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1.
J Neurooncol ; 143(3): 369-379, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31049827

RESUMO

PURPOSE: Point mutations of TP53 tumour suppressor are very rare in schwannomas. We aim to characterize the frequency of exonic copy-number changes of the gene in the tumour and to examine the association between TP53 alterations, phosphorylation status of p53 protein and clinical phenotypes. METHODS: The alterations of TP53 were screened by a combination of Sanger sequencing and multiplex ligation-dependent probe amplification (MLPA) in a total of 44 vestibular schwannomas. The mutation index (MI) in a tumour was defined as the number of exons mutated/ the number of exons tested. Phosphorylation status of p53 protein was investigated by immunoblotting and immunofluorescence. RESULTS: MLPA analysis showed single and multi-exon deletion mutations of TP53 in 65.7% of the cases. Comparisons of clinical features between mutated and non-mutated patients established an association of TP53 mutations with progressive phenotypes, including an earlier formation and a larger tumour. In addition, there were significant correlations between MI and both patients' age and tumour size. The Ser 392 phosphorylation level of p53 varied among tumours, and correlation analysis revealed an age-dependent phosphorylation pattern. The majority of tumours with hyperphosphorylated p53 were from mutated and young patients, suggesting an association of Ser392 phosphorylation with the mutational status of TP53 involved in the acceleration of tumour growth in young individuals. Moreover, Ser 392 phosphorylation contributed to a nuclear accumulation of p53 in schwannona cultures with TP53 mutation. CONCLUSIONS: An interplay between the mutation status of TP53, phosphorylation patterns and tumour behaviors might be established in the disease.


Assuntos
Biomarcadores Tumorais/análise , Variações do Número de Cópias de DNA , Mutação , Neurilemoma/genética , Neurilemoma/metabolismo , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismo , Adolescente , Adulto , Fatores Etários , Idoso , Criança , Estudos de Coortes , Éxons , Feminino , Seguimentos , Regulação Neoplásica da Expressão Gênica , Humanos , Masculino , Pessoa de Meia-Idade , Neurilemoma/patologia , Fosforilação , Prognóstico , Adulto Jovem
2.
Eur J Med Genet ; 62(8): 103680, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31128261

RESUMO

Schwannomatosis is a rare affection predisposing to multiple peripheral neurologic tumors development. Approximatively, one third of patients with schwannomatosis are carriers of a germline mutation in LZTR1 (Leucin Zipper Transcription Regulator 1). Tumorigenesis in schwannomatosis responds to a somatic 5-hit/3-step mechanism resulting in a loss of function (LOF) of LZTR1 and the contiguous genes of locus 22q11.2q12.2. Effectively, LZTR1 is mapped on 22q11.2 and centromeric to SMARCB1 also implicated in the determinism of schwannomatosis and NF2, responsible for neurofibromatosis type 2. On a somatic point of view, LZTR1 mutations are known to drive with a significant frequency glioblastoma (GB) development. We report here two families in which segregate both multiple schwannomas and GB. In the first family, the proband received a diagnosis with of schwannomatosis after a surgery for a lumbar schwannoma at age 43, molecularly confirmed by identification of a germline heterozygous mutation in LZTR1. Her father, having unremarkable medical history deceased from an apparently isolated GB at age 59. In the second family, LZTR1-related schwannomatosis was diagnosed in the index case at age 70 after multiple schwannomas surgeries. Her elder sister had no neurological medical history before occurrence of a lethal GB at age 78. Molecular analysis of GB sample from both affected relatives showed the presence of the familial mutation. These observations hypothesize a potential link between schwannomatosis and the GB development.


Assuntos
Predisposição Genética para Doença , Glioblastoma/diagnóstico , Neurilemoma/diagnóstico , Neurofibromatoses/diagnóstico , Neoplasias Cutâneas/diagnóstico , Fatores de Transcrição/genética , Adulto , Idoso , Carcinogênese/genética , Feminino , Mutação em Linhagem Germinativa/genética , Glioblastoma/complicações , Glioblastoma/genética , Glioblastoma/patologia , Humanos , Masculino , Neurilemoma/complicações , Neurilemoma/genética , Neurilemoma/patologia , Neurofibromatoses/complicações , Neurofibromatoses/genética , Neurofibromatoses/patologia , Linhagem , Proteína SMARCB1/genética , Neoplasias Cutâneas/complicações , Neoplasias Cutâneas/genética , Neoplasias Cutâneas/patologia
3.
Ann Neurol ; 85(3): 316-330, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30706531

