Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 858
Filtrar
1.
Virchows Arch ; 476(1): 81-96, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31686193

RESUMO

Epithelioid cell features mimicking carcinomas characterize a variety of histogenetically, phenotypically, and molecularly distinct subsets of mesenchymal neoplasms. In a pathogenetic sense, epithelioid soft tissue tumors basically fall into three main genetic categories: (1) switch/sucrose non-fermenting (SWI/SNF) complex-deficient tumors (with epithelioid sarcoma as their prototype); (2) epithelioid neoplasms driven by specific rare gene fusions (such as sclerosing epithelioid fibrosarcoma with EWSR1 fusions and GLI1-related malignant epithelioid soft tissue neoplasms); and (3) a heterogeneous group encompassing epithelioid variants of diverse other entities. Notably, lesions in the first and third groups may display variable, occasionally prominent, rhabdoid cell morphology, thus further complicating their differential diagnosis. This review summarizes the main clinicopathological, phenotypic, and genotypic features of these diseases and discusses their pertinent differential diagnostic considerations.


Assuntos
Células Epitelioides/patologia , Neoplasias de Tecidos Moles/patologia , Proteínas Cromossômicas não Histona/fisiologia , Diagnóstico Diferencial , Humanos , Imuno-Histoquímica , Proteínas de Neoplasias/genética , Neoplasias da Bainha Neural/diagnóstico , Neoplasias da Bainha Neural/patologia , Proteínas Nucleares/genética , Tumor Rabdoide/diagnóstico , Tumor Rabdoide/patologia , Neoplasias de Tecidos Moles/diagnóstico , Fatores de Transcrição/fisiologia
2.
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
3.
Folia Neuropathol ; 57(3): 295-300, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31588716

RESUMO

We report a case of atypical teratoid/rhabdoid tumour (AT/RT) in an adult patient in the deep grey matter with extension into the lateral ventricle. To our knowledge, this is the first example of AT/RT involving the lateral ventricle in an adult. The patient presented with headache and confusion, and subsequently required emergent surgery. His postoperative course was complicated by hemorrhage into the surgical site. The location and vascularity of the tumour affected the extent of resection achieved and likely contributed to postoperative complications. We discuss radiological features of AT/RT in adults and implications for investigations and management.


Assuntos
Neoplasias do Ventrículo Cerebral/patologia , Tumor Rabdoide/patologia , Teratoma/patologia , Adulto , Humanos , Masculino
4.
Pathologe ; 40(6): 600-608, 2019 Nov.
Artigo em Alemão | MEDLINE | ID: mdl-31338565

RESUMO

Pediatric kidney tumors are rare and account for about 6% of all childhood malignancies. By far the most common tumors are nephroblastomas. This review presents rare childhood renal tumors. Mesoblastic nephroma, as tumors of the low risk group, as well as the clear-cell sarcomas of the kidney and malignant rhabdoid tumors, as tumors of the high-risk group, and the so-called anaplastic sarcomas of the kidney will be discussed.Due to the significantly divergent therapy, a correct diagnosis is important. Due to the often overlapping morphology, pathologic diagnosis is often difficult. In addition to the typical morphologic features, the specific immunohistochemical aspects as well as the known molecular changes will be presented.


Assuntos
Neoplasias Renais , Humanos , Neoplasias Renais/diagnóstico , Neoplasias Renais/genética , Neoplasias Renais/patologia , Nefroma Mesoblástico/diagnóstico , Nefroma Mesoblástico/genética , Nefroma Mesoblástico/patologia , Tumor Rabdoide/diagnóstico , Tumor Rabdoide/genética , Tumor Rabdoide/patologia , Sarcoma/diagnóstico , Sarcoma/genética , Sarcoma/patologia , Tumor de Wilms/diagnóstico , Tumor de Wilms/genética , Tumor de Wilms/patologia
6.
Acta Cytol ; 63(5): 438-444, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31230044

