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Neurofibromatosis type 1 (NF1) is a rare autosomal dominant disorder characterized by proliferation of cells from neural crest origin. The most common manifestations are cutaneous, neurologic, skeletal and ocular. The distinction of NF1 from other syndromes with multiple café-au-lait macules may be difficult in the pediatric age group, and ocular findings, especially Lisch nodules (i.e., melanocytic hamartomas on the irides), are a useful, early diagnostic tool. In recent years, novel ocular manifestations descriptively referred to as "choroidal abnormalities", choroidal "hyperpigmented spots" and "retinal vascular abnormalities" have been recognized in NF1. Choroidal abnormalities (CA) appear as bright patchy nodules that can be best detected with near-infrared ocular coherence tomography imaging (NIR-OCT). Because of their high specificity and sensitivity for NF1, CA have been added as an ocular diagnostic criterion of NF1 as an alternative to Lisch nodules. Although CA are important ocular diagnostic criteria for NF1, the histologic correlates are controversial. We present the postmortem ocular pathology findings of an NF1 patient for whom clinical notes and ocular imaging were available. Findings in this patient included choroidal hyperpigmented spots on funduscopy and retinal vascular abnormalities, both of which have been reported to be closely associated with CA. Histologic examination of the eyes showed multiple clusters of melanocytes of varying sizes in the choroid. Pathologic review of 12 additional postmortem eyes from 6 NF1 patients showed multiple, bilateral choroidal melanocytic aggregates in all eyes. These findings suggest that the CA seen on NIR-OCT and the hyperpigmented spots seen clinically in NF1 patients are manifestations of multifocal choroidal melanocytic clusters, consistent with choroidal melanocytic hamartomas. Lisch nodules, often multiple, were present in all eyes with morphology that differed from the choroidal hamartomas. As such, although CA and Lisch nodules are melanocytic hamartomas, there are clear phenotypical differences in their morphologies.
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Hamartoma , Neurofibromatosis 1 , Humanos , Niño , Neurofibromatosis 1/complicaciones , Coroides/diagnóstico por imagen , AutopsiaRESUMEN
Immune checkpoint blockade (CPB) improves melanoma outcomes, but many patients still do not respond. Tumor mutational burden (TMB) and tumor-infiltrating T cells are associated with response, and integrative models improve survival prediction. However, integrating immune/tumor-intrinsic features using data from a single assay (DNA/RNA) remains underexplored. Here, we analyze whole-exome and bulk RNA sequencing of tumors from new and published cohorts of 189 and 178 patients with melanoma receiving CPB, respectively. Using DNA, we calculate T cell and B cell burdens (TCB/BCB) from rearranged TCR/Ig sequences and find that patients with TMBhigh and TCBhigh or BCBhigh have improved outcomes compared to other patients. By combining pairs of immune- and tumor-expressed genes, we identify three gene pairs associated with response and survival, which validate in independent cohorts. The top model includes lymphocyte-expressed MAP4K1 and tumor-expressed TBX3. Overall, RNA or DNA-based models combining immune and tumor measures improve predictions of melanoma CPB outcomes.
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Melanoma , Transcriptoma , Humanos , Melanoma/tratamiento farmacológico , ARN , Análisis de Secuencia de ARN , Transcriptoma/genética , Secuenciación del ExomaRESUMEN
B-lymphoblastic leukemia/lymphoma (B-ALL) is the most common pediatric malignancy and the most commonly diagnosed adult lymphoblastic leukemia. Recent advances have broadened the spectrum of B-ALL, with DUX4 gene fusions implicated in a subclass occurring in adolescents and young adults and harboring a favorable prognosis. DUX4 fusions have been challenging to identify. We aimed to determine whether expression of the DUX4 oncoprotein, as detected by targeted immunohistochemistry, might serve as a surrogate for molecular detection of DUX4 fusions in B-ALL. A cohort of investigational B-ALLs was generated with enrichment for DUX4 fusions by the inclusion of cases with characteristic demographic features and immunophenotypic properties. B-ALLs with mutually exclusive cytogenetics were collected. Immunohistochemical staining by a monoclonal antibody raised against the N-terminus of the DUX4 protein was performed. N-DUX4 immunohistochemistry demonstrated strong, crisp nuclear staining in blasts of seven investigational cases, six of which had nucleic acid material available for molecular evaluation. Five of these cases demonstrated RNA-seq DUX4-fusion positivity. One N-DUX4 immunohistochemistry positive case lacked a definitive DUX4-fusion by RNA-seq, though demonstrated a gene expression profile characteristic of DUX4-rearranged B-ALLs, a CD2+ immunophenotype, and a lack of staining by C-terminus DUX4 antibody immunohistochemistry. At least 83.3% [5/6] positive predictive value. N-DUX4 immunohistochemistry was negative in blasts of three RNA-seq DUX4-fusion-negative cases (3/3; 100% negative predictive value). B-ALLs with mutually exclusive cytogenetic profiles were all N-DUX4 negative (0/10, specificity 100%). N-DUX4 immunohistochemistry is reliable for the distinction of DUX4-rearranged B-ALLs from other B-ALLs. We recommend its use for subclassification of B-ALLs in adolescents and young adults and in B-ALLs that remain "not otherwise specified."
