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1.
Exp Suppl ; 111: 129-147, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31588531

RESUMO

Pheochromocytomas (Pheo) and paragangliomas (PGL) are rare tumors originating from catecholamine-producing chromaffin cells. They occur approximately in 0.1% of patients affected with hypertonia. Pheo/PGL may manifest itself at any age; in 10% of the patients, the disease is bilateral, and also in 10% it occurs outside of the adrenal medulla. From a genetic aspect, a considerable proportion of these tumors represents a prototype for an autosomal dominantly inherited syndrome with incomplete penetrance. In addition, to date more than 15 genes have been identified representing genetic susceptibility for Pheo/PGL and accounting for 40% of all cases. In general, in familiar cases, the tumor manifests at younger age, and they are often occurring as multiplex tumors. Permanent recovery can be achieved with an early diagnosis and with a successful surgical removal of the tumor tissue. On the other hand, undiagnosed, hormonally active Pheos may lead to severe, or even lethal, consequences. This chapter will summarize our recent knowledge about the genetics of Pheo/PGL, focusing on tumor syndromes where Pheo/PGLs are among the main manifestations.


Assuntos
Neurofibromina 1/genética , Feocromocitoma/genética , Proteína Supressora de Tumor Von Hippel-Lindau/genética , Neoplasias das Glândulas Suprarrenais/genética , Catecolaminas , Humanos , Paraganglioma/genética
2.
Nat Commun ; 10(1): 2506, 2019 06 07.
Artigo em Inglês | MEDLINE | ID: mdl-31175295

RESUMO

Although there are many known Mendelian genes linked to epileptic or developmental and epileptic encephalopathy (EE/DEE), its genetic architecture is not fully explained. Here, we address this incompleteness by analyzing exomes of 743 EE/DEE cases and 2366 controls. We observe that damaging ultra-rare variants (dURVs) unique to an individual are significantly overrepresented in EE/DEE, both in known EE/DEE genes and the other non-EE/DEE genes. Importantly, enrichment of dURVs in non-EE/DEE genes is significant, even in the subset of cases with diagnostic dURVs (P = 0.000215), suggesting oligogenic contribution of non-EE/DEE gene dURVs. Gene-based analysis identifies exome-wide significant (P = 2.04 × 10-6) enrichment of damaging de novo mutations in NF1, a gene primarily linked to neurofibromatosis, in infantile spasm. Together with accumulating evidence for roles of oligogenic or modifier variants in severe neurodevelopmental disorders, our results highlight genetic complexity in EE/DEE, and indicate that EE/DEE is not an aggregate of simple Mendelian disorders.


Assuntos
Variação Genética , Espasmos Infantis/genética , Proteínas Adaptadoras de Transporte Vesicular/genética , Grupo com Ancestrais do Continente Asiático/genética , Estudos de Casos e Controles , DNA (Citosina-5-)-Metiltransferases/genética , Epilepsias Mioclônicas/genética , Fatores de Troca do Nucleotídeo Guanina/genética , Humanos , Lactente , Japão , Síndrome de Lennox Gastaut/genética , Modelos Logísticos , Mutação , Neurofibromina 1/genética , Polimorfismo de Nucleotídeo Único , Análise de Componente Principal , Canais de Cátion TRPM/genética , Sequenciamento Completo do Exoma
3.
J Exp Clin Cancer Res ; 38(1): 185, 2019 May 03.
Artigo em Inglês | MEDLINE | ID: mdl-31053152

RESUMO

BACKGROUND: Malignant peripheral nerve sheath tumours (MPNSTs) are sarcomas of Schwann cell lineage origin that occur sporadically or in association with the inherited syndrome, neurofibromatosis type 1 (NF1). This study aimed to examine the function of High mobility group protein A2 (HMGA2) in NF1 MPNST progression and the underlying molecular mechanism. METHODS: Immunohistochemistry (IHC) was used to detect HMGA2 expression in MPNST and neurofibroma patient samples. Cell Cycle Kit-8 (CCK-8) and 5-ethynyl-20-deoxyuridine (EdU) assays, terminal deoxynucleotidyl transferase-mediated nick end labelling, and transmission electron microscopy were performed to reveal HMGA2 functions in NF1 MPNST cells in vitro and in vivo. Chromatin immunoprecipitation sequencing (ChIP-Seq) and RNA sequencing (RNA-Seq) were used to detect HMGA2-modulated genes regulating autophagy and growth in NF1 MPNSTs in vitro and in vivo. RESULTS: NF1 MPNST samples exhibit higher HMGA2 positivity rates (13/16) than sporadic MPNST (16/41) and neurofibroma (0/7) patient samples. High HMGA2 expression is correlated with poor prognosis. Neurofibromin 1 (NF1)-deficient MPNST cells display elevated HMGA2 expression. Functional experiments revealed that HMGA2 knockdown inhibits NF1 MPNST cell growth in vitro and in vivo. In addition to promoting cell cycle arrest and apoptosis, HMGA2 knockdown inhibits autophagy, favouring cell death. RNA-Seq and ChIP-Seq revealed that HMGA2 directly activates the Musashi-2 (MSI2) promoter region, and MSI2 overexpression reverses autophagy and growth in shHMGA2-transfected cells. MSI2 interacts with Beclin1, and Beclin1 blockade inhibits autophagy, thereby inhibiting cell proliferation. CONCLUSIONS: HMGA2 knockdown regulates autophagy via MSI2-Beclin1 interactions to inhibit NF1 MPNST growth, revealing potential therapeutic targets for these untreatable tumours.