RESUMO

OBJECTIVE: Evidence shows that the switch/sucrose nonfermenting chromatin remodeling complex plays a critical role in DNA repair, cancer progression and dedifferentiation. BRG1 is one of its key catalytic subunits. While the loss of BRG1 expression by immunocytochemistry has been identified in a subset of malignancies arising in various sites with undifferentiated/rhabdoid morphology and poor prognosis, the underlying basis for its loss is unclear. METHODS: A retrospective search was conducted in our cytopathology archive for undifferentiated malignant tumors with rhabdoid phenotype and BRG1 loss. Clinical information was obtained from electronic medical records. Next-generation sequencing was performed following macro-dissection of paraffin-embedded cellblock tissue. RESULTS: Three cases were identified; all presented with widely metastatic disease with no previously diagnosed primary malignancy, and subsequently died within 6 months of initial presentation. Cytologically, the aspirates showed dyshesive and undifferentiated cells with rhabdoid features. Extensive immunocytochemical workup demonstrated immunoreactivity with vimentin only and could not establish a specific lineage. BRG1 expression was absent, while INI1 expression was retained. Two cases harbored deleterious mutations in BRG1/SMARCA4. Pathogenic mutations in TP53 were identified in all tumors. CONCLUSIONS: BRG1 deficiency reflects underlying mutation in SMARCA4 gene in some but not all cases, suggesting that additional mechanisms may be causing BRG1 silencing. Pathogenic mutations in TP53 in all tumors are consistent with their highly aggressive nature. Recognizing the cytomorphology of this group of neoplasms and confirming their BRG1-deficient status by immunocytochemistry not only has prognostic implications, but may also impart potentially therapeutic value in the near future.


Assuntos
Biomarcadores Tumorais/genética , Diferenciação Celular , DNA Helicases/genética , Neoplasias Pulmonares/genética , Mutação , Proteínas Nucleares/genética , Tumor Rabdoide/genética , Neoplasias da Glândula Submandibular/genética , Fatores de Transcrição/genética , Idoso , Biomarcadores Tumorais/deficiência , Biópsia por Agulha Fina , DNA Helicases/deficiência , Análise Mutacional de DNA , Evolução Fatal , Feminino , Predisposição Genética para Doença , Humanos , Imuno-Histoquímica , Neoplasias Pulmonares/enzimologia , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/terapia , Masculino , Pessoa de Meia-Idade , Proteínas Nucleares/deficiência , Fenótipo , Valor Preditivo dos Testes , Estudos Retrospectivos , Tumor Rabdoide/enzimologia , Tumor Rabdoide/patologia , Tumor Rabdoide/terapia , Neoplasias da Glândula Submandibular/enzimologia , Neoplasias da Glândula Submandibular/patologia , Neoplasias da Glândula Submandibular/terapia , Fatores de Transcrição/deficiência , Resultado do Tratamento , Proteína Supressora de Tumor p53/genética
7.
Nat Commun ; 10(1): 2014, 2019 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-31043611

RESUMO

SMARCB1 encodes the SNF5 subunit of the SWI/SNF chromatin remodeler. SNF5 also interacts with the oncoprotein transcription factor MYC and is proposed to stimulate MYC activity. The concept that SNF5 is a coactivator for MYC, however, is at odds with its role as a tumor-suppressor, and with observations that loss of SNF5 leads to activation of MYC target genes. Here, we reexamine the relationship between MYC and SNF5 using biochemical and genome-wide approaches. We show that SNF5 inhibits the DNA-binding ability of MYC and impedes target gene recognition by MYC in cells. We further show that MYC regulation by SNF5 is separable from its role in chromatin remodeling, and that reintroduction of SNF5 into SMARCB1-null cells mimics the primary transcriptional effects of MYC inhibition. These observations reveal that SNF5 antagonizes MYC and provide a mechanism to explain how loss of SNF5 can drive malignancy.