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Linfoma de Burkitt , Leucemia-Linfoma Linfoblástico de Células Precursoras , Adolescente , Niño , Fusión Génica , Humanos , Inmunohistoquímica , Inmunofenotipificación , Leucemia-Linfoma Linfoblástico de Células Precursoras/diagnóstico , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/metabolismo , Adulto JovenRESUMEN
Neurofibromatosis Type 2 (NF2) is an autosomal dominant genetic syndrome caused by mutations in the NF2 tumor suppressor gene resulting in multiple schwannomas and meningiomas. There are no FDA approved therapies for these tumors and their relentless progression results in high rates of morbidity and mortality. Through a combination of high throughput screens, preclinical in vivo modeling, and evaluation of the kinome en masse, we identified actionable drug targets and efficacious experimental therapeutics for the treatment of NF2 related schwannomas and meningiomas. These efforts identified brigatinib (ALUNBRIG®), an FDA-approved inhibitor of multiple tyrosine kinases including ALK, to be a potent inhibitor of tumor growth in established NF2 deficient xenograft meningiomas and a genetically engineered murine model of spontaneous NF2 schwannomas. Surprisingly, neither meningioma nor schwannoma cells express ALK. Instead, we demonstrate that brigatinib inhibited multiple tyrosine kinases, including EphA2, Fer and focal adhesion kinase 1 (FAK1). These data demonstrate the power of the de novo unbiased approach for drug discovery and represents a major step forward in the advancement of therapeutics for the treatment of NF2 related malignancies.
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Neoplasias Meníngeas/genética , Meningioma/genética , Neurilemoma/genética , Neurofibromina 2/deficiencia , Neurofibromina 2/genética , Compuestos Organofosforados/farmacología , Proteínas Tirosina Quinasas/antagonistas & inhibidores , Pirimidinas/farmacología , Proliferación Celular , Humanos , Mutación , Neurilemoma/patologíaRESUMEN
The metabolic gene isocitrate dehydrogenase 1 (IDH1) is commonly mutated in lower grade glioma (LGG) and secondary glioblastoma (GBM). Regulatory T cells (Tregs) play a significant role in the suppression of antitumor immunity in human glioma. Given the importance of Tregs in the overall framework of designing immune-based therapies, a better understanding on their association with IDH mutational status remains of critical clinical importance. Using multispectral imaging analysis, we compared the incidence of Tregs in IDH-mutant and IDH wild-type glioma from patient tumor samples of LGG. An orthotopic IDH-mutant murine model was generated to evaluate the role of mutant IDH on Treg infiltration by immunohistochemistry. When compared to IDH wild-type controls, Tregs are disproportionally underrepresented in mutant disease, even when taken as a proportion of all infiltrating T cells. Our findings suggest that therapeutic agents targeting Tregs may be more appropriate in modulating the immune response to wild-type disease.
