Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 79
Filtrar
Mais filtros










Base de dados
Intervalo de ano de publicação
1.
Mol Cell ; 81(16): 3356-3367.e6, 2021 08 19.
Artigo em Inglês | MEDLINE | ID: mdl-34297910

RESUMO

RNA polymerase II (RNAP II) pausing is essential to precisely control gene expression and is critical for development of metazoans. Here, we show that the m6A RNA modification regulates promoter-proximal RNAP II pausing in Drosophila cells. The m6A methyltransferase complex (MTC) and the nuclear reader Ythdc1 are recruited to gene promoters. Depleting the m6A MTC leads to a decrease in RNAP II pause release and in Ser2P occupancy on the gene body and affects nascent RNA transcription. Tethering Mettl3 to a heterologous gene promoter is sufficient to increase RNAP II pause release, an effect that relies on its m6A catalytic domain. Collectively, our data reveal an important link between RNAP II pausing and the m6A RNA modification, thus adding another layer to m6A-mediated gene regulation.


Assuntos
Proteínas de Drosophila/genética , Complexos Multiproteicos/genética , Proteínas Nucleares/genética , RNA Polimerase II/genética , Transcrição Genética , Animais , Drosophila melanogaster/genética , Metiltransferases/genética , Regiões Promotoras Genéticas/genética
2.
Acta Neuropathol ; 142(2): 361-374, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34003336

RESUMO

Loss of nuclear SMARCB1 (INI1/hSNF5/BAF47) protein expression due to biallelic mutations of the SMARCB1 tumor suppressor gene is a hallmark of atypical teratoid/rhabdoid tumors (ATRT), but the presence of cytoplasmic SMARCB1 protein in these tumors has not yet been described. In a series of 102 primary ATRT, distinct cytoplasmic SMARCB1 staining on immunohistochemistry was encountered in 19 cases (19%) and was highly over-represented in cases showing pathogenic sequence variants leading to truncation or mutation of the C-terminal part of SMARCB1 (15/19 vs. 4/83; Chi-square: 56.04, p = 1.0E-10) and, related to this, in tumors of the molecular subgroup ATRT-TYR (16/36 vs. 3/66; Chi-square: 24.47, p = 7.6E-7). Previous reports have indicated that while SMARCB1 lacks a bona fide nuclear localization signal, it harbors a masked nuclear export signal (NES) and that truncation of the C-terminal region results in unmasking of this NES leading to cytoplasmic localization. To determine if cytoplasmic localization found in ATRT is due to unmasking of NES, we generated GFP fusions of one of the SMARCB1 truncating mutations (p.Q318X) found in the tumors along with a p.L266A mutation, which was shown to disrupt the interaction of SMARCB1-NES with exportin-1. We found that while the GFP-SMARCB1(Q318X) mutant localized to the cytoplasm, the double mutant GFP-SMARCB1(Q318X;L266A) localized to the nucleus, confirming NES requirement for cytoplasmic localization. Furthermore, cytoplasmic SMARCB1(Q318X) was unable to cause senescence as determined by morphological observations and by senescence-associated ß-galactosidase assay, while nuclear SMARCB1(Q318X;L266A) mutant regained this function. Selinexor, a selective exportin-1 inhibitor, was effective in inhibiting the nuclear export of SMARCB1(Q318X) and caused rapid cell death in rhabdoid tumor cells. In conclusion, inhibition of nuclear export restores nuclear localization and residual tumor suppressor function of truncated SMARCB1. Therapies aimed at preventing nuclear export of mutant SMARCB1 protein may represent a promising targeted therapy in ATRT harboring truncating C-terminal SMARCB1 mutations.

3.
BMJ Case Rep ; 14(4)2021 Apr 13.
Artigo em Inglês | MEDLINE | ID: mdl-33849881

RESUMO

A 39-year-old woman was referred to the cancer genetics outpatient clinic for a clinical diagnosis of Carney complex (CNC) in her deceased brother. The patient had some characteristic clinical features such as periorbital lentigines and coarse facial features, suggestive of CNC; however, she did not meet major diagnostic criteria for CNC. Previous extensive investigations revealed a mild insulin-like growth factor 1 elevation, a stable left adrenal gland adenoma and a slightly enlarged pituitary gland. Single gene sequencing confirmed a novel pathogenic mutation in the PRKAR1A gene. This case, to our knowledge, is the first report of this mutation identified in a family of French-Canadian origin. This report broadens our understanding of the genotypic and phenotypic spectrum of this rare disease, while it highlights the value of a multidisciplinary approach in rare diseases, for genetic testing facilitated a timely diagnosis and enabled the initiation of early surveillance of CNC-related manifestations in our patient.


