fusion variants tested, except a variant lacking the Rel homology domain, were able to induce tumor formation, albeit with different efficacy. Furthermore, expression of YAP1-FAM118B and YAP1-MAMLD1 fusions induced the formation of spindle-cell-like tumors at varying efficacy. Our results indicate that chromosomal rearrangements involving the Rela locus are the causal event for the formation of Rela fusion-driven ependymomas in mice. Furthermore, the type of RELA. fusion might affect the aggressiveness of tumors and that the Rel homology domain is essential for the oncogenic functions of RELA. fusions. The YAP1 fusion genes are also oncogenic when expressed in mice.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Neoplasias Encefálicas/genética , Carcinogênese/genética , Proteínas de Ligação a DNA/genética , Ependimoma/genética , Fusão Oncogênica/genética , Fator de Transcrição RelA/genética , Fatores de Transcrição/genética , Animais , Sistemas CRISPR-Cas , Células Cultivadas , Cromotripsia , Variações do Número de Cópias de DNA , Edição de Genes , Técnicas de Transferência de Genes , Camundongos , Fenótipo
16.
Epigenetics Chromatin ; 13(1): 49, 2020 11 10.
Artigo em Inglês | MEDLINE | ID: mdl-33168103

RESUMO

With the rapid development of next-generation sequencing technology, chromosome structural variation has gradually gained increased clinical significance in tumorigenesis. However, the molecular mechanism(s) underlying this structural variation remain poorly understood. A search of the literature shows that a three-dimensional chromatin state plays a vital role in inducing structural variation and in the gene expression profiles in tumorigenesis. Structural variants may result in changes in copy number or deletions of coding sequences, as well as the perturbation of structural chromatin features, especially topological domains, and disruption of interactions between genes and their regulatory elements. This review focuses recent work aiming at elucidating how structural variations develop and misregulate oncogenes and tumor suppressors, to provide general insights into tumor formation mechanisms and to provide potential targets for future anticancer therapies.


Assuntos
Carcinogênese/genética , Instabilidade Cromossômica , Animais , Cromotripsia , Reparo do DNA , Humanos
17.
Exp Mol Med ; 52(11): 1777-1786, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-33230251

RESUMO

Micronuclei are small DNA-containing nuclear structures that are spatially isolated from the main nucleus. They are frequently found in pathologies, including cancer. It was recently shown that these nuclear structures are not only biomarkers of disease but also play an active role in tumor biology. Many consequences of micronucleus formation on tumor biology are dependent on the frequent and irreversible rupture of their nuclear envelopes, which results in the exposure of their DNA contents to the cytoplasm. In this review, we discuss models of defective nuclear envelope deposition on missegregated chromosomes that lead to nuclear envelope rupture. Furthermore, we expound upon the various downstream consequences of micronucleus nuclear envelope rupture on cells. These consequences include a massive DNA rearrangement phenomenon called chromothripsis and activation of the cGAS-STING innate immune signaling pathway, which can be a double-edged sword with tumorigenesis and tumor prevention functions. Although micronuclei are small structures, the impact they have on cells and their microenvironment is quite large.


Assuntos
Núcleo Celular , Micronúcleos com Defeito Cromossômico , Membrana Nuclear/metabolismo , Animais , Núcleo Celular/genética , Núcleo Celular/metabolismo , Cromotripsia , Citoplasma/metabolismo , Dano ao DNA , Instabilidade Genômica , Humanos , Imunidade Inata , Mitose , Transdução de Sinais
18.
Nature ; 586(7828): 292-298, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32999459

RESUMO

The RecQ DNA helicase WRN is a synthetic lethal target for cancer cells with microsatellite instability (MSI), a form of genetic hypermutability that arises from impaired mismatch repair1-4. Depletion of WRN induces widespread DNA double-strand breaks in MSI cells, leading to cell cycle arrest and/or apoptosis. However, the mechanism by which WRN protects MSI-associated cancers from double-strand breaks remains unclear. Here we show that TA-dinucleotide repeats are highly unstable in MSI cells and undergo large-scale expansions, distinct from previously described insertion or deletion mutations of a few nucleotides5. Expanded TA repeats form non-B DNA secondary structures that stall replication forks, activate the ATR checkpoint kinase, and require unwinding by the WRN helicase. In the absence of WRN, the expanded TA-dinucleotide repeats are susceptible to cleavage by the MUS81 nuclease, leading to massive chromosome shattering. These findings identify a distinct biomarker that underlies the synthetic lethal dependence on WRN, and support the development of therapeutic agents that target WRN for MSI-associated cancers.