Assuntos
Proteína HMGA2/genética , Neurofibromina 1/genética , Neurofibrossarcoma/genética , Proteínas de Ligação a RNA/genética , Adulto , Apoptose/genética , Autofagia/genética , Proteína Beclina-1/genética , Linhagem da Célula/genética , Proliferação de Células/genética , Feminino , Regulação Neoplásica da Expressão Gênica , Técnicas de Silenciamento de Genes , Proteína HMGA2/antagonistas & inibidores , Humanos , Masculino , Pessoa de Meia-Idade , Neurofibrossarcoma/patologia , Células de Schwann/metabolismo , Células de Schwann/patologia , Transdução de Sinais/genética
4.
PLoS Genet ; 15(4): e1008039, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30970016

RESUMO

The SWI/SNF-family chromatin remodeling protein ATRX is a tumor suppressor in sarcomas, gliomas and other malignancies. Its loss of function facilitates the alternative lengthening of telomeres (ALT) pathway in tumor cells, while it also affects Polycomb repressive complex 2 (PRC2) silencing of its target genes. To further define the role of inactivating ATRX mutations in carcinogenesis, we knocked out atrx in our previously reported p53/nf1-deficient zebrafish line that develops malignant peripheral nerve sheath tumors and gliomas. Complete inactivation of atrx using CRISPR/Cas9 was lethal in developing fish and resulted in an alpha-thalassemia-like phenotype including reduced alpha-globin expression. In p53/nf1-deficient zebrafish neither peripheral nerve sheath tumors nor gliomas showed accelerated onset in atrx+/- fish, but these fish developed various tumors that were not observed in their atrx+/+ siblings, including epithelioid sarcoma, angiosarcoma, undifferentiated pleomorphic sarcoma and rare types of carcinoma. These cancer types are included in the AACR Genie database of human tumors associated with mutant ATRX, indicating that our zebrafish model reliably mimics a role for ATRX-loss in the early pathogenesis of these human cancer types. RNA-seq of p53/nf1- and p53/nf1/atrx-deficient tumors revealed that down-regulation of telomerase accompanied ALT-mediated lengthening of the telomeres in atrx-mutant samples. Moreover, inactivating mutations in atrx disturbed PRC2-target gene silencing, indicating a connection between ATRX loss and PRC2 dysfunction in cancer development.


Assuntos
Sarcoma Experimental/etiologia , Proteína Supressora de Tumor p53/deficiência , Proteína Supressora de Tumor p53/genética , Proteína Nuclear Ligada ao X/deficiência , Proteína Nuclear Ligada ao X/genética , Proteínas de Peixe-Zebra/deficiência , Proteínas de Peixe-Zebra/genética , Animais , Animais Geneticamente Modificados , Sistemas CRISPR-Cas , Carcinogênese/genética , Carcinogênese/metabolismo , Modelos Animais de Doenças , Eritropoese , Feminino , Técnicas de Inativação de Genes , Globinas/genética , Humanos , Mutação com Perda de Função , Masculino , Neurofibromina 1/deficiência , Neurofibromina 1/genética , Sarcoma Experimental/genética , Sarcoma Experimental/metabolismo , Homeostase do Telômero/genética , Peixe-Zebra/embriologia , Peixe-Zebra/genética , Peixe-Zebra/metabolismo
5.
Mol Genet Genomic Med ; 7(5): e616, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30843352

RESUMO

BACKGROUND: Neurofibromatosis type 1 (NF1) is an autosomal dominant condition caused by inactivating mutations of the NF1 gene. The wide allelic heterogeneity of this condition, with more than 3,000 pathogenic variants reported so far, is paralleled by its high clinical variability, which is observed even within the same family. The definition of genotype-phenotype correlations has been hampered by the complexity of the NF1 gene and, although a few exceptions have been recognized, the clinical course remains unpredictable in most patients. METHODS: Sequencing of NF1 in patients with cafè-au-lait spots identified the c.3112A>G variant. RNA analysis and a minigene assay were employed to investigate splicing. RESULTS: Here we report a novel genotype-phenotype correlation in NF1: the identification of the missense variant NM_000267.3:c.3112A>G p.(Arg1038Gly) in seven individuals from two unrelated families with a mild phenotype. All the patients manifest cafè-au-lait spots without neurofibromas or other NF1-associated complications, and Noonan syndrome features in most cases. The missense variant was not previously reported in available databases, segregates with the phenotype and involves a highly conserved residue. Both a minigene assay and patient's RNA analysis excluded an effect on splicing. CONCLUSION: Our data support the correlation of the p.Arg1038Gly missense substitution with the cutaneous phenotype without neurofibromas or other complications. This finding may have relevant implications for patients and genetic counseling, but also to get insights into the function of neurofibromin.