Assuntos
Genes Supressores de Tumor , Proteínas Proto-Oncogênicas c-myc/genética , Tumor Rabdoide/genética , Proteína SMARCB1/metabolismo , Linhagem Celular Tumoral , Cromatina/metabolismo , Montagem e Desmontagem da Cromatina/genética , Regulação Neoplásica da Expressão Gênica , Células HEK293 , Humanos , Proteínas Proto-Oncogênicas c-myc/metabolismo , Tumor Rabdoide/patologia , Proteína SMARCB1/genética
8.
World Neurosurg ; 129: e264-e272, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31128308

RESUMO

BACKGROUND: We evaluated the factors influencing overall survival (OS) and event-free survival (EFS) in children with atypical teratoid/rhabdoid tumors (ATRTs). METHODS: We performed a retrospective study of children aged <16 years and tumor histological diagnosis of ATRT. Univariate and multivariate analyses were performed to determine the effect of individual and interdependent variables and survival. RESULTS: A total of 34 children had undergone surgery, with a male/female ratio of 1.8:1. On univariate analysis, the factors with statistically significant influence on OS and EFS were the extent of resection (P = 0.012 and P = 0.015, respectively), adjuvant therapy (P ≤ 0.001 and P = 0.001, respectively), and rhabdoid cell percentage (P = 0.004 and P = 0.005, respectively). On survival analysis, the median OS and EFS were better for those who had completed adjuvant therapy versus those who had not received adjuvant therapy (OS, 22.7 months vs. 3.5 months; EFS, 10.9 months vs. 3.5 months), those who had undergone gross total resection versus those who had undergone partial decompression (OS, 10.9 months vs. 2 months; EFS, 8.9 months vs. 2.5 months), and those with <50% rhabdoid cells in the biopsy specimen versus those with >50% rhabdoid cells (OS, 10.9 months vs. 3.7 months; EFS, 8.9 months vs. 3.5 months). On multivariate analysis, only the extent of resection and adjuvant therapy status had a significant influence on OS and EFS. CONCLUSION: Achieving gross total resection should be the aim of surgery, depending on the tumor location, and these children should undergo upfront adjuvant treatment.


Assuntos
Neoplasias do Sistema Nervoso Central/mortalidade , Tumor Rabdoide/mortalidade , Teratoma/mortalidade , Adolescente , Neoplasias do Sistema Nervoso Central/patologia , Neoplasias do Sistema Nervoso Central/cirurgia , Quimiorradioterapia Adjuvante , Criança , Pré-Escolar , Terapia Combinada , Países em Desenvolvimento , Intervalo Livre de Doença , Feminino , Humanos , Lactente , Masculino , Estudos Retrospectivos , Tumor Rabdoide/patologia , Tumor Rabdoide/cirurgia , Fatores de Risco , Análise de Sobrevida , Taxa de Sobrevida , Teratoma/patologia , Teratoma/cirurgia
9.
J Vet Med Sci ; 81(7): 975-979, 2019 Jul 11.
Artigo em Inglês | MEDLINE | ID: mdl-31092741

RESUMO

A 21-year-old male masked palm civet died after 2 months of continuous abdominal distention and poor appetite. Grossly, both musk glands were markedly swelled. Microscopically, round, polygonal and spindle neoplastic cells proliferated diffusely in the right musk gland and a metastatic focus was observed in the lung. The neoplastic cells had abundant cytoplasm with faintly eosinophilic inclusions that ultrastructurally corresponded to whorl aggregates of intermediate filaments. Immunohistochemically, these cells were positive for vimentin, cytokeratins and glial fibrillary acidic protein and negative for desmin. Based on these findings, the tumor was diagnosed as malignant rhabdoid tumor. Papillary adenoma was seen in the opposite musk gland. T-cell lymphoma of the lymph nodes, small intestine and liver was considered as the cause of death.


Assuntos
Linfoma de Células T/veterinária , Tumor Rabdoide/veterinária , Glândulas Odoríferas , Viverridae , Adenoma/complicações , Adenoma/veterinária , Animais , Linfoma de Células T/complicações , Linfoma de Células T/patologia , Masculino , Tumor Rabdoide/complicações , Tumor Rabdoide/patologia , Glândulas Odoríferas/patologia
10.
Nat Commun ; 10(1): 1881, 2019 04 23.
Artigo em Inglês | MEDLINE | ID: mdl-31015438