Assuntos
Quebras de DNA de Cadeia Dupla , Expansão das Repetições de DNA/genética , Repetições de Dinucleotídeos/genética , Neoplasias/genética , Helicase da Síndrome de Werner/metabolismo , Proteínas Mutadas de Ataxia Telangiectasia/metabolismo , Linhagem Celular Tumoral , Cromossomos Humanos/genética , Cromossomos Humanos/metabolismo , Cromotripsia , Clivagem do DNA , Replicação do DNA , Proteínas de Ligação a DNA/metabolismo , Endodesoxirribonucleases/metabolismo , Endonucleases/metabolismo , Instabilidade Genômica , Humanos , Recombinases/metabolismo
19.
Cell ; 183(1): 197-210.e32, 2020 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-33007263

RESUMO

Cancer genomes often harbor hundreds of somatic DNA rearrangement junctions, many of which cannot be easily classified into simple (e.g., deletion) or complex (e.g., chromothripsis) structural variant classes. Applying a novel genome graph computational paradigm to analyze the topology of junction copy number (JCN) across 2,778 tumor whole-genome sequences, we uncovered three novel complex rearrangement phenomena: pyrgo, rigma, and tyfonas. Pyrgo are "towers" of low-JCN duplications associated with early-replicating regions, superenhancers, and breast or ovarian cancers. Rigma comprise "chasms" of low-JCN deletions enriched in late-replicating fragile sites and gastrointestinal carcinomas. Tyfonas are "typhoons" of high-JCN junctions and fold-back inversions associated with expressed protein-coding fusions, breakend hypermutation, and acral, but not cutaneous, melanomas. Clustering of tumors according to genome graph-derived features identified subgroups associated with DNA repair defects and poor prognosis.


Assuntos
Variação Estrutural do Genoma/genética , Genômica/métodos , Neoplasias/genética , Inversão Cromossômica/genética , Cromotripsia , Variações do Número de Cópias de DNA/genética , Rearranjo Gênico/genética , Genoma Humano/genética , Humanos , Mutação/genética , Sequenciamento Completo do Genoma/métodos
20.
Cancer Res ; 80(22): 4918-4931, 2020 11 15.
Artigo em Inglês | MEDLINE | ID: mdl-32973084

RESUMO

Chromothripsis is a form of genome instability by which a presumably single catastrophic event generates extensive genomic rearrangements of one or a few chromosomes. Widely assumed to be an early event in tumor development, this phenomenon plays a prominent role in tumor onset. In this study, an analysis of chromothripsis in 252 human breast cancers from two patient cohorts (149 metastatic breast cancers, 63 untreated primary tumors, 29 local relapses, and 11 longitudinal pairs) using whole-genome and whole-exome sequencing reveals that chromothripsis affects a substantial proportion of human breast cancers, with a prevalence over 60% in a cohort of metastatic cases and 25% in a cohort comprising predominantly luminal breast cancers. In the vast majority of cases, multiple chromosomes per tumor were affected, with most chromothriptic events on chromosomes 11 and 17 including, among other significantly altered drivers, CCND1, ERBB2, CDK12, and BRCA1. Importantly, chromothripsis generated recurrent fusions that drove tumor development. Chromothripsis-related rearrangements were linked with univocal mutational signatures, with clusters of point mutations due to kataegis in close proximity to the genomic breakpoints and with the activation of specific signaling pathways. Analyzing the temporal order of events in tumors with and without chromothripsis as well as longitudinal analysis of chromothriptic patterns in tumor pairs offered important insights into the role of chromothriptic chromosomes in tumor evolution. SIGNIFICANCE: These findings identify chromothripsis as a major driving event in human breast cancer.


Assuntos
Neoplasias da Mama/genética , Cromotripsia , Rearranjo Gênico , Recidiva Local de Neoplasia/genética , Algoritmos , Cromossomos Humanos Par 11 , Cromossomos Humanos Par 17 , Ciclina D1/genética , Quinases Ciclina-Dependentes/genética , Reparo do DNA , Feminino , Fusão Gênica , Genes BRCA1 , Genes BRCA2 , Genes erbB-2 , Genes p53 , Humanos , Mutação INDEL , Transdução de Sinais , Sequenciamento Completo do Exoma , Sequenciamento Completo do Genoma
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