RESUMO

OBJECTIVE: Genetic modifiers in rare disease have long been suspected to contribute to the considerable variance in disease expression, including Charcot-Marie-Tooth disease type 1A (CMT1A). To address this question, the Inherited Neuropathy Consortium collected a large standardized sample of such rare CMT1A patients over a period of 8 years. CMT1A is caused in most patients by a uniformly sized 1.5 Mb duplication event involving the gene PMP22. METHODS: We genotyped DNA samples from 971 CMT1A patients on Illumina BeadChips. Genome-wide analysis was performed in a subset of 330 of these patients, who expressed the extremes of a hallmark symptom: mild and severe foot dorsiflexion strength impairment. SIPA1L2 (signal-induced proliferation-associated 1 like 2), the top identified candidate modifier gene, was expressed in the peripheral nerve, and our functional studies identified and confirmed interacting proteins using coimmunoprecipitation analysis, mass spectrometry, and immunocytochemistry. Chromatin immunoprecipitation and in vitro siRNA experiments were used to analyze gene regulation. RESULTS: We identified significant association of 4 single nucleotide polymorphisms (rs10910527, rs7536385, rs4649265, rs1547740) in SIPA1L2 with foot dorsiflexion strength (p < 1 × 10-7 ). Coimmunoprecipitation and mass spectroscopy studies identified ß-actin and MYH9 as SIPA1L2 binding partners. Furthermore, we show that SIPA1L2 is part of a myelination-associated coexpressed network regulated by the master transcription factor SOX10. Importantly, in vitro knockdown of SIPA1L2 in Schwannoma cells led to a significant reduction of PMP22 expression, hinting at a potential strategy for drug development. INTERPRETATION: SIPA1L2 is a potential genetic modifier of CMT1A phenotypic expressions and offers a new pathway to therapeutic interventions. ANN NEUROL 2019;85:316-330.


Assuntos
Doença de Charcot-Marie-Tooth/genética , Pé/fisiopatologia , Genes Modificadores/genética , Debilidade Muscular/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , Linhagem Celular Tumoral , Doença de Charcot-Marie-Tooth/fisiopatologia , Criança , Pré-Escolar , Feminino , Proteínas Ativadoras de GTPase/genética , Regulação da Expressão Gênica , Técnicas de Silenciamento de Genes , Redes Reguladoras de Genes , Humanos , Técnicas In Vitro , Masculino , Pessoa de Meia-Idade , Debilidade Muscular/fisiopatologia , Proteínas da Mielina/genética , Neurilemoma/genética , Fenótipo , Polimorfismo de Nucleotídeo Único , Ratos , Índice de Gravidade de Doença , Adulto Jovem
4.
World Neurosurg ; 123: 318-322, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30576819

RESUMO

BACKGROUND: Schwannomatosis is the third subtype of neurofibromatosis. Because the tumor is multiple and prone to recurrence, it often brings challenges to clinical diagnosis and treatment. In the past decade, researchers have come to realize the relationship between the SMARCB1 gene and schwannomatosis, which is expected to improve the current level of diagnosis and treatment. CASE DESCRIPTION: We collected the clinical data of intraspinal schwannomatosis in the same family, which is rare, and carried out the genetic tests on 3 generations of family members (N = 25). We found that 8 family members had germline mutations of the SMARCB1 gene, manifested as mutation at the splice site between SMARCB1 gene exon 8 and 9 (c.1118 + 1G > A). CONCLUSIONS: The structural and functional abnormalities of proteins caused by the mutations of the SMARCB1 gene may be the molecular basis for the pathogenesis of schwannomatosis in this family. This study may provide clues for the study of schwannomatosis in the future.


Assuntos
Saúde da Família , Mutação em Linhagem Germinativa/genética , Neurilemoma/genética , Neurofibromatoses/genética , Proteína SMARCB1/genética , Neoplasias Cutâneas/genética , Neoplasias da Medula Espinal/genética , Adulto , Grupo com Ancestrais do Continente Asiático , Feminino , Testes Genéticos , Humanos , Espectroscopia de Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Neurilemoma/diagnóstico por imagem , Neurofibromatoses/diagnóstico por imagem , Neoplasias Cutâneas/diagnóstico por imagem , Neoplasias da Medula Espinal/diagnóstico por imagem
5.
Hum Mol Genet ; 28(4): 572-583, 2019 02 15.
Artigo em Inglês | MEDLINE | ID: mdl-30335132

RESUMO

Schwannomas are common, highly morbid and medically untreatable tumors that can arise in patients with germ line as well as somatic mutations in neurofibromatosis type 2 (NF2). These mutations most commonly result in the loss of function of the NF2-encoded protein, Merlin. Little is known about how Merlin functions endogenously as a tumor suppressor and how its loss leads to oncogenic transformation in Schwann cells (SCs). Here, we identify nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB)-inducing kinase (NIK) as a potential drug target driving NF-κB signaling and Merlin-deficient schwannoma genesis. Using a genomic approach to profile aberrant tumor signaling pathways, we describe multiple upregulated NF-κB signaling elements in human and murine schwannomas, leading us to identify a caspase-cleaved, proteasome-resistant NIK kinase domain fragment that amplifies pathogenic NF-κB signaling. Lentiviral-mediated transduction of this NIK fragment into normal SCs promotes proliferation, survival, and adhesion while inducing schwannoma formation in a novel in vivo orthotopic transplant model. Furthermore, we describe an NF-κB-potentiated hepatocyte growth factor (HGF) to MET proto-oncogene receptor tyrosine kinase (c-Met) autocrine feed-forward loop promoting SC proliferation. These innovative studies identify a novel signaling axis underlying schwannoma formation, revealing new and potentially druggable schwannoma vulnerabilities with future therapeutic potential.