Assuntos
Mutação de Sentido Incorreto , Neurofibromatose 1/genética , Neurofibromina 1/genética , Fenótipo , Adulto , Idoso , Criança , Feminino , Células HeLa , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , Neurofibromatose 1/patologia , Neurofibromina 1/metabolismo , Linhagem
6.
J Mol Neurosci ; 68(1): 11-18, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30778836

RESUMO

Scoliosis is a common manifestation of neurofibromatosis type 1, causing significant morbidity. The etiology of dystrophic scoliosis in neurofibromatosis type 1 is not fully understood and therapies are lacking. Somatic mutations in NF1 have been shown in tibial pseudarthrosis providing rationale for similar processes in neurofibromatosis type 1-associated dystrophic scoliosis. Spinal samples from surgical procedures with matched peripheral blood of two individuals with neurofibromatosis type 1 and dystrophic scoliosis were obtained and DNA extracted. Next generation sequencing of various spinal sections as well as the germline/blood sample were performed using a RASopathy gene panel (includes the NF1 gene). Variants were compared between the spinal tissue samples and the germline data. In addition, the next generation sequencing allele frequency data were used to detect somatic loss of heterozygosity. All samples had a detected potentially inactivating NF1 germline mutation. Both individuals demonstrated an allelic imbalance inclusive of NF1 in the next generation sequencing data. In addition, for the same two individuals, there was an increase in the % variant reads for the germline mutation in some of the surgical spinal samples corresponding to the allelic imbalance. Contra analysis did not show any deletion in Chromosome 17 next generation sequencing data. Microarray analysis verified somatic copy neutral loss of heterozygosity for these two individuals for the majority of the chromosome 17 q-arm, inclusive of the NF1 gene. These results suggest that the cause of dystrophic scoliosis is multifactorial and that a somatic NF1 mutation contributes to the etiology.


Assuntos
Neurofibromatose 1/genética , Neurofibromina 1/genética , Escoliose/genética , Criança , Feminino , Frequência do Gene , Humanos , Perda de Heterozigosidade , Masculino , Mutação , Neurofibromatose 1/complicações , Neurofibromatose 1/patologia , Escoliose/etiologia , Escoliose/patologia , Coluna Vertebral/metabolismo , Coluna Vertebral/patologia
7.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 36(2): 132-135, 2019 Feb 10.
Artigo em Chinês | MEDLINE | ID: mdl-30703230

RESUMO

OBJECTIVE: To explore the molecular basis for a Chinese family affected with neurofibromatosis type I. METHODS: Peripheral blood samples were collected from the proband and his parents. Potential mutations of NF1 gene were screened by PCR and Sanger sequencing. Pathogenicity of candidate mutations was analyzed using Polyphen-2 and Provean software. RESULTS: Two mutations of the NF1 gene, including c.702G>A (synonymous mutation) and c.1733T>G (missense mutation), were discovered in the proband. Neither mutation was found in his parents and 50 healthy controls. Bioinformatics analysis indicated that the c.1733T>G mutation (p.Leu578Arg) was probably damaging. The affected codon L578 is highly conserved across various species. CONCLUSION: The c.1733T>C mutation of the NF1 gene probably underlies the neurofibromatosis type I in this family.


Assuntos
Genes da Neurofibromatose 1 , Neurofibromatose 1 , Neurofibromina 1/genética , Grupo com Ancestrais do Continente Asiático , Humanos , Mutação , Neurofibromatose 1/genética , Linhagem
8.
Hum Genomics ; 13(1): 4, 2019 01 10.
Artigo em Inglês | MEDLINE | ID: mdl-30630526