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Neoplasias Encefálicas , Glioma , Animales , Neoplasias Encefálicas/genética , Glioma/genética , Humanos , Isocitrato Deshidrogenasa/genética , Ratones , Mutación , Linfocitos T ReguladoresRESUMEN
Introduction: Carbon monoxide (CO) poisoning causes hypoxia and inflammation, which could adversely affect muscle. We could find no published information about CO poisoning causing myositis. Case report: A 53-year-old previously healthy female semi truck driver had CO poisoning from a faulty diesel engine exhaust intermittently over three months, culminating in an episode of acute CO poisoning, with syncope after exiting the truck at the end of the three-month period. Neuropsychological symptoms immediately after the acute poisoning event were followed by the development of fatigue, weakness and myalgias within two months and a diagnosis of "polymyositis" within four months. C-reactive protein and creatine kinase were elevated. Electromyogram showed pure myopathy without sensory abnormalities. Occult malignancy was ruled out. Thigh muscle biopsy revealed severe inflammatory myopathy and myonecrosis. Muscle specialist pathologists interpreted the biopsy as toxic or viral inflammatory myopathy, not polymyositis, with CO poisoning as the likely etiology. She received steroids and mycophenolate. Nineteen months later, a repeat biopsy was negative for inflammation or myopathic process. Alternative diagnoses were ruled out by clinical investigation and her course over the next five years. Conclusion: This patient's presentation and clinical course support a diagnosis of myositis from CO poisoning, although it is possible that the myositis was either idiopathic or post-viral (without evidence of a causative virus).
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Intoxicación por Monóxido de Carbono/complicaciones , Miositis/etiología , Enfermedades Profesionales/complicaciones , Conducción de Automóvil , Intoxicación por Monóxido de Carbono/sangre , Carboxihemoglobina/análisis , Femenino , Humanos , Persona de Mediana Edad , Músculo Esquelético/patología , Síncope/etiologíaRESUMEN
Neurofibromatosis Type 1 (NF1) is a genetic disease caused by mutations in Neurofibromin 1 (NF1). NF1 patients present with a variety of clinical manifestations and are predisposed to cancer development. Many NF1 animal models have been developed, yet none display the spectrum of disease seen in patients and the translational impact of these models has been limited. We describe a minipig model that exhibits clinical hallmarks of NF1, including café au lait macules, neurofibromas, and optic pathway glioma. Spontaneous loss of heterozygosity is observed in this model, a phenomenon also described in NF1 patients. Oral administration of a mitogen-activated protein kinase/extracellular signal-regulated kinase inhibitor suppresses Ras signaling. To our knowledge, this model provides an unprecedented opportunity to study the complex biology and natural history of NF1 and could prove indispensable for development of imaging methods, biomarkers, and evaluation of safety and efficacy of NF1-targeted therapies.
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Progressive meningiomas that have failed surgery and radiation have a poor prognosis and no standard therapy. While meningiomas are more common in females overall, progressive meningiomas are enriched in males. We performed a comprehensive molecular characterization of 169 meningiomas from 53 patients with progressive/high-grade tumors, including matched primary and recurrent samples. Exome sequencing in an initial cohort (n = 24) detected frequent alterations in genes residing on the X chromosome, with somatic intragenic deletions of the dystrophin-encoding and muscular dystrophy-associated DMD gene as the most common alteration (n = 5, 20.8%), along with alterations of other known X-linked cancer-related genes KDM6A (n =2, 8.3%), DDX3X, RBM10 and STAG2 (n = 1, 4.1% each). DMD inactivation (by genomic deletion or loss of protein expression) was ultimately detected in 17/53 progressive meningioma patients (32%). Importantly, patients with tumors harboring DMD inactivation had a shorter overall survival (OS) than their wild-type counterparts [5.1 years (95% CI 1.3-9.0) vs. median not reached (95% CI 2.9-not reached, p = 0.006)]. Given the known poor prognostic association of TERT alterations in these tumors, we also assessed for these events, and found seven patients with TERT promoter mutations and three with TERT rearrangements in this cohort (n = 10, 18.8%), including a recurrent novel RETREG1-TERT rearrangement that was present in two patients. In a multivariate model, DMD inactivation (p = 0.033, HR = 2.6, 95% CI 1.0-6.6) and TERT alterations (p = 0.005, HR = 3.8, 95% CI 1.5-9.9) were mutually independent in predicting unfavorable outcomes. Thus, DMD alterations identify a subset of progressive/high-grade meningiomas with worse outcomes.