Assuntos
Neurilemoma/genética , Neurofibromatose 2/genética , Neurofibromina 2/genética , Proteínas Serina-Treonina Quinases/genética , Animais , Comunicação Autócrina/genética , Carcinogênese/genética , Caspase 1/genética , Proliferação de Células/genética , Modelos Animais de Doenças , Regulação Neoplásica da Expressão Gênica , Fator de Crescimento de Hepatócito/genética , Humanos , Camundongos , Terapia de Alvo Molecular , NF-kappa B/genética , Neurilemoma/complicações , Neurilemoma/tratamento farmacológico , Neurilemoma/patologia , Neurofibromatose 2/complicações , Neurofibromatose 2/tratamento farmacológico , Neurofibromatose 2/patologia , Complexo de Endopeptidases do Proteassoma/genética , Proteínas Proto-Oncogênicas c-met/genética , Células de Schwann , Transdução de Sinais/genética
6.
World Neurosurg ; 122: e487-e497, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30366145

RESUMO

BACKGROUND: Malignant peripheral nerve sheath tumors (MPNSTs) and cellular schwannomas (CSs) of the eighth cranial nerve are exceedingly rare. The purpose of the present study was to evaluate clinical and genetic characterization of these rare tumors. METHODS: The clinical and radiological features were analyzed retrospectively. The histopathological characteristics were assessed by hematoxylin and eosin staining and immunohistochemistry. Genomic abnormalities were evaluated using array comparative genomic hybridization. RESULTS: Of the 1287 surgeries for vestibular schwannomas from 2014 to 2017, 2 were for MPNSTs and 5 were for CSs. The mean age at diagnosis was older for patients with MPNSTs (57.0 ± 4.2 years) than that of patients with CS (35.8 ± 9.4 years; P = 0.03). Two patients with MPNST died of tumor recurrence. None of the patients with CS died. The 2-year overall and progression-free survival of patients with MPNSTs were worse than those for patients with CSs (overall survival, 50.0% ± 35.4% vs. 100%, P = 0.027; progression-free survival, 0% vs. 100%; P = 0.012). The Ki-67 index for the MPNSTs (29.0% ± 3.5%) was greater than that for the CSs (10.3% ± 3.1%; P = 0.001). The common alterations in MPNSTs mainly included gains of chromosomes 7p, 8p, 9q, 12, and 17 and loss of heterozygosity of 1p, 6 and 9p. The common alterations in CSs included gain of 4p16.3, loss of heterozygosity of 2p15-14, and 22q11.1-13.3. CONCLUSIONS: To the best of our knowledge, the present study is the first high-resolution genomic analysis of MPNSTs and CSs of the eighth cranial nerve and has shown a significant difference that might be more accurate to distinguish between these 2 types of rare tumors.


Assuntos
Genômica/métodos , Neoplasias da Bainha Neural/diagnóstico por imagem , Neurilemoma/diagnóstico por imagem , Neoplasias do Sistema Nervoso Periférico/diagnóstico por imagem , Nervo Vestibulococlear/diagnóstico por imagem , Adulto , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias da Bainha Neural/genética , Neoplasias da Bainha Neural/cirurgia , Neurilemoma/genética , Neurilemoma/cirurgia , Neoplasias do Sistema Nervoso Periférico/genética , Neoplasias do Sistema Nervoso Periférico/cirurgia , Nervo Vestibulococlear/cirurgia
8.
EBioMedicine ; 36: 252-265, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30274821

RESUMO

BACKGROUND: The great majority of sporadic vestibular schwannomas (VSs) are due to the mutations of the NF2 gene encoding merlin. Sporadic VSs exhibit variable growth patterns and only a small fraction of the tumours are fast-growing; however, the underlying mechanisms remain undefined. METHODS: DNA sequencing and dosage analysis were used to identify the NF2 mutation status in sporadic schwannomas. The expression and sub-cellular localization of merlin and p53-MDM2 were assessed by immunoblotting, qRT-PCR and immunofluorescence. In vitro and in vivo studies were performed to reveal the effects of Nutlin-3 (a MDM2 inhibitor) and/or MG-132(a proteasome inhibitor) on schwannomas. The proliferation of schwannoma cells was assessed by CCK-8 assay, EdU staining and Flow cytometry analysis. FINDINGS: Double genetic hits of NF2 tended to occur in fast-growing tumours, characterized by the absence of merlin. The deregulation of p53-MDM2 was demonstrated to mediate merlin-deficient tumour growth, characterized by a nuclear accumulation of stabilized MDM2, contributing to a nuclear export of p53 for degradation. Nutlin-3 blocked the proliferation of schwannoma cells via a cooperative recovery of merlin and p53, accompanied by the shuttling of both proteins from the cytoplasm to the nucleus. We further demonstrated a difference in the sensitivity to Nutlin-3 between schwannoma cells with and without merlin expression. Nutlin-3 combined with MG-132 narrowed this between-group difference and triggered stronger inhibitory effects on the growth of schwannomas through coordinated reactivation of p53. INTERPRETATION: These findings present treatment strategies directed on the pathogenesis of sporadic schwannomas. FUND: National Natural Science Foundation of China.