Assuntos
Complexo de Carney , Adulto , Canadá , Complexo de Carney/diagnóstico , Complexo de Carney/genética , Subunidade RIalfa da Proteína Quinase Dependente de AMP Cíclico/genética , Feminino , Testes Genéticos , Humanos , Masculino , Mutação
4.
Acta Neuropathol ; 141(6): 929-944, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33644822

RESUMO

Pituitary blastoma (PitB) has recently been identified as a rare and potentially lethal pediatric intracranial tumor. All cases that have been studied molecularly possess at least one DICER1 pathogenic variant. Here, we characterized nine pituitary samples, including three fresh frozen PitBs, three normal fetal pituitary glands and three normal postnatal pituitary glands using small-RNA-Seq, RNA-Seq, methylation profiling, whole genome sequencing and Nanostring® miRNA analyses; an extended series of 21 pituitary samples was used for validation purposes. These analyses demonstrated that DICER1 RNase IIIb hotspot mutations in PitBs induced improper processing of miRNA precursors, resulting in aberrant 5p-derived miRNA products and a skewed distribution of miRNAs favoring mature 3p over 5p miRNAs. This led to dysregulation of hundreds of 5p and 3p miRNAs and concomitant dysregulation of numerous mRNA targets. Gene expression analysis revealed PRAME as the most significantly upregulated gene (500-fold increase). PRAME is a member of the Retinoic Acid Receptor (RAR) signaling pathway and in PitBs, the RAR, WNT and NOTCH pathways are dysregulated. Cancer Hallmarks analysis showed that PI3K pathway is activated in the tumors. Whole genome sequencing demonstrated a quiet genome with very few somatic alterations. The comparison of methylation profiles to publicly available data from ~ 3000 other central nervous system tumors revealed that PitBs have a distinct methylation profile compared to all other tumors, including pituitary adenomas. In conclusion, this comprehensive characterization of DICER1-related PitB revealed key molecular underpinnings of PitB and identified pathways that could potentially be exploited in the treatment of this tumor.

5.
Genome Biol ; 22(1): 75, 2021 03 05.
Artigo em Inglês | MEDLINE | ID: mdl-33673854

RESUMO

Controlling quality of next-generation sequencing (NGS) data files is a necessary but complex task. To address this problem, we statistically characterize common NGS quality features and develop a novel quality control procedure involving tree-based and deep learning classification algorithms. Predictive models, validated on internal and external functional genomics datasets, are to some extent generalizable to data from unseen species. The derived statistical guidelines and predictive models represent a valuable resource for users of NGS data to better understand quality issues and perform automatic quality control. Our guidelines and software are available at https://github.com/salbrec/seqQscorer .

6.
Front Hum Neurosci ; 15: 646426, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33746727

RESUMO

Successful surgical treatment of patients with focal drug-resistant epilepsy remains challenging, especially in cases for which it is difficult to define the area of cortex from which seizures originate, the seizure onset zone (SOZ). Various diagnostic methods are needed to select surgical candidates and determine the extent of resection. Interictal magnetoencephalography (MEG) with source imaging has proven to be useful for presurgical evaluation, but the use of ictal MEG data remains limited. The purpose of the present study was to determine whether pre-ictal variations of spectral properties of neural activity from ictal MEG recordings are predictive of SOZ location.We performed a 4 h overnight MEG recording in an 8-year-old child with drug-resistant focal epilepsy of suspected right fronto-temporal origin and captured one ~45-s seizure. The patient underwent a right temporal resection from the anterior temporal neocortex and amygdala to the mid-posterior temporal neocortex, sparing the hippocampus proper. She remains seizure-free 21 months postoperatively. The histopathological assessment confirmed frank focal cortical dysplasia (FCD) type IIa in the MEG-defined SOZ, which was based on source imaging of averaged ictal spikes at seizure onset. We investigated temporal changes (inter-ictal, pre-ictal, and ictal periods) together with spatial differences (SOZ vs. control regions) in spectral parameters of background brain activity, namely the aperiodic broadband offset and slope, and assessed how they confounded the interpretation of apparent variations of signal power in typical electrophysiological bands. Our data show that the SOZ was associated with a higher aperiodic offset and exponent during the seizure compared to control regions. Both parameters increased in all regions from 2 min before the seizure onwards. Regions anatomically closer to the SOZ also expressed higher values compared to contralateral regions, potentially indicating ictal spread. We also show that narrow-band power changes were caused by these fluctuations in the aperiodic component of ongoing brain activity. Our results indicate that the broadband aperiodic component of ongoing brain activity cannot be reduced to background noise of no physiological interest, and rather may be indicative of the neuropathophysiology of the SOZ. We believe these findings will inspire future studies of ictal MEG cases and confirm their significance.