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Distrofina/genética , Eliminación de Gen , Neoplasias Meníngeas/genética , Meningioma/genética , Anciano , Anciano de 80 o más Años , Línea Celular Tumoral/patología , Línea Celular Tumoral/ultraestructura , Estudios de Cohortes , Progresión de la Enfermedad , Distrofina/metabolismo , Femenino , Humanos , Imagen por Resonancia Magnética , Masculino , Neoplasias Meníngeas/diagnóstico por imagen , Neoplasias Meníngeas/patología , Meningioma/diagnóstico por imagen , Meningioma/patología , Microscopía Electrónica de Transmisión , Persona de Mediana Edad , Reacción en Cadena de la Polimerasa Multiplex , ARN Mensajero/metabolismo , Cromatina Sexual/genética , Telomerasa/genética , Telomerasa/metabolismo , Secuenciación del ExomaRESUMEN
The malignant primary brain tumor, glioblastoma (GBM) is generally incurable. New approaches are desperately needed. Adeno-associated virus (AAV) vector-mediated delivery of anti-tumor transgenes is a promising strategy, however direct injection leads to focal transgene spread in tumor and rapid tumor division dilutes out the extra-chromosomal AAV genome, limiting duration of transgene expression. Intravenous (IV) injection gives widespread distribution of AAV in normal brain, however poor transgene expression in tumor, and high expression in non-target cells which may lead to ineffective therapy and high toxicity, respectively. Delivery of transgenes encoding secreted, anti-tumor proteins to tumor stromal cells may provide a more stable and localized reservoir of therapy as they are more differentiated than fast-dividing tumor cells. Reactive astrocytes and tumor-associated macrophage/microglia (TAMs) are stromal cells that comprise a large portion of the tumor mass and are associated with tumorigenesis. In mouse models of GBM, we used IV delivery of exosome-associated AAV vectors driving green fluorescent protein expression by specific promoters (NF-κB-responsive promoter and a truncated glial fibrillary acidic protein promoter), to obtain targeted transduction of TAMs and reactive astrocytes, respectively, while avoiding transgene expression in the periphery. We used our approach to express the potent, yet toxic anti-tumor cytokine, interferon beta, in tumor stroma of a mouse model of GBM, and achieved a modest, yet significant enhancement in survival compared to controls. Noninvasive genetic modification of tumor microenvironment represents a promising approach for therapy against cancers. Additionally, the vectors described here may facilitate basic research in the study of tumor stromal cells in situ.
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Astrocitos/metabolismo , Neoplasias Encefálicas/terapia , Dependovirus/genética , Terapia Genética , Interferón beta/genética , Células del Estroma/metabolismo , Animales , Astrocitos/citología , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patología , Modelos Animales de Enfermedad , Femenino , Proteínas Fluorescentes Verdes/genética , Proteínas Fluorescentes Verdes/metabolismo , Ratones , Ratones Endogámicos C57BL , Ratones Desnudos , Regiones Promotoras Genéticas , Células del Estroma/citologíaRESUMEN
Malignant peripheral nerve sheath tumors (MPNSTs) are highly aggressive Schwann cell (SC)-lineage-derived sarcomas. Molecular events driving SC-to-MPNST transformation are incompletely understood. Here, we show that human MPNSTs exhibit elevated HIPPO-TAZ/YAP expression, and that TAZ/YAP hyperactivity in SCs caused by Lats1/2 loss potently induces high-grade nerve-associated tumors with full penetrance. Lats1/2 deficiency reprograms SCs to a cancerous, progenitor-like phenotype and promotes hyperproliferation. Conversely, disruption of TAZ/YAP activity alleviates tumor burden in Lats1/2-deficient mice and inhibits human MPNST cell proliferation. Moreover, genome-wide profiling reveals that TAZ/YAP-TEAD1 directly activates oncogenic programs, including platelet-derived growth factor receptor (PDGFR) signaling. Co-targeting TAZ/YAP and PDGFR pathways inhibits tumor growth. Thus, our findings establish a previously unrecognized convergence between Lats1/2-TAZ/YAP signaling and MPNST pathogenesis, revealing potential therapeutic targets in these untreatable tumors.