RESUMO

Bromodomain-containing protein 9 (BRD9) is a recently identified subunit of SWI/SNF(BAF) chromatin remodeling complexes, yet its function is poorly understood. Here, using a genome-wide CRISPR-Cas9 screen, we show that BRD9 is a specific vulnerability in pediatric malignant rhabdoid tumors (RTs), which are driven by inactivation of the SMARCB1 subunit of SWI/SNF. We find that BRD9 exists in a unique SWI/SNF sub-complex that lacks SMARCB1, which has been considered a core subunit. While SMARCB1-containing SWI/SNF complexes are bound preferentially at enhancers, we show that BRD9-containing complexes exist at both promoters and enhancers. Mechanistically, we show that SMARCB1 loss causes increased BRD9 incorporation into SWI/SNF thus providing insight into BRD9 vulnerability in RTs. Underlying the dependency, while its bromodomain is dispensable, the DUF3512 domain of BRD9 is essential for SWI/SNF integrity in the absence of SMARCB1. Collectively, our results reveal a BRD9-containing SWI/SNF subcomplex is required for the survival of SMARCB1-mutant RTs.


Assuntos
Montagem e Desmontagem da Cromatina , Tumor Rabdoide/genética , Proteína SMARCB1/genética , Fatores de Transcrição/metabolismo , Sistemas CRISPR-Cas/genética , Linhagem Celular Tumoral , Elementos Facilitadores Genéticos/genética , Técnicas de Silenciamento de Genes , Técnicas de Inativação de Genes , Humanos , Mutação , Regiões Promotoras Genéticas/genética , Domínios Proteicos/efeitos dos fármacos , RNA Interferente Pequeno/metabolismo , Tumor Rabdoide/patologia , Proteína SMARCB1/metabolismo , Fatores de Transcrição/antagonistas & inibidores , Fatores de Transcrição/genética
11.
Neuroradiol J ; 32(4): 259-266, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31017042

RESUMO

BACKGROUND: Magnetic resonance imaging (MRI) with a gadolinium injection is currently used in the follow-up of children in remission of cerebral tumors (CTs). Intracerebral gadolinium deposition has been recently reported with unknown risks. The aim of this study was to evaluate the sensitivity of unenhanced brain MRI (U-MRI) in detection of tumor recurrence. METHODS AND MATERIALS: A set of 58 U-MRIs of children in remission was retrospectively evaluated by three seniors (a neuroradiologist, a pediatric and a general radiologist) and one junior to look for any recurrence. Clinical, tumoral and imaging data were collected. The final diagnosis was anatomopathological when available, or the clinicoradiological evolution. Sensitivity, specificity, predictive values and interobserver agreement were calculated. A Fisher test and Fleiss kappa coefficient were performed. RESULTS: For the seniors, the U-MRI had a sensitivity of 81% (95% confidence interval (CI): 0.56-0.90), and a negative predictive value (NPV) of 82% (95% CI: 0.63-0.94). The U-MRI sensitivity, regardless of the observer, was not significantly different from the contrast-enhanced MRI sensitivity (86%) according to a Fisher test (p > 0.05). No significant difference in sensitivity within the subgroups was found. The interobserver agreement of seniors was good (κ = 0.68). CONCLUSION: U-MRI brain was suboptimal for 80% of patients. Three-dimensional millimetric, fluid-attenuated inversion recovery, and diffusion would constitute helpful sequences in follow-up. Further specific studies depending on each tumor type are still required to determine whether a potential abstention of gadolinium intravenous injection should be discussed for children.


Assuntos
Neoplasias Encefálicas/patologia , Recidiva Local de Neoplasia/patologia , Criança , Pré-Escolar , Meios de Contraste , Ependimoma/patologia , Feminino , Humanos , Lactente , Imagem por Ressonância Magnética/métodos , Masculino , Meduloblastoma/patologia , Gradação de Tumores , Variações Dependentes do Observador , Estudos Retrospectivos , Tumor Rabdoide/patologia , Sensibilidade e Especificidade
12.
Am J Surg Pathol ; 43(6): 810-818, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30829727