7.
Cell ; 183(6): 1617-1633.e22, 2020 12 10.
Artigo em Inglês | MEDLINE | ID: mdl-33259802

RESUMO

Histone H3.3 glycine 34 to arginine/valine (G34R/V) mutations drive deadly gliomas and show exquisite regional and temporal specificity, suggesting a developmental context permissive to their effects. Here we show that 50% of G34R/V tumors (n = 95) bear activating PDGFRA mutations that display strong selection pressure at recurrence. Although considered gliomas, G34R/V tumors actually arise in GSX2/DLX-expressing interneuron progenitors, where G34R/V mutations impair neuronal differentiation. The lineage of origin may facilitate PDGFRA co-option through a chromatin loop connecting PDGFRA to GSX2 regulatory elements, promoting PDGFRA overexpression and mutation. At the single-cell level, G34R/V tumors harbor dual neuronal/astroglial identity and lack oligodendroglial programs, actively repressed by GSX2/DLX-mediated cell fate specification. G34R/V may become dispensable for tumor maintenance, whereas mutant-PDGFRA is potently oncogenic. Collectively, our results open novel research avenues in deadly tumors. G34R/V gliomas are neuronal malignancies where interneuron progenitors are stalled in differentiation by G34R/V mutations and malignant gliogenesis is promoted by co-option of a potentially targetable pathway, PDGFRA signaling.


Assuntos
Neoplasias Encefálicas/genética , Carcinogênese/genética , Glioma/genética , Histonas/genética , Interneurônios/metabolismo , Mutação/genética , Células-Tronco Neurais/metabolismo , Receptor alfa de Fator de Crescimento Derivado de Plaquetas/genética , Animais , Astrócitos/metabolismo , Astrócitos/patologia , Neoplasias Encefálicas/patologia , Carcinogênese/patologia , Linhagem da Célula , Reprogramação Celular/genética , Cromatina/metabolismo , Embrião de Mamíferos/metabolismo , Epigênese Genética , Regulação Neoplásica da Expressão Gênica , Inativação Gênica , Glioma/patologia , Histonas/metabolismo , Lisina/metabolismo , Camundongos Endogâmicos C57BL , Modelos Biológicos , Gradação de Tumores , Oligodendroglia/metabolismo , Regiões Promotoras Genéticas/genética , Prosencéfalo/embriologia , Receptor alfa de Fator de Crescimento Derivado de Plaquetas/metabolismo , Transcrição Genética , Transcriptoma/genética
8.
BMJ Case Rep ; 13(12)2020 Dec 22.
Artigo em Inglês | MEDLINE | ID: mdl-33370980

RESUMO

We illustrate a case of post-traumatic recurrent transient prosopagnosia in a paediatric patient with a right posterior inferior temporal gyrus haemorrhage seen on imaging and interictal electroencephalogram abnormalities in the right posterior quadrant. Face recognition area mapping with magnetoencephalography (MEG) and functional MRI (fMRI) was performed to clarify the relationship between the lesion and his prosopagnosia, which showed activation of the right fusiform gyrus that colocalised with the lesion. Lesions adjacent to the right fusiform gyrus can result in seizures presenting as transient prosopagnosia. MEG and fMRI can help to attribute this unique semiology to the lesion.