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Proteínas Adaptadoras Transductoras de Señales/genética , Fosfoproteínas/genética , Proteínas Serina-Treonina Quinasas/genética , Células de Schwann/citología , Animales , Proteínas de Ciclo Celular , Diferenciación Celular/genética , Proliferación Celular/genética , Transformación Celular Neoplásica , Humanos , Ratones , Transducción de Señal/genética , Factores de Transcripción , Proteínas Señalizadoras YAPRESUMEN
Ex vivo systems that incorporate features of the tumor microenvironment and model the dynamic response to immune checkpoint blockade (ICB) may facilitate efforts in precision immuno-oncology and the development of effective combination therapies. Here, we demonstrate the ability to interrogate ex vivo response to ICB using murine- and patient-derived organotypic tumor spheroids (MDOTS/PDOTS). MDOTS/PDOTS isolated from mouse and human tumors retain autologous lymphoid and myeloid cell populations and respond to ICB in short-term three-dimensional microfluidic culture. Response and resistance to ICB was recapitulated using MDOTS derived from established immunocompetent mouse tumor models. MDOTS profiling demonstrated that TBK1/IKKε inhibition enhanced response to PD-1 blockade, which effectively predicted tumor response in vivo Systematic profiling of secreted cytokines in PDOTS captured key features associated with response and resistance to PD-1 blockade. Thus, MDOTS/PDOTS profiling represents a novel platform to evaluate ICB using established murine models as well as clinically relevant patient specimens.Significance: Resistance to PD-1 blockade remains a challenge for many patients, and biomarkers to guide treatment are lacking. Here, we demonstrate feasibility of ex vivo profiling of PD-1 blockade to interrogate the tumor immune microenvironment, develop therapeutic combinations, and facilitate precision immuno-oncology efforts. Cancer Discov; 8(2); 196-215. ©2017 AACR.See related commentary by Balko and Sosman, p. 143See related article by Deng et al., p. 216This article is highlighted in the In This Issue feature, p. 127.
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Antineoplásicos Inmunológicos/farmacología , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Animales , Técnicas de Cultivo de Célula , Línea Celular Tumoral , Citocinas/metabolismo , Resistencia a Antineoplásicos , Citometría de Flujo , Humanos , Inmunohistoquímica , Inmunofenotipificación , Ratones , Técnicas Analíticas Microfluídicas , Receptor de Muerte Celular Programada 1/metabolismo , Esferoides Celulares , Imagen de Lapso de Tiempo , Células Tumorales CultivadasRESUMEN
OBJECTIVE Patients with atypical and malignant (WHO Grade II and III) meningiomas have a worse prognosis than patients with benign (WHO Grade I) meningiomas. However, there is limited understanding of the pathological risk factors that affect long-term tumor control following combined treatment with surgery and radiation therapy. Here, the authors identify clinical and histopathological risk factors for the progression and/or recurrence (P/R) of high-grade meningiomas based on the largest series of patients with atypical and malignant meningiomas, as defined by the 2007 WHO classification. METHODS Patients diagnosed with WHO Grade II and III meningiomas between 2007 and 2014 per the WHO 2007 criteria and treated with both surgery and external beam radiation therapy were retrospectively reviewed for clinical and histopathological factors at the time of diagnosis and assessed for P/R outcomes at the last available follow-up. RESULTS A total of 76 patients met the inclusion criteria (66 Grade II meningiomas, 10 Grade III meningiomas). Median follow-up from the time of pathological diagnosis was 52.6 months. Three factors were found to predict P/R: Grade III histology, brain and/or bone invasion, and a Ki-67 proliferation rate at or above 3%. The crude P/R rate was 80% for patients with Grade III histology, 40% for those with brain and/or bone involvement (regardless of WHO tumor grade), and 20% for those with a proliferative index ≥ 3% (regardless of WHO tumor grade). The median proliferation index was significantly different between patients in whom treatment failed and those in whom it did not fail (11% and 1%, respectively). CONCLUSIONS In patients with atypical or malignant meningiomas, the presence of Grade III histology, brain and/or bone involvement, and a high mitotic index significantly predicted an increased risk of treatment failure despite combination therapy. These patients can be stratified into risk groups predicting P/R. Patients with high-risk features may benefit from more treatment and counseling than is typically offered currently.