Assuntos
Antineoplásicos/farmacologia , Imidazóis/farmacologia , Neurilemoma/genética , Piperazinas/farmacologia , Proteína Supressora de Tumor p53/genética , Animais , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/genética , Modelos Animais de Doenças , Sinergismo Farmacológico , Regulação Neoplásica da Expressão Gênica , Genes da Neurofibromatose 2 , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Camundongos , Mutação , Neurilemoma/metabolismo , Neurilemoma/patologia , Complexo de Endopeptidases do Proteassoma/metabolismo , Ligação Proteica , Estabilidade Proteica , Proteólise , Proteína Supressora de Tumor p53/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto
9.
Hum Genet ; 137(6-7): 543-552, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30006736

RESUMO

Schwannomatosis and neurofibromatosis type 2 (NF2) are both characterized by the development of multiple schwannomas but represent different genetic entities. Whereas NF2 is caused by mutations of the NF2 gene, schwannomatosis is associated with germline mutations of SMARCB1 or LZTR1. Here, we studied 15 sporadic patients with multiple non-intradermal schwannomas, but lacking vestibular schwannomas and ophthalmological abnormalities, who fulfilled the clinical diagnostic criteria for schwannomatosis. None of them harboured germline NF2 or SMARCB1 mutations as determined by the analysis of blood samples but seven had germline LZTR1 variants predicted to be pathogenic. At least two independent schwannomas from each patient were subjected to NF2 mutation testing. In five of the 15 patients, identical somatic NF2 mutations were identified (33%). If only those patients without germline LZTR1 variants are considered (n = 8), three of them (37.5%) had mosaic NF2 as concluded from identical NF2 mutations identified in independent schwannomas from the same patient. These findings imply that a sizeable proportion of patients who fulfil the diagnostic criteria for schwannomatosis, are actually examples of mosaic NF2. Hence, the molecular characterization of tumours in patients with a clinical diagnosis of schwannomatosis is very important. Remarkably, two of the patients with germline LZTR1 variants also had identical NF2 mutations in independent schwannomas from each patient which renders differential diagnosis of LZTR1-associated schwannomatosis versus mosaic NF2 in these patients very difficult.


Assuntos
Genótipo , Mutação em Linhagem Germinativa , Neurilemoma/genética , Neurofibromatoses/genética , Neurofibromatose 2/genética , Neurofibrossarcoma/genética , Neoplasias Cutâneas/genética , Adolescente , Adulto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Neurilemoma/patologia , Neurofibromatoses/patologia , Neurofibromatose 2/patologia , Neurofibrossarcoma/patologia , Proteína SMARCB1/genética , Neoplasias Cutâneas/patologia , Fatores de Transcrição/genética
10.
PLoS One ; 13(6): e0197350, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29897904

RESUMO

Neurofibromatosis 2 (NF2) is a rare tumor suppressor syndrome that manifests with multiple schwannomas and meningiomas. There are no effective drug therapies for these benign tumors and conventional therapies have limited efficacy. Various model systems have been created and several drug targets have been implicated in NF2-driven tumorigenesis based on known effects of the absence of merlin, the product of the NF2 gene. We tested priority compounds based on known biology with traditional dose-concentration studies in meningioma and schwann cell systems. Concurrently, we studied functional kinome and gene expression in these cells pre- and post-treatment to determine merlin deficient molecular phenotypes. Cell viability results showed that three agents (GSK2126458, Panobinostat, CUDC-907) had the greatest activity across schwannoma and meningioma cell systems, but merlin status did not significantly influence response. In vivo, drug effect was tumor specific with meningioma, but not schwannoma, showing response to GSK2126458 and Panobinostat. In culture, changes in both the transcriptome and kinome in response to treatment clustered predominantly based on tumor type. However, there were differences in both gene expression and functional kinome at baseline between meningioma and schwannoma cell systems that may form the basis for future selective therapies. This work has created an openly accessible resource (www.synapse.org/SynodosNF2) of fully characterized isogenic schwannoma and meningioma cell systems as well as a rich data source of kinome and transcriptome data from these assay systems before and after treatment that enables single and combination drug discovery based on molecular phenotype.