Assuntos
Hemorragia Cerebral/diagnóstico , Procedimentos Neurocirúrgicos , Prosopagnosia/etiologia , Convulsões/diagnóstico , Lobo Temporal/diagnóstico por imagem , Mapeamento Encefálico , Hemorragia Cerebral/complicações , Hemorragia Cerebral/cirurgia , Criança , Eletroencefalografia , Reconhecimento Facial/fisiologia , Humanos , Imageamento por Ressonância Magnética , Masculino , Prosopagnosia/diagnóstico , Prosopagnosia/fisiopatologia , Prosopagnosia/cirurgia , Convulsões/etiologia , Convulsões/fisiopatologia , Convulsões/cirurgia , Lobo Temporal/fisiopatologia , Resultado do Tratamento
9.
J Neurosurg Pediatr ; : 1-10, 2020 Dec 25.
Artigo em Inglês | MEDLINE | ID: mdl-33361483

RESUMO

OBJECTIVE: The authors sought to assess the utility of arterial spin labeling (ASL) perfusion 3T-MRI for the presurgical evaluation of poorly defined focal epilepsy in pediatric patients. METHODS: Pseudocontinuous ASL perfusion 3T-MRI was performed in 25 consecutive children with poorly defined focal epilepsy. ASL perfusion abnormalities were detected qualitatively by visual inspection and quantitatively by calculating asymmetry index (AI) maps and significant z-score cluster maps based on successfully operated cases. ASL results were prospectively compared to scalp EEG, structural 3T-MRI, FDG-PET, ictal/interictal SPECT, magnetoencephalography (MEG), and intracranial recording results, as well as the final surgically proven epileptogenic zone (EZ) in operated patients who had at least 1 year of good (Engel class I/II) seizure outcome and positive histopathology results. RESULTS: Qualitative ASL perfusion abnormalities were found in 17/25 cases (68%), specifically in 17/20 MRI-positive cases (85.0%) and in none of the 5 MRI-negative cases. ASL was concordant with localizing scalp EEG findings in 66.7%, structural 3T-MRI in 90%, FDG-PET in 75%, ictal/interictal SPECT in 62.5%, and MEG in 75% of cases, and with intracranial recording results in 40% of cases. Eleven patients underwent surgery; in all 11 cases the EZ was surgically proven by positive histopathology results and the patient having at least 1 year of good seizure outcome. ASL results were concordant with this final surgically proven EZ in 10/11 cases (sensitivity 91%, specificity 50%). All 10 ASL-positive patients who underwent surgery had positive surgical pathology results and good long-term postsurgical seizure outcome at a mean follow-up of 39 months. Retrospective quantitative analysis based on significant z-score clusters found 1 true-positive result that was missed by qualitative analysis and 3 additional false-positive results (sensitivity 100%, specificity 23%). CONCLUSIONS: ASL supports the hypothesis regarding the EZ in poorly defined focal epilepsy cases in children. Due to its convenience and noninvasive nature, the authors recommend that ASL be added routinely to the presurgical MRI evaluation of epilepsy. Future optimized quantitative methods may improve the diagnostic yield of this technique.

10.
J Neurosurg Pediatr ; : 1-5, 2020 Oct 30.
Artigo em Inglês | MEDLINE | ID: mdl-33126205

RESUMO

Here, the authors present 2 cases of nongerminomatous germ cell tumor (NGGCT): a neonate with a mixed malignant germ cell tumor, 5% yolk sac tumor (YST) and 95% immature teratoma components, originating from the right mesial temporal lobe; and a 2-month-old infant with a pure YST originating from the left middle cranial fossa. These tumors with yolk sac components, which are thought to have a poor prognosis, were successfully treated with complete tumor resection alone and subtotal tumor resection with chemotherapy, respectively. Event-free survival exceeds 5 years for each patient even though neither received radiotherapy. The authors highlight the role of radical surgery and the successful treatment of neonatal YST with aggressive resection (and chemotherapy in 1 case) while avoiding radiation therapy. They also report the very rare non-midline location of these neonatal NGGCTs and emphasize the importance of considering YSTs and mixed NGGCTs with YST components in the differential diagnosis of non-midline hemispheric or skull base tumors in newborns.