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Neoplasias Encefálicas/patología , Neoplasias Encefálicas/terapia , Meningioma/patología , Meningioma/terapia , Adulto , Anciano , Neoplasias Encefálicas/radioterapia , Proliferación Celular , Terapia Combinada , Progresión de la Enfermedad , Femenino , Humanos , Antígeno Ki-67 , Masculino , Meningioma/radioterapia , Persona de Mediana Edad , Índice Mitótico , Clasificación del Tumor , Invasividad Neoplásica , Procedimientos Neuroquirúrgicos , Pronóstico , Recurrencia , Estudios Retrospectivos , Medición de Riesgo , Neoplasias de la Base del Cráneo/patología , Neoplasias de la Base del Cráneo/radioterapia , Neoplasias de la Base del Cráneo/terapia , Insuficiencia del TratamientoRESUMEN
Proliferative diabetic retinopathy (PDR) is a common cause of blindness in the developed world's working adult population and affects those with type 1 and type 2 diabetes. We identified Runt-related transcription factor 1 (RUNX1) as a gene upregulated in CD31+ vascular endothelial cells obtained from human PDR fibrovascular membranes (FVMs) via transcriptomic analysis. In vitro studies using human retinal microvascular endothelial cells (HRMECs) showed increased RUNX1 RNA and protein expression in response to high glucose, whereas RUNX1 inhibition reduced HRMEC migration, proliferation, and tube formation. Immunohistochemical staining for RUNX1 showed reactivity in vessels of patient-derived FVMs and angiogenic tufts in the retina of mice with oxygen-induced retinopathy, suggesting that RUNX1 upregulation is a hallmark of aberrant retinal angiogenesis. Inhibition of RUNX1 activity with the Ro5-3335 small molecule resulted in a significant reduction of neovascular tufts in oxygen-induced retinopathy, supporting the feasibility of targeting RUNX1 in aberrant retinal angiogenesis.
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Subunidad alfa 2 del Factor de Unión al Sitio Principal/genética , Retinopatía Diabética/genética , Células Endoteliales/metabolismo , Retina/metabolismo , Neovascularización Retiniana/genética , Adulto , Anciano , Anciano de 80 o más Años , Animales , Movimiento Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Subunidad alfa 2 del Factor de Unión al Sitio Principal/antagonistas & inhibidores , Subunidad alfa 2 del Factor de Unión al Sitio Principal/metabolismo , Diabetes Mellitus Tipo 1/complicaciones , Diabetes Mellitus Tipo 1/metabolismo , Diabetes Mellitus Tipo 2/complicaciones , Diabetes Mellitus Tipo 2/metabolismo , Retinopatía Diabética/etiología , Retinopatía Diabética/metabolismo , Modelos Animales de Enfermedad , Células Endoteliales/efectos de los fármacos , Femenino , Glucosa/farmacología , Humanos , Inmunohistoquímica , Masculino , Ratones , Persona de Mediana Edad , Oxígeno/efectos adversos , ARN Mensajero/metabolismo , Neovascularización Retiniana/metabolismoRESUMEN
Malignant gliomas exhibit extensive heterogeneity and poor prognosis. Here we identify mitotic Olig2-expressing cells as tumor-propagating cells in proneural gliomas, elimination of which blocks tumor initiation and progression. Intriguingly, deletion of Olig2 resulted in tumors that grow, albeit at a decelerated rate. Genome occupancy and expression profiling analyses reveal that Olig2 directly activates cell-proliferation machinery to promote tumorigenesis. Olig2 deletion causes a tumor phenotypic shift from an oligodendrocyte precursor-correlated proneural toward an astroglia-associated gene expression pattern, manifest in downregulation of platelet-derived growth factor receptor-α and reciprocal upregulation of epidermal growth factor receptor (EGFR). Olig2 deletion further sensitizes glioma cells to EGFR inhibitors and extends the lifespan of animals. Thus, Olig2-orchestrated receptor signaling drives mitotic growth and regulates glioma phenotypic plasticity. Targeting Olig2 may circumvent resistance to EGFR-targeted drugs.
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Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/genética , Proliferación Celular/genética , Receptores ErbB/genética , Glioma/genética , Proteínas del Tejido Nervioso/genética , Receptores del Factor de Crecimiento Derivado de Plaquetas/genética , Animales , Astrocitos/metabolismo , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/metabolismo , Línea Celular Tumoral , Transformación Celular Neoplásica/genética , Receptores ErbB/metabolismo , Perfilación de la Expresión Génica/métodos , Regulación Neoplásica de la Expresión Génica , Glioma/metabolismo , Glioma/patología , Humanos , Ratones de la Cepa 129 , Ratones Endogámicos C57BL , Ratones Noqueados , Ratones Transgénicos , Proteínas del Tejido Nervioso/metabolismo , Oligodendroglía/metabolismo , Fenotipo , Receptores del Factor de Crecimiento Derivado de Plaquetas/metabolismo , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Transducción de Señal/genética , Esferoides Celulares/metabolismo , Análisis de SupervivenciaRESUMEN
To identify genes and signaling pathways that initiate Neurofibromatosis type 1 (NF1) neurofibromas, we used unbiased insertional mutagenesis screening, mouse models, and molecular analyses. We mapped an Nf1-Stat3-Arid1b/ß-catenin pathway that becomes active in the context of Nf1 loss. Genetic deletion of Stat3 in Schwann cell progenitors (SCPs) and Schwann cells (SCs) prevents neurofibroma formation, decreasing SCP self-renewal and ß-catenin activity. ß-catenin expression rescues effects of Stat3 loss in SCPs. Importantly, P-STAT3 and ß-catenin expression correlate in human neurofibromas. Mechanistically, P-Stat3 represses Gsk3ß and the SWI/SNF gene Arid1b to increase ß-catenin. Knockdown of Arid1b or Gsk3ß in Stat3(fl/fl);Nf1(fl/fl);DhhCre SCPs rescues neurofibroma formation after in vivo transplantation. Stat3 represses Arid1b through histone modification in a Brg1-dependent manner, indicating that epigenetic modification plays a role in early tumorigenesis. Our data map a neural tumorigenesis pathway and support testing JAK/STAT and Wnt/ß-catenin pathway inhibitors in neurofibroma therapeutic trials.