RESUMO

Genetic aberrations among uterine epithelioid leiomyosarcomas are unknown. Following identification of an index case with NR4A3-PGR fusion demonstrating monomorphic morphologic features, we interrogated additional uterine tumors demonstrating similar histology and sought to describe the morphologic and immunohistochemical characteristics of PGR-rearranged sarcomas. Targeted next-generation RNA sequencing was performed on RNA extracted from formalin-fixed paraffin-embedded tissue of the index case. Fluorescence in situ hybridization using custom probes flanking PGR and NR4A3 genes was applied to 17 epithelioid leiomyosarcomas, 6 endometrial stromal tumors, and 3 perivascular epithelioid cell tumors. NR4A3-PGR fusion (n=4) and PGR rearrangement (n=2) were detected in 6 (35%) epithelioid leiomyosarcomas. Median patient age was 45 years, and all presented with FIGO stage I or II tumors, 2 being alive with disease at 75 and 180 months. All tumors were centered in the cervical stroma or myometrium and consisted of cells with abundant eosinophilic cytoplasm (epithelioid), including many displaying dense intracytoplasmic inclusions (rhabdoid). Myxoid matrix and hydropic change imparted a microcystic growth pattern in 4 tumors. Five also showed a minor spindle cell component which was low-grade in 3, consisting of bland spindle cells with low mitotic activity. High-grade spindle cell morphology was seen in 2 tumors, exhibiting a storiform pattern of atypical spindle cells associated with brisk mitotic activity. Desmin, estrogen receptor, and progesterone receptor were positive in all 6 tumors, while CD10 and HMB45 were negative. PGR rearrangements define a genetic subset of epithelioid leiomyosarcomas with often biphasic morphology consisting of epithelioid and rhabdoid as well as spindle cell components.


Assuntos
Biomarcadores Tumorais/genética , Proteínas de Ligação a DNA/genética , Fusão Gênica , Rearranjo Gênico , Leiomiossarcoma/genética , Neoplasias de Células Epitelioides Perivasculares/genética , Receptores de Progesterona/genética , Receptores de Esteroides/genética , Receptores dos Hormônios Tireóideos/genética , Tumor Rabdoide/genética , Sarcoma do Estroma Endometrial/genética , Neoplasias Uterinas/genética , Adulto , Biomarcadores Tumorais/análise , Feminino , Predisposição Genética para Doença , Humanos , Hibridização in Situ Fluorescente , Leiomiossarcoma/química , Leiomiossarcoma/patologia , Leiomiossarcoma/cirurgia , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Neoplasias de Células Epitelioides Perivasculares/química , Neoplasias de Células Epitelioides Perivasculares/patologia , Neoplasias de Células Epitelioides Perivasculares/cirurgia , Fenótipo , Estudos Retrospectivos , Tumor Rabdoide/química , Tumor Rabdoide/patologia , Tumor Rabdoide/cirurgia , Sarcoma do Estroma Endometrial/química , Sarcoma do Estroma Endometrial/patologia , Sarcoma do Estroma Endometrial/cirurgia , Análise de Sequência de RNA , Neoplasias Uterinas/química , Neoplasias Uterinas/patologia , Neoplasias Uterinas/cirurgia
13.
Virchows Arch ; 475(2): 245-249, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30852641

RESUMO

BACKGROUND: Rhabdoid colorectal carcinoma (RC) is a rare lesion localized to the proximal colon of patients with a mean age at diagnosis of around 70 years. This tumor shows an aggressive behavior with an overall survival period shorter than 12 months. The diagnostic hallmark is the presence of rhabdoid cells. Alterations in chromatin remodeling (SMARCB1) and in the centrosome structure (CROCC) are reported in RC usually BRAFmut and MSI-H. RKO intestinal neoplastic cells culture (BRAFmut, SMARCB1wt, MSI-H) with CROCC knockdown exhibit rhabdoid features and develop prominent projections from the edge of the cell. METHODS: Here, we investigated two cases of CROCCmutSMARCB1wt RC by scanning and transmission electron microscopy (SEM, TEM). RESULTS: TEM confirmed the diagnostic presence of intermediate cytoplasmic filaments and nucleolar margination. SEM showed cellular protrusions (lamellipodia) in the intercellular spaces not evident at light microscopy. CONCLUSIONS: These protrusions CROCC-related might represent the pathogenetic mechanism underlying the rhabdoid aggressive behavior, independently of tumor staging. To our knowledge, the SEM technique was applied in the study of this neoplasm for the first time.