11.
Nucleic Acids Res ; 48(9): e53, 2020 05 21.
Artigo em Inglês | MEDLINE | ID: mdl-32187374

RESUMO

Chromatin immunoprecipitation followed by sequencing (ChIP-seq) is used to identify genome-wide DNA regions bound by proteins. Given one ChIP-seq experiment with replicates, binding sites not observed in all the replicates will usually be interpreted as noise and discarded. However, the recent discovery of high-occupancy target (HOT) regions suggests that there are regions where binding of multiple transcription factors can be identified. To investigate ChIP-seq variability, we developed a reproducibility score and a method that identifies cell-specific variable regions in ChIP-seq data by integrating replicated ChIP-seq experiments for multiple protein targets on a particular cell type. Using our method, we found variable regions in human cell lines K562, GM12878, HepG2, MCF-7 and in mouse embryonic stem cells (mESCs). These variable-occupancy target regions (VOTs) are CG dinucleotide rich, and show enrichment at promoters and R-loops. They overlap significantly with HOT regions, but are not blacklisted regions producing non-specific binding ChIP-seq peaks. Furthermore, in mESCs, VOTs are conserved among placental species suggesting that they could have a function important for this taxon. Our method can be useful to point to such regions along the genome in a given cell type of interest, to improve the downstream interpretative analysis before follow-up experiments.


Assuntos
Sequenciamento de Cromatina por Imunoprecipitação , Fatores de Transcrição/metabolismo , Animais , Sítios de Ligação , Linhagem Celular , Linhagem Celular Tumoral , Cromatina/metabolismo , Células-Tronco Embrionárias/metabolismo , Evolução Molecular , Variação Genética , Genômica/métodos , Humanos , Células K562 , Células MCF-7 , Camundongos , Nucleotídeos/análise , Análise de Componente Principal , Regiões Promotoras Genéticas , Estruturas R-Loop
12.
J Clin Invest ; 130(3): 1479-1490, 2020 03 02.
Artigo em Inglês | MEDLINE | ID: mdl-31805011

RESUMO

BACKGROUNDDICER1 is the only miRNA biogenesis component associated with an inherited tumor syndrome, featuring multinodular goiter (MNG) and rare pediatric-onset lesions. Other susceptibility genes for familial forms of MNG likely exist.METHODSWhole-exome sequencing of a kindred with early-onset MNG and schwannomatosis was followed by investigation of germline pathogenic variants that fully segregated with the disease. Genome-wide analyses were performed on 13 tissue samples from familial and nonfamilial DGCR8-E518K-positive tumors, including MNG, schwannomas, papillary thyroid cancers (PTCs), and Wilms tumors. miRNA profiles of 4 tissue types were compared, and sequencing of miRNA, pre-miRNA, and mRNA was performed in a subset of 9 schwannomas, 4 of which harbor DGCR8-E518K.RESULTSWe identified c.1552G>A;p.E518K in DGCR8, a microprocessor component located in 22q, in the kindred. The variant identified is a somatic hotspot in Wilms tumors and has been identified in 2 PTCs. Copy number loss of chromosome 22q, leading to loss of heterozygosity at the DGCR8 locus, was found in all 13 samples harboring c.1552G>A;p.E518K. miRNA profiling of PTCs, MNG, schwannomas, and Wilms tumors revealed a common profile among E518K hemizygous tumors. In vitro cleavage demonstrated improper processing of pre-miRNA by DGCR8-E518K. MicroRNA and RNA profiling show that this variant disrupts precursor microRNA production, impacting populations of canonical microRNAs and mirtrons.CONCLUSIONWe identified DGCR8 as the cause of an unreported autosomal dominant mendelian tumor susceptibility syndrome: familial multinodular goiter with schwannomatosis.FUNDINGCanadian Institutes of Health Research, Compute Canada, Alex's Lemonade Stand Foundation, the Mia Neri Foundation for Childhood Cancer, Cassa di Sovvenzioni e Risparmio fra il Personale della Banca d'Italia, and the KinderKrebsInitiative Buchholz/Holm-Seppensen.


Assuntos
Predisposição Genética para Doença , Bócio Nodular/genética , Mutação de Sentido Incorreto , Proteínas de Neoplasias/genética , Neurilemoma/genética , Neurofibromatoses/genética , Proteínas de Ligação a RNA/genética , Neoplasias Cutâneas/genética , Substituição de Aminoácidos , Criança , Cromossomos Humanos Par 22/genética , Feminino , Dosagem de Genes , Estudo de Associação Genômica Ampla , Bócio Nodular/patologia , Células HEK293 , Humanos , Masculino , Neurilemoma/patologia , Neurofibromatoses/patologia , Neoplasias Cutâneas/patologia , Sequenciamento Completo do Exoma
13.
Bio Protoc ; 10(4): e3520, 2020 Feb 20.
Artigo em Inglês | MEDLINE | ID: mdl-33654745