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Carcinogénesis/genética , Proteínas de Unión al ADN/genética , Regulación Neoplásica de la Expresión Génica , Acetiltransferasa A N-Terminal/genética , Neurofibromatosis 1/genética , Neoplasias del Sistema Nervioso Periférico/genética , Factor de Transcripción STAT3/genética , beta Catenina/genética , Animales , Carcinogénesis/metabolismo , Carcinogénesis/patología , ADN Helicasas/genética , ADN Helicasas/metabolismo , Proteínas de Unión al ADN/antagonistas & inhibidores , Proteínas de Unión al ADN/metabolismo , Modelos Animales de Enfermedad , Femenino , Glucógeno Sintasa Quinasa 3 beta/antagonistas & inhibidores , Glucógeno Sintasa Quinasa 3 beta/genética , Glucógeno Sintasa Quinasa 3 beta/metabolismo , Histonas/genética , Histonas/metabolismo , Humanos , Ratones , Ratones Desnudos , Mutagénesis Insercional , Acetiltransferasa A N-Terminal/antagonistas & inhibidores , Acetiltransferasa A N-Terminal/metabolismo , Trasplante de Neoplasias , Células-Madre Neurales/metabolismo , Células-Madre Neurales/patología , Neurofibromatosis 1/metabolismo , Neurofibromatosis 1/patología , Neurofibromina 1/genética , Neurofibromina 1/metabolismo , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Neoplasias del Sistema Nervioso Periférico/metabolismo , Neoplasias del Sistema Nervioso Periférico/patología , Fosforilación , ARN Interferente Pequeño/genética , ARN Interferente Pequeño/metabolismo , Factor de Transcripción STAT3/antagonistas & inhibidores , Factor de Transcripción STAT3/metabolismo , Células de Schwann/metabolismo , Células de Schwann/patología , Transducción de Señal , Factores de Transcripción/genética , Factores de Transcripción/metabolismo , beta Catenina/metabolismoRESUMEN
OBJECT World Health Organization (WHO) Grade I (benign) meningiomas with atypical features may behave more aggressively than similarly graded tumors without atypical features. Here, the prognostic significance of atypical features in benign meningiomas was determined. METHODS Data from patients diagnosed with WHO Grade I benign meningiomas per the 2007 WHO criteria and who underwent surgery between 2002 and 2012 were retrospectively reviewed. Patients were stratified by the absence or presence of 1 to 2 atypical features with review of the clinical and histological factors. RESULTS A total of 148 patients met the inclusion criteria (n = 77 with atypia; n = 71 without atypia). The median follow-up duration after pathological diagnosis was 37.5 months. Thirty patients had progression/recurrence (P/R) after initial treatment, and 22 (73%) of 30 patients with P/R had 1-2 atypical features. The presence of atypical features was significantly associated with P/R (p = 0.03) and independent of the MIB-1 labeling index. The 1-year and 5-year actuarial rates of P/R were 9.6% versus 1.4% and 30.8% versus 13.8% fortumors with and without atypical features, respectively. Higher Simpson grade resection (II-IV vs I) was associated with the increased risk of P/R (p < 0.001). Stratification of patients into low-risk (Simpson Grade I), intermediate-risk (Simpson Grade II-IV with no atypical features), and high-risk groups (Simpson Grade II-IV with atypical features) was significantly correlated with increased risk of P/R (p < 0.001). CONCLUSIONS Patients with benign meningiomas with atypical features and those undergoing Simpson Grade II-IV resection are at significantly increased risk of P/R. Patients with these features may benefit from the consideration of additional surgery and/or radiation therapy.