Assuntos
Neoplasias Meníngeas/genética , Neurilemoma/genética , Neurofibromatose 2/genética , Neurofibromina 2/genética , Animais , Carcinogênese/genética , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias Meníngeas/tratamento farmacológico , Neoplasias Meníngeas/patologia , Camundongos , Morfolinas/farmacologia , Neurilemoma/tratamento farmacológico , Neurilemoma/patologia , Neurofibromatose 2/tratamento farmacológico , Neurofibromatose 2/patologia , Panobinostat/farmacologia , Pirimidinas/farmacologia , Quinolinas/farmacologia , Sulfonamidas/farmacologia , Biologia de Sistemas , Transcriptoma/genética
11.
J Neurol Neurosurg Psychiatry ; 89(11): 1215-1219, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-29909380

RESUMO

OBJECTIVES: Schwannomatosis is a dominantly inherited condition predisposing to schwannomas of mainly spinal and peripheral nerves with some diagnostic overlap with neurofibromatosis-2 (NF2), but the underlying epidemiology is poorly understood. We present the birth incidence and prevalence allowing for overlap with NF2. METHODS: Schwannomatosis and NF2 cases were ascertained from the Manchester region of England (population=4.8 million) and from across the UK. Point prevalence and birth incidence were calculated from regional birth statistics. Genetic analysis was also performed on NF2, LZTR1 and SMARCB1 on blood and tumour DNA samples when available. RESULTS: Regional prevalence for schwannomatosis and NF2 were 1 in 126 315 and 50 500, respectively, with calculated birth incidences of 1 in 68 956 and 1 in 27 956. Mosaic NF2 causes a substantial overlap with schwannomatosis resulting in the misdiagnosis of at least 9% of schwannomatosis cases. LZTR1-associated schwannomatosis also causes a small number of cases that are misdiagnosed with NF2 (1%-2%), due to the occurrence of a unilateral vestibular schwannoma. Patients with schwannomatosis had lower numbers of non-vestibular cranial schwannomas, but more peripheral and spinal nerve schwannomas with pain as a predominant presenting symptom. Life expectancy was significantly better in schwannomatosis (mean age at death 76.9) compared with NF2 (mean age at death 66.2; p=0.004). CONCLUSIONS: Within the highly ascertained North-West England population, schwannomatosis has less than half the birth incidence and prevalence of NF2.


Assuntos
Neurilemoma/epidemiologia , Neurilemoma/genética , Neurofibromatoses/epidemiologia , Neurofibromatoses/genética , Neurofibromina 2/genética , Proteína SMARCB1/genética , Neoplasias Cutâneas/epidemiologia , Neoplasias Cutâneas/genética , Fatores de Transcrição/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Bases de Dados Factuais , Inglaterra/epidemiologia , Feminino , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Neurofibromatose 2/epidemiologia , Neurofibromatose 2/genética , Prevalência , Adulto Jovem
12.
Adv Anat Pathol ; 25(5): 353-368, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-29762158

RESUMO

The diagnosis of a neurofibroma or a malignant peripheral nerve sheath tumor (MPNST) often raises the question of whether the patient has the genetic disorder neurofibromatosis type 1 (NF1) as well as how this will impact the patient's outcome, what their risk is for developing additional neoplasms and whether treatment options differ for NF1-associated and sporadic peripheral nerve sheath tumors. Establishing a diagnosis of NF1 is challenging as this disorder has numerous neoplastic and non-neoplastic manifestations which are variably present in individual patients. Further, other genetic diseases affecting the Ras signaling cascade (RASopathies) mimic many of the clinical features of NF1. Here, we review the clinical manifestations of NF1 and compare and contrast them with those of the RASopathies. We also consider current approaches to genetic testing for germline NF1 mutations. We then focus on NF1-associated neurofibromas, considering first the complicated clinical behavior and pathology of these neoplasms and then discussing our current understanding of the genomic abnormalities that drive their pathogenesis, including the mutations encountered in atypical neurofibromas. As several neurofibroma subtypes are capable of undergoing malignant transformation to become MPNSTs, we compare and contrast patient outcomes in sporadic, NF1-associated and radiation-induced MPNSTs, and review the challenging pathology of these lesions. The mutations involved in neurofibroma-MPNST progression, including the recent identification of mutations affecting epigenetic regulators, are then considered. Finally, we explore how our current understanding of neurofibroma and MPNST pathogenesis is informing the design of new therapies for these neoplasms.


Assuntos
Neurilemoma/patologia , Neurofibromatose 1/patologia , Neoplasias do Sistema Nervoso Periférico/patologia , Biomarcadores Tumorais/genética , Biópsia , Análise Mutacional de DNA , Diagnóstico Diferencial , Progressão da Doença , Epigênese Genética , Genes da Neurofibromatose 1 , Genes ras , Predisposição Genética para Doença , Humanos , Mutação , Neurilemoma/genética , Neurilemoma/terapia , Neurofibromatose 1/genética , Neurofibromatose 1/terapia , Neoplasias do Sistema Nervoso Periférico/genética , Neoplasias do Sistema Nervoso Periférico/terapia , Fenótipo , Valor Preditivo dos Testes
13.
Eur J Hum Genet ; 26(8): 1083-1093, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-29706634

RESUMO

Germline variants that affect function are found in seven genes of the BAF chromatin-remodeling complex. They are linked to a broad range of diseases that, according to the gene affected, range from non-syndromic or syndromic neurodevelopmental disorders to low-grade tumors and malignancies. In the current meta-analysis, we evaluate genetic and clinical data from more than 400 families and 577 patients affected by BAF germline alterations. We focus on SMARCB1, including 43 unpublished patients from the EU-RHAB registry and our institution. For this gene, we further demonstrate whole gene as well as exon deletions and truncating variants to be associated with malignancy and early-onset disease. In contrast, non-truncating variants are associated with non-malignant disorders, such as Coffin-Siris syndrome or late-onset tumors like schwannoma or meningioma (p < 0.0001). SMARCB1 germline variants are distributed across the gene with variants in exons 1, 2, 8, and 9 being associated with low-grade entities, and single-nucleotide variants or indels outside of exon 9 that appear in patients with malignancies (p < 0.001). We attribute variants in specific BAF genes to certain disease entities. Finally, single-nucleotide variants and indels are sometimes detected in the healthy relatives of tumor patients, while Coffin-Siris syndrome and Nicolaides-Baraitser syndrome generally seem to appear de novo. Our findings add further information on the genotype-phenotype association of germline variants detected in genes of the BAF complex. Functional studies are urgently needed for a deeper understanding of BAF-related disorders and may take advantage from the comprehensive information gathered in this article.


Assuntos
Anormalidades Múltiplas/genética , Face/anormalidades , Mutação em Linhagem Germinativa , Deformidades Congênitas da Mão/genética , Deficiência Intelectual/genética , Neoplasias Meníngeas/genética , Meningioma/genética , Micrognatismo/genética , Pescoço/anormalidades , Neurilemoma/genética , Proteína SMARCB1/genética , Anormalidades Múltiplas/patologia , Face/patologia , Deformidades Congênitas da Mão/patologia , Humanos , Deficiência Intelectual/patologia , Neoplasias Meníngeas/patologia , Meningioma/patologia , Micrognatismo/patologia , Pescoço/patologia , Neurilemoma/patologia , Fenótipo , Polimorfismo de Nucleotídeo Único
14.
Semin Neurol ; 38(1): 73-85, 2018 02.
Artigo em Inglês | MEDLINE | ID: mdl-29548054

RESUMO

Neurofibromatosis 1, neurofibromatosis 2, and schwannomatosis are a group of related classically inherited but often times sporadic tumor suppressor syndromes. Neuro-oncologists should recognize these syndromes, initiate necessary tests in patients with a clinical suspicion, and support genetic counseling of patients and families. In this review, clinical presentation, diagnostic criteria, day-to-day management including supportive care as well as updates on genetics, and experimental treatment strategies are discussed.


Assuntos
Neoplasias do Sistema Nervoso , Neurilemoma , Neurofibromatoses , Neoplasias Cutâneas , Humanos , Neoplasias do Sistema Nervoso/genética , Neoplasias do Sistema Nervoso/patologia , Neoplasias do Sistema Nervoso/terapia , Neurilemoma/genética , Neurilemoma/patologia , Neurilemoma/terapia , Neurofibromatoses/genética , Neurofibromatoses/patologia , Neurofibromatoses/terapia , Neoplasias Cutâneas/genética , Neoplasias Cutâneas/patologia , Neoplasias Cutâneas/terapia
15.
Anticancer Res ; 38(4): 2149-2154, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-29599333

RESUMO

BACKGROUND/AIM: Individuals with type 2 Neurofibromatosis are predisposed for the appearance of schwannomas. In the present study we analyzed the loss of heterozygosity and mutations in the NF2 gene in patients with sporadic Schwannoma without Neurofibromatosis type 2. MATERIALS AND METHODS: We analyzed 39 patients with sporadic spinal schwannoma. We quantified the number of alleles by FISH and sequenced the NF2 gene. RESULTS: We identified 16/39 patients with point mutations and/or LOHs in the tumor samples analyzed. The LOHs were found in 7/39 patients. Two homozygous mutations were detected in 4/39 tumors, and the presence of the mutation in heterozygosis was revealed in 3/39 patients. In two tumors, we detected the loss of one allele of the NF2 gene, with no mutation. CONCLUSION: The genetic alterations observed in the NF2 gene indicated that spinal schwannomas are associated with genetic alterations also found in other schwannomas and type 2 Neurofibromatosis, which reinforces the etiological role of this gene.


Assuntos
Genes da Neurofibromatose 2 , Perda de Heterozigosidade , Neurilemoma/epidemiologia , Neurilemoma/genética , Neoplasias da Coluna Vertebral/epidemiologia , Neoplasias da Coluna Vertebral/genética , Adulto , Brasil/epidemiologia , Feminino , Frequência do Gene , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Neurofibromatose 2/epidemiologia , Neurofibromatose 2/genética
16.
Medicine (Baltimore) ; 97(5): e9717, 2018 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-29384852