RESUMO

Chromatin immunoprecipitation is extensively used to investigate the epigenetic profile and transcription factor binding sites in the genome. However, when the starting material is limited, the conventional ChIP-Seq approach cannot be implemented. This protocol describes a method that can be used to generate the chromatin profiles from as low as 100 human or 1,000 Drosophila cells. The method employs tagmentation to fragment the chromatin with concomitant addition of sequencing adaptors. The method generates datasets with high signal to noise ratio and can be subjected to standard tools for ChIP-Seq analysis.

14.
Nat Genet ; 51(12): 1702-1713, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31768071

RESUMO

Childhood brain tumors have suspected prenatal origins. To identify vulnerable developmental states, we generated a single-cell transcriptome atlas of >65,000 cells from embryonal pons and forebrain, two major tumor locations. We derived signatures for 191 distinct cell populations and defined the regional cellular diversity and differentiation dynamics. Projection of bulk tumor transcriptomes onto this dataset shows that WNT medulloblastomas match the rhombic lip-derived mossy fiber neuronal lineage and embryonal tumors with multilayered rosettes fully recapitulate a neuronal lineage, while group 2a/b atypical teratoid/rhabdoid tumors may originate outside the neuroectoderm. Importantly, single-cell tumor profiles reveal highly defined cell hierarchies that mirror transcriptional programs of the corresponding normal lineages. Our findings identify impaired differentiation of specific neural progenitors as a common mechanism underlying these pediatric cancers and provide a rational framework for future modeling and therapeutic interventions.


Assuntos
Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patologia , Encéfalo/embriologia , Regulação da Expressão Gênica no Desenvolvimento , Animais , Encéfalo/patologia , Linhagem Celular Tumoral , Humanos , Lactente , Meduloblastoma/genética , Meduloblastoma/patologia , Camundongos , Neoplasias Embrionárias de Células Germinativas/genética , Neoplasias Embrionárias de Células Germinativas/patologia , Fibras Nervosas/patologia , Fibras Nervosas/fisiologia , Prosencéfalo/citologia , Prosencéfalo/embriologia , Tumor Rabdoide/genética , Tumor Rabdoide/patologia , Análise de Célula Única
15.
Life Sci Alliance ; 2(4)2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31331983

RESUMO

Chromatin immunoprecipitation (ChIP) followed by next generation sequencing (ChIP-Seq) is a powerful technique to study transcriptional regulation. However, the requirement of millions of cells to generate results with high signal-to-noise ratio precludes it in the study of small cell populations. Here, we present a tagmentation-assisted fragmentation ChIP (TAF-ChIP) and sequencing method to generate high-quality histone profiles from low cell numbers. The data obtained from the TAF-ChIP approach are amenable to standard tools for ChIP-Seq analysis, owing to its high signal-to-noise ratio. The epigenetic profiles from TAF-ChIP approach showed high agreement with conventional ChIP-Seq datasets, thereby underlining the utility of this approach.


Assuntos
Sequenciamento de Cromatina por Imunoprecipitação/métodos , Drosophila/genética , Histonas/metabolismo , Animais , Epigênese Genética , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Células K562 , Razão Sinal-Ruído , Software , Sequenciamento Completo do Genoma
16.
Fam Cancer ; 18(2): 161-163, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30284660

RESUMO

One of a pair of monozygous twins was diagnosed and died of small cell carcinoma of the ovary of hypercalcemic type (SCCOHT) at the age of 30 years. Her sister remained unaffected and was very concerned about her risk for developing SCCOHT. By performing comprehensive molecular analysis using whole exome sequencing (WES) approach, we showed that the deceased twin's tumour has bi-allelic somatic genetic defects (a pathogenic frameshift deletion in SMARCA4 and LOH on chr19p). Results of WES of constitutional DNA from her unaffected sister were confirmatory. Based on our findings, we concluded that the living twin is not at risk for SCCOHT and does not need to consider preventive oophorectomy.