Asunto(s)
Meningioma/patología , Meningioma/terapia , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Terapia Combinada , Progresión de la Enfermedad , Femenino , Estudios de Seguimiento , Humanos , Antígeno Ki-67 , Masculino , Meningioma/cirugía , Persona de Mediana Edad , Recurrencia Local de Neoplasia/epidemiología , Procedimientos Neuroquirúrgicos , Pronóstico , Radioterapia Adyuvante , Estudios Retrospectivos , Medición de Riesgo , Resultado del Tratamiento , Organización Mundial de la Salud , Adulto JovenRESUMEN
BACKGROUND: Risk stratification of meningiomas by histopathological grade alone does not reliably predict which patients will progress/recur after treatment. We sought to determine whether preoperative imaging and clinical characteristics could predict histopathological grade and/or improve prognostication of progression/recurrence (P/R). METHODS: We retrospectively reviewed preoperative MR and CT imaging features of 144 patients divided into low-grade (2007 WHO grade I; n = 118) and high-grade (2007 WHO grades II/III; n = 26) groups that underwent surgery between 2002 and 2013 (median follow-up of 49 months). RESULTS: Multivariate analysis demonstrated that the risk factors most strongly associated with high-grade histopathology were male sex, low apparent diffusion coefficient (ADC), absent calcification, and high peritumoral edema. Remarkably, multivariate Cox proportional hazards analysis demonstrated that, in combination with extent of resection, ADC outperformed WHO histopathological grade for predicting which patients will suffer P/R after initial treatment. Stratification of patients into 3 risk groups based on non-Simpson grade I resection and low ADC as risk factors correlated with the likelihood of P/R (P < .001). The high-risk group (2 risk factors; n = 39) had a 45% cumulative incidence of P/R, whereas the low-risk group (0 risk factors; n = 31) had no P/R events at 5 years after treatment. Independent of histopathological grade, high-risk patients who received adjuvant radiotherapy had a lower 5-year crude rate of P/R than those without (17% vs 59%; P = .04). CONCLUSIONS: Patients with non-Simpson grade I resection and low ADC meningiomas are at significantly increased risk of P/R and may benefit from adjuvant radiotherapy and/or additional surgery.
Asunto(s)
Neoplasias Meníngeas/diagnóstico , Meningioma/diagnóstico , Recurrencia Local de Neoplasia/patología , Adulto , Anciano , Supervivencia sin Enfermedad , Femenino , Humanos , Masculino , Neoplasias Meníngeas/cirugía , Meningioma/cirugía , Persona de Mediana Edad , Clasificación del Tumor , Recurrencia Local de Neoplasia/cirugía , Procedimientos Neuroquirúrgicos/métodos , Pronóstico , Radioterapia Adyuvante/métodos , Estudios Retrospectivos , Factores de Riesgo , Resultado del Tratamiento , Organización Mundial de la SaludRESUMEN
Gain-of-function IDH mutations are initiating events that define major clinical and prognostic classes of gliomas. Mutant IDH protein produces a new onco-metabolite, 2-hydroxyglutarate, which interferes with iron-dependent hydroxylases, including the TET family of 5'-methylcytosine hydroxylases. TET enzymes catalyse a key step in the removal of DNA methylation. IDH mutant gliomas thus manifest a CpG island methylator phenotype (G-CIMP), although the functional importance of this altered epigenetic state remains unclear. Here we show that human IDH mutant gliomas exhibit hypermethylation at cohesin and CCCTC-binding factor (CTCF)-binding sites, compromising binding of this methylation-sensitive insulator protein. Reduced CTCF binding is associated with loss of insulation between topological domains and aberrant gene activation. We specifically demonstrate that loss of CTCF at a domain boundary permits a constitutive enhancer to interact aberrantly with the receptor tyrosine kinase gene PDGFRA, a prominent glioma oncogene. Treatment of IDH mutant gliomaspheres with a demethylating agent partially restores insulator function and downregulates PDGFRA. Conversely, CRISPR-mediated disruption of the CTCF motif in IDH wild-type gliomaspheres upregulates PDGFRA and increases proliferation. Our study suggests that IDH mutations promote gliomagenesis by disrupting chromosomal topology and allowing aberrant regulatory interactions that induce oncogene expression.