RESUMO

BACKGROUND: Germline BRCA1/2 prevalence is relatively low in sporadic triple-negative breast cancer (TNBC). We hypothesized that non-BRCA genes may also have significant germline contribution to Chinese sporadic TNBC, and the somatic mutational landscape of TNBC may vary between ethnic groups. We therefore conducted this study to investigate germline and somatic mutations in 43 cancer susceptibility genes in Chinese sporadic TNBC. PATIENTS AND METHODS: Sixty-six Chinese sporadic TNBC patients were enrolled in this study. Germline and tumor DNA of each patient were subjected to capture-based next-generation sequencing using a 43-gene panel. Standard bioinformatic analysis and variant classification were performed to identify deleterious/likely deleterious germline mutations and somatic mutations. Mutational analysis was conducted to identify significantly mutated genes. RESULTS: Deleterious/likely deleterious germline mutations were identified in 27 (27/66, 40.9%) patients. Among the 27 patients, 9 (9/66, 13.6%) were TP53 carriers, 5 (5/66, 7.6%) were MSH6 carriers, and 5 (5/66, 7.6%) were BRCA1 carriers. Somatic mutations were identified in 64 (64/66, 97.0%) patients. TP53 somatic mutations occurred in most of the patients (45/66, 68.2%) and with highest mean allele frequency (28.1%), while NF1 and POLE were detected to have the highest mutation counts. CONCLUSIONS: Our results supported our hypotheses and suggested great potentials of TP53 and MSH6 as novel candidates for TNBC predisposition genes. The high frequency of somatic NF1 and POLE mutations in this study showed possibilities for clinical benefits from androgen-blockade therapies and immunotherapies in Chinese TNBC patients. Our study indicated necessity of multi-gene testing for TNBC prevention and treatment.


Assuntos
Proteínas de Ligação a DNA/genética , Mutação em Linhagem Germinativa , Neoplasias de Mama Triplo Negativas/genética , Proteína Supressora de Tumor p53/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Grupo com Ancestrais do Continente Asiático/genética , Proteínas Mutadas de Ataxia Telangiectasia/genética , DNA Polimerase II/genética , Feminino , Humanos , Pessoa de Meia-Idade , Neurofibromina 1/genética , Proteínas de Ligação a Poli-ADP-Ribose/genética
9.
Nat Med ; 25(1): 176-187, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30531922

RESUMO

Neurofibromatosis type 1 (NF1) is a common tumor predisposition syndrome in which glioma is one of the prevalent tumors. Gliomagenesis in NF1 results in a heterogeneous spectrum of low- to high-grade neoplasms occurring during the entire lifespan of patients. The pattern of genetic and epigenetic alterations of glioma that develops in NF1 patients and the similarities with sporadic glioma remain unknown. Here, we present the molecular landscape of low- and high-grade gliomas in patients affected by NF1 (NF1-glioma). We found that the predisposing germline mutation of the NF1 gene was frequently converted to homozygosity and the somatic mutational load of NF1-glioma was influenced by age and grade. High-grade tumors harbored genetic alterations of TP53 and CDKN2A, frequent mutations of ATRX associated with Alternative Lengthening of Telomere, and were enriched in genetic alterations of transcription/chromatin regulation and PI3 kinase pathways. Low-grade tumors exhibited fewer mutations that were over-represented in genes of the MAP kinase pathway. Approximately 50% of low-grade NF1-gliomas displayed an immune signature, T lymphocyte infiltrates, and increased neo-antigen load. DNA methylation assigned NF1-glioma to LGm6, a poorly defined Isocitrate Dehydrogenase 1 wild-type subgroup enriched with ATRX mutations. Thus, the profiling of NF1-glioma defined a distinct landscape that recapitulates a subset of sporadic tumors.


Assuntos
Neoplasias Encefálicas/complicações , Neoplasias Encefálicas/genética , Glioma/complicações , Glioma/genética , Neurofibromatose 1/complicações , Neurofibromatose 1/genética , Adolescente , Adulto , Antígenos de Neoplasias/metabolismo , Neoplasias Encefálicas/imunologia , Criança , Pré-Escolar , Estudos de Coortes , Metilação de DNA/genética , Feminino , Mutação em Linhagem Germinativa/genética , Glioma/imunologia , Humanos , Masculino , Pessoa de Meia-Idade , Neurofibromina 1/genética , Reprodutibilidade dos Testes , Linfócitos T/imunologia , Transcriptoma/genética , Proteína Nuclear Ligada ao X/genética , Adulto Jovem
10.
Int J Cancer ; 144(2): 290-296, 2019 01 15.
Artigo em Inglês | MEDLINE | ID: mdl-30230541

RESUMO

NF1 is a tumor suppressor gene that negatively regulates Ras signaling. NF1 deficiency plays an important role in carcinogenesis. To investigate the frequency and clinical significance of NF1 mutation, we examined mutation status of NF1, TP53, LKB1 and RB1 in 704 surgically resected lung adenocarcinomas from East Asian patients using semiconductor-based Ion Torrent sequencing platform. Common driver events, including mutations in EGFR, KRAS, HER2, BRAF, MET, and fusions affecting ALK, RET and ROS1, were also concurrently detected. The correlation between NF1 mutations and clinicomolecular features of patients was further evaluated. Among 704 patients, 42 NF1 mutations were found in 33 patients (33/704, 4.7%), including 14 patients harboring EGFR/NF1 comutations (14/33, 42.4%). Comparing with EGFR-mutant patients, patients harboring NF1 mutations were closely associated with solid component subtype (p = 0.028). Comparing with KRAS mutations, NF1 mutations were found more common in female and never smokers (p = 0.003 and p = 0.004, respectively). Kaplan-Meier survival analysis revealed that patients harboring NF1 mutation had similar disease-free survival (DFS) and overall survival (OS) with patients with KRAS mutation. Although frequently overlapped with EGFR mutation, patients harboring NF1 mutation had significantly shorter DFS (p = 0.019) and OS (p = 0.004) than patients with EGFR mutation. During follow-up, one female patient with EGFR exon 19 deletion and NF1 Q1815X comutation showed poor response to EGFR TKIs (Gefitinib and Osimertinib) after disease relapse. In conclusion, NF1 mutations define a unique molecular and clinicopathologic subtype of lung adenocarcinoma. Examination of NF1 mutation may contribute to molecular subtyping and therapeutic intervention of lung adenocarcinoma.