Assuntos
Carcinoma de Células Pequenas/diagnóstico , Doenças em Gêmeos/diagnóstico , Hipercalcemia/diagnóstico , Neoplasias Ovarianas/diagnóstico , Adulto , Carcinoma de Células Pequenas/genética , Carcinoma de Células Pequenas/patologia , DNA Helicases/genética , Análise Mutacional de DNA , Doenças em Gêmeos/genética , Doenças em Gêmeos/patologia , Evolução Fatal , Feminino , Humanos , Hipercalcemia/genética , Hipercalcemia/patologia , Proteínas Nucleares/genética , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/patologia , Ovário/patologia , Fatores de Transcrição/genética , Gêmeos Monozigóticos , Sequenciamento Completo do Exoma
19.
Cancer Cell ; 32(5): 684-700.e9, 2017 11 13.
Artigo em Inglês | MEDLINE | ID: mdl-29107533

RESUMO

Gain-of-function mutations in histone 3 (H3) variants are found in a substantial proportion of pediatric high-grade gliomas (pHGG), often in association with TP53 loss and platelet-derived growth factor receptor alpha (PDGFRA) amplification. Here, we describe a somatic mouse model wherein H3.3K27M and Trp53 loss alone are sufficient for neoplastic transformation if introduced in utero. H3.3K27M-driven lesions are clonal, H3K27me3 depleted, Olig2 positive, highly proliferative, and diffusely spreading, thus recapitulating hallmark molecular and histopathological features of pHGG. Addition of wild-type PDGFRA decreases latency and increases tumor invasion, while ATRX knockdown is associated with more circumscribed tumors. H3.3K27M-tumor cells serially engraft in recipient mice, and preliminary drug screening reveals mutation-specific vulnerabilities. Overall, we provide a faithful H3.3K27M-pHGG model which enables insights into oncohistone pathogenesis and investigation of future therapies.


Assuntos
Células-Tronco Embrionárias/metabolismo , Glioma/genética , Histonas/genética , Células-Tronco Neurais/metabolismo , Receptor alfa de Fator de Crescimento Derivado de Plaquetas/genética , Proteína Supressora de Tumor p53/genética , Animais , Encéfalo/metabolismo , Encéfalo/patologia , Transformação Celular Neoplásica/genética , Regulação Neoplásica da Expressão Gênica , Glioma/metabolismo , Glioma/patologia , Humanos , Camundongos , Mutação , Gradação de Tumores , Invasividade Neoplásica , Interferência de RNA , Receptor alfa de Fator de Crescimento Derivado de Plaquetas/metabolismo , Proteína Supressora de Tumor p53/metabolismo , Proteína Nuclear Ligada ao X/genética , Proteína Nuclear Ligada ao X/metabolismo
20.
Nat Genet ; 49(5): 780-788, 2017 May.
Artigo em Inglês | MEDLINE | ID: mdl-28394352

RESUMO

Spatial heterogeneity of transcriptional and genetic markers between physically isolated biopsies of a single tumor poses major barriers to the identification of biomarkers and the development of targeted therapies that will be effective against the entire tumor. We analyzed the spatial heterogeneity of multiregional biopsies from 35 patients, using a combination of transcriptomic and genomic profiles. Medulloblastomas (MBs), but not high-grade gliomas (HGGs), demonstrated spatially homogeneous transcriptomes, which allowed for accurate subgrouping of tumors from a single biopsy. Conversely, somatic mutations that affect genes suitable for targeted therapeutics demonstrated high levels of spatial heterogeneity in MB, malignant glioma, and renal cell carcinoma (RCC). Actionable targets found in a single MB biopsy were seldom clonal across the entire tumor, which brings the efficacy of monotherapies against a single target into question. Clinical trials of targeted therapies for MB should first ensure the spatially ubiquitous nature of the target mutation.


Assuntos
Neoplasias Cerebelares/genética , Regulação Neoplásica da Expressão Gênica , Meduloblastoma/genética , Transcriptoma , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias Cerebelares/patologia , Criança , Pré-Escolar , Análise por Conglomerados , Variações do Número de Cópias de DNA , Feminino , Perfilação da Expressão Gênica/métodos , Heterogeneidade Genética , Estudo de Associação Genômica Ampla , Humanos , Mutação INDEL , Masculino , Meduloblastoma/patologia , Pessoa de Meia-Idade , Mutação , Polimorfismo de Nucleotídeo Único , Análise de Componente Principal , Reação em Cadeia da Polimerase Via Transcriptase Reversa
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...