Assuntos
Adenocarcinoma/ultraestrutura , Neoplasias Colorretais/ultraestrutura , Proteínas do Citoesqueleto/genética , Tumor Rabdoide/ultraestrutura , Adenocarcinoma/genética , Adenocarcinoma/patologia , Idoso , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Feminino , Humanos , Microscopia Eletrônica , Pseudópodes/patologia , Pseudópodes/ultraestrutura , Tumor Rabdoide/genética , Tumor Rabdoide/patologia
14.
Cancer Res ; 79(9): 2404-2414, 2019 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-30755442

RESUMO

Malignant rhabdoid tumors (MRT) are highly aggressive pediatric cancers that respond poorly to current therapies. In this study, we screened several MRT cell lines with large-scale RNAi, CRISPR-Cas9, and small-molecule libraries to identify potential drug targets specific for these cancers. We discovered MDM2 and MDM4, the canonical negative regulators of p53, as significant vulnerabilities. Using two compounds currently in clinical development, idasanutlin (MDM2-specific) and ATSP-7041 (MDM2/4-dual), we show that MRT cells were more sensitive than other p53 wild-type cancer cell lines to inhibition of MDM2 alone as well as dual inhibition of MDM2/4. These compounds caused significant upregulation of the p53 pathway in MRT cells, and sensitivity was ablated by CRISPR-Cas9-mediated inactivation of TP53. We show that loss of SMARCB1, a subunit of the SWI/SNF (BAF) complex mutated in nearly all MRTs, sensitized cells to MDM2 and MDM2/4 inhibition by enhancing p53-mediated apoptosis. Both MDM2 and MDM2/4 inhibition slowed MRT xenograft growth in vivo, with a 5-day idasanutlin pulse causing marked regression of all xenografts, including durable complete responses in 50% of mice. Together, these studies identify a genetic connection between mutations in the SWI/SNF chromatin-remodeling complex and the tumor suppressor gene TP53 and provide preclinical evidence to support the targeting of MDM2 and MDM4 in this often-fatal pediatric cancer. SIGNIFICANCE: This study identifies two targets, MDM2 and MDM4, as vulnerabilities in a deadly pediatric cancer and provides preclinical evidence that compounds inhibiting these proteins have therapeutic potential.


Assuntos
Proteínas de Ciclo Celular/antagonistas & inibidores , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-mdm2/antagonistas & inibidores , Proteínas Proto-Oncogênicas/antagonistas & inibidores , Tumor Rabdoide/tratamento farmacológico , Animais , Antineoplásicos/farmacologia , Apoptose , Sistemas CRISPR-Cas , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/metabolismo , Proliferação de Células , Feminino , Humanos , Camundongos , Camundongos Nus , Proteínas Proto-Oncogênicas/genética , Proteínas Proto-Oncogênicas/metabolismo , Proteínas Proto-Oncogênicas c-mdm2/genética , Proteínas Proto-Oncogênicas c-mdm2/metabolismo , Tumor Rabdoide/genética , Tumor Rabdoide/metabolismo , Tumor Rabdoide/patologia , Proteína SMARCB1/genética , Proteína SMARCB1/metabolismo , Células Tumorais Cultivadas , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto
15.
Cancer Cell ; 35(2): 204-220.e9, 2019 02 11.
Artigo em Inglês | MEDLINE | ID: mdl-30753823

RESUMO

Alterations in chromatin remodeling genes have been increasingly implicated in human oncogenesis. Specifically, the biallelic inactivation of the SWI/SNF subunit SMARCB1 results in the emergence of extremely aggressive pediatric malignancies. Here, we developed embryonic mosaic mouse models of malignant rhabdoid tumors (MRTs) that faithfully recapitulate the clinical-pathological features of the human disease. We demonstrated that SMARCB1-deficient malignancies exhibit dramatic activation of the unfolded protein response (UPR) and ER stress response via a genetically intact MYC-p19ARF-p53 axis. As a consequence, these tumors display an exquisite sensitivity to agents inducing proteotoxic stress and inhibition of the autophagic machinery. In conclusion, our findings provide a rationale for drug repositioning trials investigating combinations of agents targeting the UPR and autophagy in SMARCB1-deficient MRTs.