RESUMO

Schwannomatosis has been linked to germline mutations in the SMARCB1 and LZTR1 genes, and is frequently associated with pain.In a cohort study, we assessed the mutation status of 37 patients with clinically diagnosed schwannomatosis and compared to clinical data, whole body MRI (WBMRI), visual analog pain scale, and Short Form 36 (SF-36) bodily pain subscale.We identified a germline mutation in LZTR1 in 5 patients (13.5%) and SMARCB1 in 15 patients (40.5%), but found no germline mutation in 17 patients (45.9%). Peripheral schwannomas were detected in 3 LZTR1-mutant (60%) and 10 SMARCB1-mutant subjects (66.7%). Among those with peripheral tumors, the median tumor number was 4 in the LZTR1 group (median total body tumor volume 30 cc) and 10 in the SMARCB1 group (median volume 85cc), (P=.2915 for tumor number and P = .2289 for volume). mutation was associated with an increased prevalence of spinal schwannomas (100% vs 41%, P = .0197). The median pain score was 3.9/10 in the LZTR1 group and 0.5/10 in the SMARCB1 group (P = .0414), and SF-36 pain-associated quality of life was significantly worse in the LZTR1 group (P = .0106). Pain scores correlated with total body tumor volume (rho = 0.32471, P = .0499), but not with number of tumors (rho = 0.23065, P = .1696).We found no significant difference in quantitative tumor burden between mutational groups, but spinal schwannomas were more common in LZTR1-mutant patients. Pain was significantly higher in LZTR1-mutant than in SMARCB1-mutant patients, though spinal tumor location did not significantly correlate with pain. This suggests a possible genetic association with schwannomatosis-associated pain.


Assuntos
Dor do Câncer/genética , Mutação em Linhagem Germinativa , Neurilemoma/genética , Neurofibromatoses/genética , Neoplasias Cutâneas/genética , Adulto , Dor do Câncer/diagnóstico por imagem , Dor do Câncer/fisiopatologia , Estudos de Coortes , Feminino , Estudos de Associação Genética , Humanos , Imagem por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Neurilemoma/diagnóstico por imagem , Neurilemoma/fisiopatologia , Neurofibromatoses/diagnóstico por imagem , Neurofibromatoses/fisiopatologia , Medição da Dor , Qualidade de Vida , Proteína SMARCB1/genética , Neoplasias Cutâneas/diagnóstico por imagem , Neoplasias Cutâneas/fisiopatologia , Fatores de Transcrição/genética , Carga Tumoral , Imagem Corporal Total
17.
PLoS One ; 13(2): e0192858, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29432475

RESUMO

High-throughput technologies generate considerable amount of data which often requires bioinformatic expertise to analyze. Here we present High-Throughput Tabular Data Processor (HTDP), a platform independent Java program. HTDP works on any character-delimited column data (e.g. BED, GFF, GTF, PSL, WIG, VCF) from multiple text files and supports merging, filtering and converting of data that is produced in the course of high-throughput experiments. HTDP can also utilize itemized sets of conditions from external files for complex or repetitive filtering/merging tasks. The program is intended to aid global, real-time processing of large data sets using a graphical user interface (GUI). Therefore, no prior expertise in programming, regular expression, or command line usage is required of the user. Additionally, no a priori assumptions are imposed on the internal file composition. We demonstrate the flexibility and potential of HTDP in real-life research tasks including microarray and massively parallel sequencing, i.e. identification of disease predisposing variants in the next generation sequencing data as well as comprehensive concurrent analysis of microarray and sequencing results. We also show the utility of HTDP in technical tasks including data merge, reduction and filtering with external criteria files. HTDP was developed to address functionality that is missing or rudimentary in other GUI software for processing character-delimited column data from high-throughput technologies. Flexibility, in terms of input file handling, provides long term potential functionality in high-throughput analysis pipelines, as the program is not limited by the currently existing applications and data formats. HTDP is available as the Open Source software (https://github.com/pmadanecki/htdp).


Assuntos
Sequenciamento de Nucleotídeos em Larga Escala/estatística & dados numéricos , Gráficos por Computador , Variações do Número de Cópias de DNA , DNA de Neoplasias/genética , Interpretação Estatística de Dados , Bases de Dados Genéticas/estatística & dados numéricos , Predisposição Genética para Doença , Humanos , Neurilemoma/genética , Análise de Sequência de DNA/estatística & dados numéricos , Software , Interface Usuário-Computador
18.
Ann Neurol ; 83(4): 854-857, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-29469988

RESUMO

Schwannomatosis and neurofibromatosis type 2 are hereditary tumor syndromes, and peripheral neuropathy has been reported in both. We prospectively applied in vivo morphometric measurement of dorsal root ganglia volume in 16 schwannomatosis patients, 14 neurofibromatosis type 2 patients, and 26 healthy controls by magnetic resonance neurography. Compared to healthy controls, dorsal root ganglia hypertrophy was a consistent finding in neurofibromatosis type 2 (L3, + 267%; L4, + 235%; L5, + 241%; S1, + 300%; S2, + 242%; Bonferroni-adjusted p < 0.001) but not in schwannomatosis. Dorsal root ganglia may be a vulnerable site in origination of areflexia and sensory loss and a useful diagnostic marker in neurofibromatosis type 2. Ann Neurol 2018;83:854-857.


Assuntos
Gânglios Espinais/diagnóstico por imagem , Neurilemoma/diagnóstico por imagem , Neurofibromatoses/diagnóstico por imagem , Neurofibromatose 2/diagnóstico por imagem , Neoplasias Cutâneas/diagnóstico por imagem , Adulto , Idoso , Feminino , Humanos , Imagem Tridimensional , Imagem por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Neurilemoma/genética , Neurofibromatoses/genética , Neurofibromatose 2/genética , Curva ROC , Estudos Retrospectivos , Neoplasias Cutâneas/genética , Adulto Jovem
19.
Neuro Oncol ; 20(7): 917-929, 2018 06 18.
Artigo em Inglês | MEDLINE | ID: mdl-29409008

RESUMO

Background: Clinical overlap between neurofibromatosis type 2 (NF2), schwannomatosis, and meningiomatosis can make clinical diagnosis difficult. Hence, molecular investigation of germline and tumor tissues may improve the diagnosis. Methods: We present the targeted next-generation sequencing (NGS) of NF2, SMARCB1, LZTR1, SMARCE1, and SUFU tumor suppressor genes, using an amplicon-based approach. We analyzed blood DNA from a cohort of 196 patients, including patients with NF2 (N = 79), schwannomatosis (N = 40), meningiomatosis (N = 12), and no clearly established diagnosis (N = 65). Matched tumor DNA was analyzed when available. Forty-seven NF2-/SMARCB1-negative schwannomatosis patients and 27 NF2-negative meningiomatosis patients were also evaluated. Results: A NF2 variant was found in 41/79 (52%) NF2 patients. SMARCB1 or LZTR1 variants were identified in 5/40 (12.5%) and 13/40 (∼32%) patients in the schwannomatosis cohort. Potentially pathogenic variants were found in 12/65 (18.5%) patients with no clearly established diagnosis. A LZTR1 variant was identified in 16/47 (34%) NF2/SMARCB1-negative schwannomatosis patients. A SMARCE1 variant was found in 3/39 (∼8%) meningiomatosis patients. No SUFU variant was found in the cohort. NGS was an effective and sensitive method to detect mutant alleles in blood or tumor DNA of mosaic NF2 patients. Interestingly, we identified a 4-hit mechanism resulting in the complete NF2 loss-of-function combined with SMARCB1 and LZTR1 haploinsufficiency in two-thirds of tumors from NF2 patients. Conclusions: Simultaneous investigation of NF2, SMARCB1, LZTR1, and SMARCE1 is a key element in the differential diagnosis of NF2, schwannomatosis, and meningiomatosis. The targeted NGS strategy is suitable for the identification of NF2 mosaicism in blood and for the investigation of tumors from these patients.


Assuntos
Genes Supressores de Tumor , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Neoplasias Meníngeas/diagnóstico , Meningioma/diagnóstico , Mutação , Neurilemoma/diagnóstico , Neurofibromatoses/diagnóstico , Neurofibromatose 2/diagnóstico , Neoplasias Cutâneas/diagnóstico , Biomarcadores Tumorais , Proteínas Cromossômicas não Histona/genética , Proteínas de Ligação a DNA/genética , Diagnóstico Diferencial , Seguimentos , Humanos , Neoplasias Meníngeas/genética , Meningioma/genética , Neurilemoma/genética , Neurofibromatoses/genética , Neurofibromatose 2/genética , Neurofibromina 2/genética , Prognóstico , Estudos Prospectivos , Proteínas Repressoras/genética , Estudos Retrospectivos , Proteína SMARCB1/genética , Neoplasias Cutâneas/genética , Fatores de Transcrição/genética
20.
Medicine (Baltimore) ; 97(4): e9636, 2018 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-29369179

RESUMO

Malignant peripheral nerve sheath tumor (MPNST) is an uncommon neoplasm that rarely involves the head and neck region. Intracranial MPNSTs unrelated to cranial nerves are highly malignant tumors with poor overall survival, probably because of infiltrating growth into surrounding brain tissue. The pathogenesis of MPNST remains unclear. There are no conclusive explanations for the mechanisms underlying the initiation, progression, and metastasis of MPNST. In this paper, we describe a case of MPNST in the pterygopalatine fossa with intracranial metastatic recurrence and review related literatures. Meanwhile, targeted next-generation sequencing (NGS) revealed the presence of both a beta-catenin (CTNNB1) missense mutation p.Ser33Phe and a mediator complex subunit 12 (MED12) frameshift mutation p.Tyr1278fs in the recurrent intracranial tumor. Therapies that target CTNNB1 mutation, MED12 mutation, CTNNB1 activation, or Wnt pathway activation are worth future studying.


Assuntos
Neoplasias Encefálicas/genética , Sequenciamento de Nucleotídeos em Larga Escala , Recidiva Local de Neoplasia/genética , Neurilemoma/genética , Neoplasias Cranianas/genética , Neoplasias Encefálicas/secundário , Feminino , Humanos , Complexo Mediador/genética , Mutação de Sentido Incorreto , Recidiva Local de Neoplasia/secundário , Neurilemoma/secundário , Fossa Pterigopalatina/patologia , Neoplasias Cranianas/patologia , Adulto Jovem , beta Catenina/genética
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