Assuntos
Adenocarcinoma de Pulmão/genética , Neoplasias Pulmonares/genética , Neurofibromina 1/genética , Adenocarcinoma de Pulmão/mortalidade , Adulto , Idoso , Idoso de 80 Anos ou mais , Grupo com Ancestrais do Continente Asiático/genética , Análise Mutacional de DNA , Feminino , Humanos , Estimativa de Kaplan-Meier , Neoplasias Pulmonares/mortalidade , Masculino , Pessoa de Meia-Idade , Mutação
11.
PLoS One ; 13(12): e0208835, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30571760

RESUMO

The fertility of men with neurofibromatosis 1 (NF1) is reduced. Despite this observation, gonadal function has not been examined in patients with NF1. In order to assess the role of reduced neurofibromin in the testes, we examined testicular morphology and function in an Nf1+/- mouse model. We found that although Nf1+/- male mice are able to reproduce, they have significantly fewer pups per litter than Nf1+/+ control males. Reduced fertility in Nf1+/- male mice is associated with disorganization of the seminiferous epithelium, with exfoliation of germ cells and immature spermatids into the tubule lumen. Morphometric analysis shows that these alterations are associated with decreased Leydig cell numbers and increased spermatid cell numbers. We hypothesized that hyper-activation of Ras in Nf1+/- males affects ectoplasmic specialization, a Sertoli-spermatid adherens junction involved in spermiation. Consistent with this idea, we found increased expression of phosphorylated ERK, a downstream effector of Ras that has been shown to alter ectoplasmic specialization, in Nf1+/- males in comparison to control Nf1+/+ littermates. These data demonstrate that neurofibromin haploinsufficiency impairs spermatogenesis and fertility in a mouse model of NF1.


Assuntos
Fertilidade , Haploinsuficiência , Neurofibromatose 1/metabolismo , Neurofibromina 1/metabolismo , Espermatogênese , Animais , Modelos Animais de Doenças , MAP Quinases Reguladas por Sinal Extracelular/genética , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Humanos , Masculino , Camundongos , Camundongos Mutantes , Neurofibromatose 1/genética , Neurofibromatose 1/patologia , Neurofibromina 1/genética , Epitélio Seminífero/metabolismo , Epitélio Seminífero/patologia , Espermátides/metabolismo , Espermátides/patologia , Proteínas ras/genética , Proteínas ras/metabolismo
12.
Anticancer Res ; 38(8): 4897-4900, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30061266

RESUMO

This case report presents the first known case of a brainstem glioblastoma multiforme (GBM) in a patient with neurofibromatosis type 1 (NF1). While research has proposed that larger germ-line mutations in NF1 may be the driving factor that predisposes patients with NF1 to high-grade astrocytomas, this patient had a nonsense mutation in the NF1 gene, suggesting a variant tumorigenesis. Limited data on targeted immunotherapy for NF1 patients with a GBM have been reported and more data are required before targeted therapies could be proven as second-line treatment options.


Assuntos
Astrocitoma/genética , Neoplasias do Tronco Encefálico/genética , Glioblastoma/genética , Neurofibromina 1/genética , Adulto , Antineoplásicos Alquilantes/uso terapêutico , Astrocitoma/patologia , Astrocitoma/terapia , Tronco Encefálico/patologia , Neoplasias do Tronco Encefálico/patologia , Neoplasias do Tronco Encefálico/terapia , Quimiorradioterapia/métodos , Códon sem Sentido/genética , Dacarbazina/análogos & derivados , Dacarbazina/uso terapêutico , Glioblastoma/patologia , Glioblastoma/terapia , Humanos , Masculino , Temozolomida , Adulto Jovem
13.
J Mol Neurosci ; 65(4): 557-563, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30046999

RESUMO

Neurofibromatosis type 1 (NF1) is an autosomal dominant disorder primarily characterized by multiple café-au-lait macules, peripheral neurofibromas, skinfold freckling, and Lisch nodules. The causative genetic factor is the neurofibromin 1 gene (NF1), which encodes a Ras GTPase-activating protein called neurofibromin. NF1 variants may lead to loss of neurofibromin function and activation of downstream cell growth. This study aims to discover the disease-causing variants responsible for NF1 in two Han Chinese families by using exome sequencing combined with Sanger sequencing. A recurrent missense variant c.269T>C (p.Leu90Pro) and a novel nonsense variant c.2993dupA (p.Tyr998*) in the NF1 gene were identified. These variants co-segregated with the disorder in the pedigrees and were absent in the normal controls. The results broaden the NF1 mutation spectrum responsible for NF1. This may be helpful in genetic counseling, clinical management, and gene-targeted therapies for NF1.


Assuntos
Mutação de Sentido Incorreto , Neurofibromatose 1/genética , Neurofibromina 1/genética , Adulto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Neurofibromatose 1/patologia , Linhagem , Polimorfismo de Nucleotídeo Único
14.
Pediatr Dermatol ; 35(5): e268-e271, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-29968256

RESUMO

A few genotype-phenotype correlations have been described in type 1 neurofibromatosis. One deletion, p.Met992del, seems to be responsible for a mild form of the condition, in which there is absence of externally visible neurofibromas. We report a mother and a son with this mutation.


Assuntos
Neurofibromatose 1/genética , Neurofibromina 1/genética , Adolescente , Adulto , Feminino , Estudos de Associação Genética , Genótipo , Humanos , Masculino , Mutação , Neurofibromatose 1/diagnóstico , Fenótipo
15.
J Clin Neurosci ; 53: 62-68, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-29680440

RESUMO

Neurofibromatosis type 1 (NF1) is a rare autosomal-dominant disorder caused by inactivation of NF1 tumour suppressor gene, which associates in the development of peripheral nerve tumours. NF1 is an important regulator of GAP and RAS proteins, mutations in NF1 results in the impairment in this function causing specific osseous lesions in any organ of the human body. In the present study, we investigated the clinical characteristics and NF1 gene mutation analysis of 3 unrelated Indian families with neurofibromatosis type 1. All the exons of NF1 gene was PCR amplified and sequenced. The structural and functional analysis was performed using molecular modelling tools. The sequence analysis of NF1 gene revealed; in family I five novel mutations p.R103K, p.D105N, p.M108I, p.L114M, p.E116X and p.A131S was observed in exon 4. In family II one missense p.A131S mutation and one silent p.L234L mutation was detected in exon 4. While, in family III one novel frame shift p.E225Rfs∗6 mutation was identified in exon 7 resulting in the truncated protein formation. Further, the structural analysis revealed all these mutations fall in the protein kinase C domain of NF1 gene causing loss of functional GRD and CSRD domains. In conclusion, novel mutations in the exon 4 and exon 7 of NF1 gene in these families correlating with genotype-phenotype characters explaining the neurofibromatosis type 1 and peripheral nerve sheath tumours condition in these patients.


Assuntos
Genes da Neurofibromatose 1 , Neoplasias da Bainha Neural/genética , Neurofibromatose 1/genética , Adolescente , Adulto , Idoso , Grupo com Ancestrais do Continente Asiático/genética , Análise Mutacional de DNA , Éxons , Feminino , Humanos , Índia , Masculino , Pessoa de Meia-Idade , Mutação de Sentido Incorreto , Neurofibromina 1/genética , Linhagem
16.
BMC Cancer ; 18(1): 479, 2018 04 27.
Artigo em Inglês | MEDLINE | ID: mdl-29703253

RESUMO

BACKGROUND: Cetuximab, an anti-EGFR monoclonal antibody, is used in combination with chemotherapy in clinic to enhance the outcome in metastatic colorectal cancer (mCRC) patients with only ~ 20% response rate. To date only activating mutations in KRAS and NRAS have been identified as poor prognosis biomarkers in cetuximab-based treatment, which makes an urgent need for identification of novel prognosis biomarkers to precisely predict patients' response in order to maximize the benefit. METHODS: In this study, we analysed the mutation profiles of 33 Chinese mCRC patients using comprehensive next-generation sequencing (NGS) targeting 416 cancer-relevant genes before cetuximab treatment. Upon receiving cetuximab-based therapy, patients were evaluated for drug response, and the progression-free survival (PFS) was monitored. The association of specific genetic alterations and cetuximab efficacy was analyzed. RESULTS: Patients carrying SMAD4 mutations (SMAD4mut, n = 8) or NF1 mutations (NF1mut, n = 4) had significantly shorter PFS comparing to those carrying wildtype SMAD4 (SMAD4wt, n = 25) (P = 0.0081) or wildtype NF1 (NF1wt, n = 29) (P = 0.0028), respectively. None of the SMAD4mut or NF1mut patients showed response to cetuximab when assessed at 12-week post-treatment. Interestingly, two patients carrying both SMAD4mut and NF1mut showed the shortest PFS among all the patients. CONCLUSIONS: Our results demonstrated that SMAD4 and NF1 mutations can serve as potential biomarkers for poor prognosis to cetuximab-based therapy in Chinese mCRC patients.


Assuntos
Neoplasias Colorretais/genética , Neoplasias Colorretais/mortalidade , Mutação , Neurofibromina 1/genética , Proteína Smad4/genética , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Biomarcadores , Cetuximab/administração & dosagem , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/patologia , Análise Mutacional de DNA , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Estadiamento de Neoplasias , Prognóstico , Proteínas Proto-Oncogênicas p21(ras)/genética
17.
Cancer Sci ; 109(5): 1513-1523, 2018 May.
Artigo em Inglês | MEDLINE | ID: mdl-29575648

RESUMO

Glioma is the most common form of malignant brain cancer in adults. The Sleeping Beauty (SB) transposon-based glioma mouse model allows for effective in vivo analysis of candidate genes. In the present study, we developed a transposon vector that encodes the triple combination of platelet-derived growth factor subunit A (PDGFA), and shRNAs against Nf1 and Trp53 (shNf1/shp53). Initiation and progression of glioma in the brain were monitored by expression of a fluorescent protein. Transduction of the vector into neural progenitor and stem cells (NPC) in the subventricular zone (SVZ) of the neonatal brain induced proliferation of oligodendrocyte precursor cells, and promoted formation of highly penetrant malignant gliomas within 2-4 months. Cells isolated from the tumors were capable of forming secondary tumors. Two transposon vectors, encoding either PDGFA or shNf1/shp53 were co-electroporated into NPC. Cells expressing PDGFA or shNf1/shp53 were labeled with unique fluorescent proteins allowing visualization of the spatial distribution of cells with different genetic alterations within the same tumor. Tumor cells located at the center of tumors expressed PDGFA at higher levels than those located at the periphery, indicating that intratumoral heterogeneity in PDGFA expression levels spontaneously developed within the same tumor. Tumor cells comprising the palisading necrosis strongly expressed PDGFA, suggesting that PDGFA signaling is involved in hypoxic responses in glioma. The transposon vectors developed are compatible with any genetically engineered mouse model, providing a useful tool for the functional analysis of candidate genes in glioma.


Assuntos
Neoplasias Encefálicas/etiologia , Elementos de DNA Transponíveis/genética , Modelos Animais de Doenças , Glioma/etiologia , Animais , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patologia , Hipóxia Celular , Proliferação de Células , Glioma/genética , Glioma/patologia , Camundongos , Camundongos Endogâmicos ICR , Células NIH 3T3 , Neurofibromina 1/genética , Fator de Crescimento Derivado de Plaquetas/genética , Fator de Crescimento Derivado de Plaquetas/fisiologia , Transdução de Sinais , Proteína Supressora de Tumor p53/genética
18.
Glia ; 66(5): 999-1015, 2018 05.
Artigo em Inglês | MEDLINE | ID: mdl-29392777

RESUMO

Malignant glioma is one of the deadliest types of cancer. Understanding how the cell of origin progressively evolves toward malignancy in greater detail could provide mechanistic insights and lead to novel concepts for tumor prevention and therapy. Previously we have identified oligodendrocyte precursor cell (OPC) as the cell of origin for glioma following the concurrent deletion of p53 and NF1 using a mouse genetic mosaic system that can reveal mutant cells prior to malignancy. In the current study, we set out to deconstruct the gliomagenic process in two aspects. First, we determined how the individual loss of p53 or NF1 contributes to aberrant behaviors of OPCs. Second, we determined how signaling aberrations in OPCs progressively change from pre-malignant to transformed stages. We found that while the deletion of NF1 leads to mutant OPC expansion through increased proliferation and decreased differentiation, the deletion of p53 impairs OPC senescence. Signaling analysis showed that, while PI3K and MEK pathways go through stepwise over-activation, mTOR signaling remains at the basal level in pre-transforming mutant OPCs but is abruptly up-regulated in tumor OPCs. Finally, inhibiting mTOR via pharmacological or genetic methods, led to a significant blockade of gliomagenesis but had little impact on pre-transforming mutant OPCs, suggesting that mTOR is necessary for final transformation but not early progression. In summary, our findings show that deconstructing the tumorigenic process reveals specific aberrations caused by individual gene mutations and altered signaling events at precise timing during tumor progression, which may shed light on tumor-prevention strategies.


Assuntos
Neoplasias Encefálicas/metabolismo , Glioma/metabolismo , Neurofibromina 1/deficiência , Proteína Supressora de Tumor p53/deficiência , Animais , Encéfalo/metabolismo , Encéfalo/patologia , Neoplasias Encefálicas/patologia , Diferenciação Celular/fisiologia , Proliferação de Células/fisiologia , Células Cultivadas , Senescência Celular/fisiologia , Modelos Animais de Doenças , Progressão da Doença , Glioma/patologia , Células HEK293 , Humanos , Camundongos Transgênicos , Células-Tronco Neoplásicas/metabolismo , Células-Tronco Neoplásicas/patologia , Células-Tronco Neurais/metabolismo , Células-Tronco Neurais/patologia , Neurofibromina 1/genética , Oligodendroglia/metabolismo , Oligodendroglia/patologia , Transdução de Sinais , Proteína Supressora de Tumor p53/genética
19.
Acta Neuropathol Commun ; 6(1): 12, 2018 02 20.
Artigo em Inglês | MEDLINE | ID: mdl-29458417

RESUMO

Mechanisms underlying sex differences in cancer incidence are not defined but likely involve dimorphism (s) in tumor suppressor function at the cellular and organismal levels. As an example, sexual dimorphism in retinoblastoma protein (Rb) activity was shown to block transformation of female, but not male, murine astrocytes in which neurofibromin and p53 function was abrogated (GBM astrocytes). Correlated sex differences in gene expression in the murine GBM astrocytes were found to be highly concordant with sex differences in gene expression in male and female GBM patients, including in the expression of components of the Rb and p53 pathways. To define the basis of this phenomenon, we examined the functions of the cyclin dependent kinase (CDK) inhibitors, p16, p21 and p27 in murine GBM astrocytes under conditions that promote Rb-dependent growth arrest. We found that upon serum deprivation or etoposide-induced DNA damage, female, but not male GBM astrocytes, respond with increased p16 and p21 activity, and cell cycle arrest. In contrast, male GBM astrocytes continue to proliferate, accumulate chromosomal aberrations, exhibit enhanced clonogenic cell activity and in vivo tumorigenesis; all manifestations of broad sex differences in cell cycle regulation and DNA repair. Differences in tumorigenesis disappeared when female GBM astrocytes are also rendered null for p16 and p21. These data elucidate mechanisms underlying sex differences in cancer incidence and demonstrate sex-specific effects of cytotoxic and targeted therapeutics. This has critical implications for lab and clinical research.


Assuntos
Astrócitos/metabolismo , Transformação Celular Neoplásica/genética , Inibidor p16 de Quinase Dependente de Ciclina/metabolismo , Inibidor de Quinase Dependente de Ciclina p21/metabolismo , Caracteres Sexuais , Animais , Astrócitos/efeitos dos fármacos , Ciclo Celular/efeitos dos fármacos , Ciclo Celular/genética , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/genética , Transformação Celular Neoplásica/efeitos dos fármacos , Transformação Celular Neoplásica/metabolismo , Meios de Cultura Livres de Soro/farmacologia , Inibidor p16 de Quinase Dependente de Ciclina/genética , Inibidor de Quinase Dependente de Ciclina p21/genética , Inibidor de Quinase Dependente de Ciclina p27/genética , Inibidor de Quinase Dependente de Ciclina p27/metabolismo , Relação Dose-Resposta a Droga , Embrião de Mamíferos , Etoposídeo/farmacologia , Feminino , Citometria de Fluxo , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/genética , Proteína Glial Fibrilar Ácida/metabolismo , Glioblastoma/genética , Glioblastoma/metabolismo , Glioblastoma/fisiopatologia , Cariotipagem , Masculino , Camundongos , Neurofibromina 1/deficiência , Neurofibromina 1/genética , Fosforilação , Piperazinas/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Piridinas/farmacologia , RNA Mensageiro/metabolismo , Proteína do Retinoblastoma/metabolismo , Soro/metabolismo , Transfecção , Células Tumorais Cultivadas
20.
Handb Clin Neurol ; 148: 799-811, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29478615

RESUMO

The neurofibromatoses are a group of three heterogeneous disorders that include neurofibromatosis type 1 (NF1), neurofibromatosis type 2 (NF2), and schwannomatosis. NF1 is the most common of these three conditions, and represents one of the most frequently diagnosed cancer predisposition disorders involving the nervous system. While NF1 primarily affects the central and peripheral nervous system, multisystem involvement is the rule, with dermatologic, cardiovascular, gastrointestinal, and orthopedic affectation often reported. Importantly, NF1 is a disorder of heterogeneity, such that affected individuals can be variably affected, even within the same family. This heterogeneity also presents significant challenges to the actualization of effective treatments. However, recent studies aimed at understanding the role of the NF1 protein (neurofibromin) as a tumor suppressor have revealed that this profound level of clinical heterogeneity may reflect tissue and region-specific effects, sexually dimorphic influences, and the contribution of germline genetics and genomics. With the availability of accurate preclinical Nf1 small-animal models, human induced pluripotent stem cells, and an efficient clinical trials consortium, we are now uniquely positioned to identify and efficiently evaluate promising therapies for NF1-related medical problems.


Assuntos
Neurofibromatose 1/metabolismo , Neurofibromina 1/metabolismo , Animais , Modelos Animais de Doenças , Genes Supressores de Tumor , Humanos , Sistema Nervoso/diagnóstico por imagem , Sistema Nervoso/patologia , Neurofibromatose 1/genética , Neurofibromatose 1/fisiopatologia , Neurofibromatose 1/terapia , Neurofibromina 1/genética , Neuroimagem
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