Assuntos
Autofagia , Estresse do Retículo Endoplasmático , Proteostase , Tumor Rabdoide/metabolismo , Proteína SMARCB1/deficiência , Proteína Supressora de Tumor p53/metabolismo , Animais , Antineoplásicos/farmacologia , Autofagia/efeitos dos fármacos , Linhagem Celular Tumoral , Inibidor p16 de Quinase Dependente de Ciclina/genética , Inibidor p16 de Quinase Dependente de Ciclina/metabolismo , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Masculino , Camundongos da Linhagem 129 , Camundongos Endogâmicos C57BL , Camundongos Knockout , Inibidores de Proteassoma/farmacologia , Proteostase/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-myc/genética , Proteínas Proto-Oncogênicas c-myc/metabolismo , Tumor Rabdoide/tratamento farmacológico , Tumor Rabdoide/genética , Tumor Rabdoide/patologia , Proteína SMARCB1/genética , Transdução de Sinais , Células Tumorais Cultivadas , Proteína Supressora de Tumor p53/deficiência , Proteína Supressora de Tumor p53/genética , Resposta a Proteínas não Dobradas
16.
Int J Cancer ; 144(8): 1983-1995, 2019 04 15.
Artigo em Inglês | MEDLINE | ID: mdl-30230537

RESUMO

Loss of SMARCB1 is the hallmark genetic event that characterizes rhabdoid tumors in children. Rhabdoid tumors of the brain (ATRT) occur in young children and are particularly challenging with poor long-term survival. SMARCB1 is a member of the SWI/SNF chromatin remodeling complex that is responsible for determining cellular pluripotency and lineage commitment. The mechanisms by which SMARCB1 deletion results in tumorigenesis remain unclear. Recent studies demonstrate that ATRT consists of 3 genomic subgroups with a subset of poor outcome tumors expressing high BMP and MYC pathway activation. Here we show that MYC occupies distinct promoter loci in ATRT compared to embryonic stem (ES) cells. Furthermore, using human ATRT cell lines, patient-derived cell culture, ex vivo patient-derived tumor, and orthotopic xenograft models, we show that MYC inhibition is a molecular vulnerability in SMARCB1-deleted tumors and that such inhibition effectively suppresses BMP and pluripotency-associated genomic programs, attenuates tumor cell self-renewal, promotes senescence, and inhibits ATRT tumor growth in vivo. Transgenic expression of Omomyc (a bona-fide MYC dominant negative) or chemical inhibition of MYC transcriptomic programs with the BET inhibitor JQ1 phenocopy genetic depletion of MYC, effectively restricting ATRT tumor growth and opening a promising therapeutic avenue for rhabdoid tumors in children.


Assuntos
Transformação Celular Neoplásica/genética , Regulação Neoplásica da Expressão Gênica/genética , Proteínas Proto-Oncogênicas c-myc/metabolismo , Tumor Rabdoide/genética , Proteína SMARCB1/genética , Teratoma/genética , Animais , Azepinas/farmacologia , Proteínas Morfogenéticas Ósseas/genética , Proteínas Morfogenéticas Ósseas/metabolismo , Linhagem Celular Tumoral , Autorrenovação Celular/efeitos dos fármacos , Autorrenovação Celular/genética , Senescência Celular/efeitos dos fármacos , Senescência Celular/genética , Cromatina/genética , Cromatina/metabolismo , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Camundongos , Camundongos Nus , Proteínas Proto-Oncogênicas c-myc/genética , Tumor Rabdoide/patologia , Teratoma/patologia , Triazóis/farmacologia , Ensaios Antitumorais Modelo de Xenoenxerto
18.
Pediatr Dev Pathol ; 22(2): 161-165, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30470167

RESUMO

Atypical teratoid/rhabdoid tumor (ATRT) is a high-grade central nervous system tumor, with poor prognosis despite intensive multimodal therapy. Loss of nuclear immunostaining for INI1 due to inactivation of the hSNF5/INI1 tumor suppressor gene is pathognomonic of ATRT. We present a patient with congenital ATRT, who had spontaneous tumor regression without therapy, and is disease-free 4 years later. Tumor histopathology showed rhabdoid cells characteristic of ATRT, but immunohistochemistry revealed heterogeneous loss of nuclear INI1 staining. The populations of INI1-intact and INI1-deficient cells were separated by laser microdissection, for molecular analysis with DNA sequencing and fluorescence in situ hybridization. The INI1-negative cells were found to harbor a heterozygous deletion and truncating mutation of the hSNF5/INI1 locus, while the INI1-intact cells had 2 copies of the wild-type INI1 gene. To our knowledge, this is the first report of spontaneous regression of ATRT, with molecular heterogeneity for SMARCB1 inactivation, with no radiographic signs of recurrence at 4 years after diagnosis.


Assuntos
Biomarcadores Tumorais/genética , Tumor Rabdoide/patologia , Proteína SMARCB1/genética , Teratoma/patologia , Feminino , Humanos , Recém-Nascido , Remissão Espontânea , Tumor Rabdoide/congênito , Tumor Rabdoide/genética , Tumor Rabdoide/metabolismo , Teratoma/congênito , Teratoma/genética , Teratoma/metabolismo
19.
Int J Surg Pathol ; 27(4): 457-463, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30563401

RESUMO

Only 1% to 2% of meningiomas have primary extrameningeal location, which is mostly head and neck region. Primary pulmonary meningiomas (PPMs) are even more uncommon with up to 50 cases reported in the literature. Only 5 cases of PPM with confirmed or possible malignancy have been previously described. Three-grade classification of meningiomas with the accordingly growing risk of aggressive behavior of the tumor has been proposed by the World Health Organization. As it is based on correlations between morphological and clinical features of intracranial meningiomas, the analogous prediction of ectopic tumors prognosis remains questionable due to scarce number of cases. In this article, we present a rare case of PPM with rhabdoid features (World Health Organization grade III), which lacked other signs of malignancy. The patient is doing well for 2 years after the thoracoscopic wedge resection without evidence of the disease recurrence.


Assuntos
Neoplasias Pulmonares/diagnóstico , Pulmão/patologia , Meningioma/diagnóstico , Tumor Rabdoide/diagnóstico , Adulto , Biópsia por Agulha , Broncoscopia , Feminino , Humanos , Achados Incidentais , Pulmão/diagnóstico por imagem , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/cirurgia , Meningioma/patologia , Meningioma/cirurgia , Invasividade Neoplásica , Tumor Rabdoide/patologia , Tumor Rabdoide/cirurgia , Cirurgia Torácica Vídeoassistida , Tomografia Computadorizada por Raios X
20.
World Neurosurg ; 123: e31-e38, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30404057

RESUMO

BACKGROUND: Atypical teratoid/rhabdoid tumors (ATRT) are uncommon malignancies of the central nervous system and are often difficult to distinguish radiographically and pathologically from other common tumors. We present the first case of sellar ATRT presenting with subarachnoid hemorrhage (SAH) and intraventricular hemorrhage (IVH). CASE DESCRIPTION: A 62-year-old woman, who had presented with symptoms of headache, diabetes insipidus, hypothyroidism, and seizures, was found to have a sellar tumor with hemorrhagic transformation. Surgical resection was performed. The pathological examination findings were consistent with ATRT. Despite early surgical intervention, she later died before starting craniospinal radiotherapy and chemotherapy. CONCLUSION: To the best of our knowledge, although known to present with intratumoral hemorrhage, to date, no cases of sellar ATRT have presented with SAH or IVH have been reported. Considering our finding that ATRT can present with SAH and IVH, establishing the correct diagnosis using radiographic imaging, gender, pathological findings, and molecular markers is paramount for speedy treatment and management.


Assuntos
Neoplasias Encefálicas/diagnóstico , Hemorragia Cerebral/diagnóstico , Tumor Rabdoide/diagnóstico , Teratoma/diagnóstico , Encéfalo/diagnóstico por imagem , Encéfalo/cirurgia , Neoplasias Encefálicas/complicações , Neoplasias Encefálicas/patologia , Neoplasias Encefálicas/cirurgia , Hemorragia Cerebral/etiologia , Hemorragia Cerebral/cirurgia , Diagnóstico Diferencial , Evolução Fatal , Feminino , Humanos , Pessoa de Meia-Idade , Tumor Rabdoide/complicações , Tumor Rabdoide/patologia , Tumor Rabdoide/cirurgia , Sela Túrcica , Teratoma/complicações , Teratoma/patologia , Teratoma/cirurgia
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA