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Although KDM5C is one of the most frequently mutated genes in X-linked intellectual disability1, the exact mechanisms that lead to cognitive impairment remain unknown. Here we use human patient-derived induced pluripotent stem cells and Kdm5c knockout mice to conduct cellular, transcriptomic, chromatin and behavioural studies. KDM5C is identified as a safeguard to ensure that neurodevelopment occurs at an appropriate timescale, the disruption of which leads to intellectual disability. Specifically, there is a developmental window during which KDM5C directly controls WNT output to regulate the timely transition of primary to intermediate progenitor cells and consequently neurogenesis. Treatment with WNT signalling modulators at specific times reveal that only a transient alteration of the canonical WNT signalling pathway is sufficient to rescue the transcriptomic and chromatin landscapes in patient-derived cells and to induce these changes in wild-type cells. Notably, WNT inhibition during this developmental period also rescues behavioural changes of Kdm5c knockout mice. Conversely, a single injection of WNT3A into the brains of wild-type embryonic mice cause anxiety and memory alterations. Our work identifies KDM5C as a crucial sentinel for neurodevelopment and sheds new light on KDM5C mutation-associated intellectual disability. The results also increase our general understanding of memory and anxiety formation, with the identification of WNT functioning in a transient nature to affect long-lasting cognitive function.
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Cognición , Embrión de Mamíferos , Desarrollo Embrionario , Histona Demetilasas , Vía de Señalización Wnt , Animales , Humanos , Ratones , Ansiedad , Cromatina/efectos de los fármacos , Cromatina/genética , Cromatina/metabolismo , Embrión de Mamíferos/metabolismo , Perfilación de la Expresión Génica , Histona Demetilasas/genética , Histona Demetilasas/metabolismo , Células Madre Pluripotentes Inducidas/citología , Células Madre Pluripotentes Inducidas/metabolismo , Discapacidad Intelectual/genética , Memoria , Ratones Noqueados , Mutación , Neurogénesis/genética , Vía de Señalización Wnt/efectos de los fármacosRESUMEN
OBJECTIVE: Training clinician-scientists is a primary objective of many academic neurology departments, as these individuals are uniquely positioned to perform insightful clinical or laboratory-based research informed both by clinical knowledge and their own experiences caring for patients. Despite its importance, training clinician-scientists has perhaps never been so challenging. The National Institute of Neurologic Disorders and Stroke (NINDS) R25 program was designed in an attempt to support these individuals, decrease the time needed to obtain National Institutes of Health K awards, and to help educate a cohort of trainees preparing for a career in academic neurology. We endeavored to describe the structure and features of the program while examining its outcomes. METHODS: R25 outcome data from 2009 to 2024 were reviewed. Statistical comparisons were made using 2-sided Mann-Whitney U testing. RESULTS: A total of 67% of adult neurologists who received an R25 had a successful application for a National Institutes of Health K award compared with 45% of adult neurologists who had not received R25 support (p < 0.0001). Among child neurologists, 73% who applied went on to receive K funding after R25 support, compared with 45% who had not been part of the R25 program (p < 0.001). The average time between completion of residency and obtaining a K award for R25 participants was decreased by 26 months among those with an MD/PhD degree, and 32 months for those with an MD degree compared with non-R25 individuals. INTERPRETATION: The R25 program has been successful in achieving its training goals, but stands as only one component of support for aspiring clinician-scientists. Investments and commitments made by academic neurology departments are key to supporting this success. ANN NEUROL 2024.
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We report that eight heterozygous missense mutations in TUBB3, encoding the neuron-specific beta-tubulin isotype III, result in a spectrum of human nervous system disorders that we now call the TUBB3 syndromes. Each mutation causes the ocular motility disorder CFEOM3, whereas some also result in intellectual and behavioral impairments, facial paralysis, and/or later-onset axonal sensorimotor polyneuropathy. Neuroimaging reveals a spectrum of abnormalities including hypoplasia of oculomotor nerves and dysgenesis of the corpus callosum, anterior commissure, and corticospinal tracts. A knock-in disease mouse model reveals axon guidance defects without evidence of cortical cell migration abnormalities. We show that the disease-associated mutations can impair tubulin heterodimer formation in vitro, although folded mutant heterodimers can still polymerize into microtubules. Modeling each mutation in yeast tubulin demonstrates that all alter dynamic instability whereas a subset disrupts the interaction of microtubules with kinesin motors. These findings demonstrate that normal TUBB3 is required for axon guidance and maintenance in mammals.
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Tubulina (Proteína)/metabolismo , Secuencia de Aminoácidos , Animales , Axones/metabolismo , Encéfalo/embriología , Encéfalo/metabolismo , Supervivencia Celular , Niño , Discapacidades del Desarrollo , Femenino , Humanos , Cinesinas/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Microtúbulos/metabolismo , Modelos Moleculares , Datos de Secuencia Molecular , Mutación Missense , Transporte de Proteínas , Tubulina (Proteína)/química , Tubulina (Proteína)/genéticaRESUMEN
Medulloblastoma is a malignant childhood cerebellar tumour type that comprises distinct molecular subgroups. Whereas genomic characteristics of these subgroups are well defined, the extent to which cellular diversity underlies their divergent biology and clinical behaviour remains largely unexplored. Here we used single-cell transcriptomics to investigate intra- and intertumoral heterogeneity in 25 medulloblastomas spanning all molecular subgroups. WNT, SHH and Group 3 tumours comprised subgroup-specific undifferentiated and differentiated neuronal-like malignant populations, whereas Group 4 tumours consisted exclusively of differentiated neuronal-like neoplastic cells. SHH tumours closely resembled granule neurons of varying differentiation states that correlated with patient age. Group 3 and Group 4 tumours exhibited a developmental trajectory from primitive progenitor-like to more mature neuronal-like cells, the relative proportions of which distinguished these subgroups. Cross-species transcriptomics defined distinct glutamatergic populations as putative cells-of-origin for SHH and Group 4 subtypes. Collectively, these data provide insights into the cellular and developmental states underlying subtype-specific medulloblastoma biology.
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Genómica , Meduloblastoma/genética , Meduloblastoma/patología , Análisis de la Célula Individual , Transcriptoma , Adolescente , Adulto , Animales , Linaje de la Célula , Cerebelo/metabolismo , Cerebelo/patología , Niño , Preescolar , Variaciones en el Número de Copia de ADN , Regulación Neoplásica de la Expresión Génica , Ácido Glutámico/metabolismo , Humanos , Lactante , Meduloblastoma/clasificación , Ratones , Neuronas/metabolismo , Neuronas/patologíaRESUMEN
PURPOSE: Clinically ascertained variants are under-utilized in neurodevelopmental disorder research. We established the Brain Gene Registry (BGR) to coregister clinically identified variants in putative brain genes with participant phenotypes. Here, we report 179 genetic variants in the first 179 BGR registrants and analyze the proportion that were novel to ClinVar at the time of entry and those that were absent in other disease databases. METHODS: From 10 academically affiliated institutions, 179 individuals with 179 variants were enrolled into the BGR. Variants were cross-referenced for previous presence in ClinVar and for presence in 6 other genetic databases. RESULTS: Of 179 variants in 76 genes, 76 (42.5%) were novel to ClinVar, and 62 (34.6%) were absent from all databases analyzed. Of the 103 variants present in ClinVar, 37 (35.9%) were uncertain (ClinVar aggregate classification of variant of uncertain significance or conflicting classifications). For 5 variants, the aggregate ClinVar classification was inconsistent with the interpretation from the BGR site-provided classification. CONCLUSION: A significant proportion of clinical variants that are novel or uncertain are not shared, limiting the evidence base for new gene-disease relationships. Registration of paired clinical genetic test results with phenotype has the potential to advance knowledge of the relationships between genes and neurodevelopmental disorders.
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Bases de Datos Genéticas , Variación Genética , Humanos , Variación Genética/genética , Pruebas Genéticas/métodos , Fenotipo , EncéfaloRESUMEN
Recent insights into the frequency of occurrence and the genetic and mechanistic basis of nervous system disease have demonstrated that neurologic disorders occur as a spectrum across all ages. To meet future needs of patients with neurologic disease of all ages and prepare for increasing implementaton of precision therapies, greater integration of child and adult neurology residency training is needed. ANN NEUROL 2023;94:1005-1007.
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Internado y Residencia , Enfermedades del Sistema Nervioso , Neurología , Adulto , Niño , Humanos , Neurología/educación , Enfermedades del Sistema Nervioso/genética , Enfermedades del Sistema Nervioso/terapiaRESUMEN
In the very young child (less than eight years of age), transient loss of consciousness represents a diagnostic and management dilemma for clinicians. While most commonly benign, syncope may be due to cardiac dysfunction which can be life-threatening. It can be secondary to an underlying ion channelopathy, cardiac inflammation, cardiac ischemia, congenital heart disease, cardiomyopathy, or pulmonary hypertension. Patients with genetic disorders require careful evaluation for a cardiac cause of syncope. Among the noncardiac causes, vasovagal syncope is the most common etiology. Breath-holding spells are commonly seen in this age group. Other causes of transient loss of consciousness include seizures, neurovascular pathology, head trauma, psychogenic pseudosyncope, and factitious disorder imposed on another and other forms of child abuse. A detailed social, present, past medical, and family medical history is important when evaluating loss of consciousness in the very young. Concerning characteristics of syncope include lack of prodromal symptoms, no preceding postural changes or occurring in a supine position, after exertion or a loud noise. A family history of sudden unexplained death, ion channelopathy, cardiomyopathy, or congenital deafness merits further evaluation. Due to inherent challenges in diagnosis at this age, often there is a lower threshold for referral to a specialist.
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Síncope/diagnóstico , Síncope/etiología , Arritmias Cardíacas/complicaciones , Cardiomiopatías/complicaciones , Niño , Preescolar , Diagnóstico Diferencial , Cardiopatías Congénitas/complicaciones , Humanos , Hipertensión Pulmonar/complicaciones , Masculino , Convulsiones/complicaciones , Síncope Vasovagal/complicaciones , Inconsciencia/diagnóstico , Inconsciencia/etiologíaRESUMEN
Progress in addressing the origins of intellectual and developmental disabilities accelerated with the establishment 50 years ago of the Eunice Kennedy Shriver National Institute of Child Health and Human Development of the National Institutes of Health and associated Intellectual and Developmental Disabilities Research Centers. Investigators at these Centers have made seminal contributions to understanding human brain and behavioral development and defining mechanisms and treatments of disorders of the developing brain. ANN NEUROL 2019;86:332-343.
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Academias e Institutos/historia , Discapacidades del Desarrollo , Discapacidad Intelectual , National Institute of Child Health and Human Development (U.S.)/historia , Historia del Siglo XX , Historia del Siglo XXI , Humanos , Estados UnidosRESUMEN
Pineoblastomas (PBs) are rare, aggressive pediatric brain tumors of the pineal gland with modest overall survival despite intensive therapy. We sought to define the clinical and molecular spectra of PB to inform new treatment approaches for this orphan cancer. Tumor, blood, and clinical data from 91 patients with PB or supratentorial primitive neuroectodermal tumor (sPNETs/CNS-PNETs), and 2 pineal parenchymal tumors of intermediate differentiation (PPTIDs) were collected from 29 centres in the Rare Brain Tumor Consortium. We used global DNA methylation profiling to define a core group of PB from 72/93 cases, which were delineated into five molecular sub-groups. Copy number, whole exome and targeted sequencing, and miRNA expression analyses were used to evaluate the clinico-pathologic significance of each sub-group. Tumors designated as group 1 and 2 almost exclusively exhibited deleterious homozygous loss-of-function alterations in miRNA biogenesis genes (DICER1, DROSHA, and DGCR8) in 62 and 100% of group 1 and 2 tumors, respectively. Recurrent alterations of the oncogenic MYC-miR-17/92-RB1 pathway were observed in the RB and MYC sub-group, respectively, characterized by RB1 loss with gain of miR-17/92, and recurrent gain or amplification of MYC. PB sub-groups exhibited distinct clinical features: group 1-3 arose in older children (median ages 5.2-14.0 years) and had intermediate to excellent survival (5-year OS of 68.0-100%), while Group RB and MYC PB patients were much younger (median age 1.3-1.4 years) with dismal survival (5-year OS 37.5% and 28.6%, respectively). We identified age < 3 years at diagnosis, metastatic disease, omission of upfront radiation, and chr 16q loss as significant negative prognostic factors across all PBs. Our findings demonstrate that PB exhibits substantial molecular heterogeneity with sub-group-associated clinical phenotypes and survival. In addition to revealing novel biology and therapeutics, molecular sub-grouping of PB can be exploited to reduce treatment intensity for patients with favorable biology tumors.
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Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patología , Glándula Pineal , Pinealoma/genética , Pinealoma/patología , Adolescente , Adulto , Factores de Edad , Neoplasias Encefálicas/mortalidad , Niño , Preescolar , Estudios de Cohortes , Femenino , Humanos , Lactante , Masculino , MicroARNs/metabolismo , Mutación/genética , Pinealoma/mortalidad , Sistema de Registros , Tasa de Supervivencia , Adulto JovenRESUMEN
INTRODUCTION: Brain tumors make up over a quarter of pediatric malignancies. Depending on the age of presentation and treatment, pediatric brain tumor survivors experience varying degrees of treatment induced morbidity and sequelae. Epigenetic mechanisms play a critical role in silencing of tumor suppressor genes and activation of driver genes involved in oncogenesis in different types of brain tumors. Epigenetic modifications in pediatric brain tumor patients may influence long-term survival and may refine the molecular response to treatment induced morbidity and sequelae. However, there is a dearth of studies on how epigenetics of pediatric brain tumors is connected with neurocognition and other treatment related sequelae in survivors. METHODS/RESULTS: In this review we explore epigenetic factors that may contribute to the survivorship and treatment of pediatric brain tumor patients. We focus on glioblastoma, medulloblastoma, and the neurocutaneous syndrome neurofibromatosis type-1 to highlight epigenetic biomarkers that can potentially serve not only as prognostic indicators of overall patient survival, but hopefully as indicators to the response to treatment neurocognitively and otherwise. CONCLUSIONS: Future studies will hopefully soon bridge the gap in our knowledge on how epigenetic modifications are linked to treatment related sequelae in pediatric brain tumor patients.
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Neoplasias Encefálicas , Neoplasias Cerebelosas , Meduloblastoma , Neoplasias Encefálicas/genética , Neoplasias Cerebelosas/genética , Niño , Epigénesis Genética , Humanos , Meduloblastoma/genética , SupervivenciaRESUMEN
PURPOSE: Medulloblastoma, the most common primary pediatric malignant brain tumor, originates in the posterior fossa of the brain. Pineoblastoma, which originates within the pineal gland, is a rarer malignancy that also presents in the pediatric population. Medulloblastoma and pineoblastoma exhibit overlapping clinical features and have similar histopathological characteristics. Histopathological similarities confound rapid diagnoses of these two tumor types. We have conducted a pilot feasibility study analyzing the molecular profile of archived frozen human tumor specimens using mass spectrometry imaging (MSI) to identify potential biomarkers capable of classifying and distinguishing between medulloblastoma and pineoblastoma. METHODS: We performed matrix-assisted laser desorption ionization Fourier transform ion cyclotron resonance mass spectrometry imaging on eight medulloblastoma biopsy specimens and three pineoblastoma biopsy specimens. Multivariate statistical analyses were performed on the MSI dataset to generate classifiers that distinguish the two tumor types. Lastly, the molecules that were discriminative of tumor type were queried against the Lipid Maps database and identified. RESULTS: In this pilot study we show that medulloblastoma and pineoblastoma can be discriminated using molecular profiles determined by MSI. The highest-ranking discriminating classifiers of medulloblastoma and pineoblastoma were glycerophosphoglycerols and sphingolipids, respectively. CONCLUSION: We demonstrate proof-of-concept that medulloblastoma and pineoblastoma can be rapidly distinguished by using MSI lipid profiles. We identified biomarker candidates capable of distinguishing these two histopathologically similar tumor types. This work expands the current molecular knowledge of medulloblastoma and pineoblastoma by characterizing their lipidomic profiles, which may be useful for developing novel diagnostic, prognostic and therapeutic strategies.
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Neoplasias Encefálicas/metabolismo , Meduloblastoma/metabolismo , Pinealoma/metabolismo , Espectrometría de Masa por Láser de Matriz Asistida de Ionización Desorción , Neoplasias Encefálicas/diagnóstico por imagen , Neoplasias Encefálicas/patología , Cerebelo/diagnóstico por imagen , Cerebelo/metabolismo , Niño , Diagnóstico Diferencial , Humanos , Meduloblastoma/diagnóstico por imagen , Meduloblastoma/patología , Proyectos Piloto , Glándula Pineal/diagnóstico por imagen , Glándula Pineal/metabolismo , Glándula Pineal/patología , Pinealoma/diagnóstico por imagen , Pinealoma/patología , Prueba de Estudio ConceptualRESUMEN
Medulloblastomas are the most common malignant brain tumours in children. Identifying and understanding the genetic events that drive these tumours is critical for the development of more effective diagnostic, prognostic and therapeutic strategies. Recently, our group and others described distinct molecular subtypes of medulloblastoma on the basis of transcriptional and copy number profiles. Here we use whole-exome hybrid capture and deep sequencing to identify somatic mutations across the coding regions of 92 primary medulloblastoma/normal pairs. Overall, medulloblastomas have low mutation rates consistent with other paediatric tumours, with a median of 0.35 non-silent mutations per megabase. We identified twelve genes mutated at statistically significant frequencies, including previously known mutated genes in medulloblastoma such as CTNNB1, PTCH1, MLL2, SMARCA4 and TP53. Recurrent somatic mutations were newly identified in an RNA helicase gene, DDX3X, often concurrent with CTNNB1 mutations, and in the nuclear co-repressor (N-CoR) complex genes GPS2, BCOR and LDB1. We show that mutant DDX3X potentiates transactivation of a TCF promoter and enhances cell viability in combination with mutant, but not wild-type, ß-catenin. Together, our study reveals the alteration of WNT, hedgehog, histone methyltransferase and now N-CoR pathways across medulloblastomas and within specific subtypes of this disease, and nominates the RNA helicase DDX3X as a component of pathogenic ß-catenin signalling in medulloblastoma.
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Neoplasias Cerebelosas/genética , Exoma/genética , Genoma Humano/genética , Meduloblastoma/genética , Mutación/genética , Neoplasias Cerebelosas/clasificación , Niño , ARN Helicasas DEAD-box/química , ARN Helicasas DEAD-box/genética , ARN Helicasas DEAD-box/metabolismo , ADN Helicasas/química , ADN Helicasas/genética , Proteínas de Unión al ADN/genética , Proteínas Hedgehog/metabolismo , Histona Metiltransferasas , N-Metiltransferasa de Histona-Lisina/genética , N-Metiltransferasa de Histona-Lisina/metabolismo , Humanos , Péptidos y Proteínas de Señalización Intracelular/genética , Proteínas con Dominio LIM/genética , Meduloblastoma/clasificación , Modelos Moleculares , Proteínas de Neoplasias/genética , Proteínas Nucleares/química , Proteínas Nucleares/genética , Receptores Patched , Receptor Patched-1 , Regiones Promotoras Genéticas/genética , Estructura Terciaria de Proteína/genética , Proteínas Proto-Oncogénicas/genética , Receptores de Superficie Celular/genética , Proteínas Represoras/genética , Transducción de Señal , Factores de Transcripción TCF/metabolismo , Factores de Transcripción/química , Factores de Transcripción/genética , Proteína p53 Supresora de Tumor/genética , Proteínas Wnt/metabolismo , beta Catenina/genética , beta Catenina/metabolismoAsunto(s)
Anticonvulsivantes/uso terapéutico , Infecciones por Coronavirus , Pandemias , Neumonía Viral , Espasmos Infantiles/diagnóstico , Espasmos Infantiles/tratamiento farmacológico , Nivel de Atención , Hormona Adrenocorticotrópica/uso terapéutico , Betacoronavirus , COVID-19 , Atención a la Salud , Manejo de la Enfermedad , Electroencefalografía , Recursos en Salud , Humanos , Lactante , Recién Nacido , Imagen por Resonancia Magnética , Neurología , Prednisolona/uso terapéutico , SARS-CoV-2 , Telemedicina , Esclerosis Tuberosa/diagnóstico , Comunicación por Videoconferencia , Vigabatrin/uso terapéuticoRESUMEN
Historical risk stratification criteria for medulloblastoma rely primarily on clinicopathological variables pertaining to age, presence of metastases, extent of resection, histological subtypes and in some instances individual genetic aberrations such as MYC and MYCN amplification. In 2010, an international panel of experts established consensus defining four main subgroups of medulloblastoma (WNT, SHH, Group 3 and Group 4) delineated by transcriptional profiling. This has led to the current generation of biomarker-driven clinical trials assigning WNT tumors to a favorable prognosis group in addition to clinicopathological criteria including MYC and MYCN gene amplifications. However, outcome prediction of non-WNT subgroups is a challenge due to inconsistent survival reports. In 2015, a consensus conference was convened in Heidelberg with the objective to further refine the risk stratification in the context of subgroups and agree on a definition of risk groups of non-infant, childhood medulloblastoma (ages 3-17). Published and unpublished data over the past 5 years were reviewed, and a consensus was reached regarding the level of evidence for currently available biomarkers. The following risk groups were defined based on current survival rates: low risk (>90 % survival), average (standard) risk (75-90 % survival), high risk (50-75 % survival) and very high risk (<50 % survival) disease. The WNT subgroup and non-metastatic Group 4 tumors with whole chromosome 11 loss or whole chromosome 17 gain were recognized as low-risk tumors that may qualify for reduced therapy. High-risk strata were defined as patients with metastatic SHH or Group 4 tumors, or MYCN-amplified SHH medulloblastomas. Very high-risk patients are Group 3 with metastases or SHH with TP53 mutation. In addition, a number of consensus points were reached that should be standardized across future clinical trials. Although we anticipate new data will emerge from currently ongoing and recently completed clinical trials, this consensus can serve as an outline for prioritization of certain molecular subsets of tumors to define and validate risk groups as a basis for future clinical trials.
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Biomarcadores de Tumor/genética , Neoplasias Cerebelosas/genética , Perfilación de la Expresión Génica , Meduloblastoma/genética , Adolescente , Neoplasias Cerebelosas/epidemiología , Neoplasias Cerebelosas/mortalidad , Niño , Preescolar , Humanos , Meduloblastoma/epidemiología , Meduloblastoma/mortalidad , Pronóstico , Factores de RiesgoRESUMEN
Pediatric low-grade gliomas (PLGGs) are among the most common solid tumors in children but, apart from BRAF kinase mutations or duplications in specific subclasses, few genetic driver events are known. Diffuse PLGGs comprise a set of uncommon subtypes that exhibit invasive growth and are therefore especially challenging clinically. We performed high-resolution copy-number analysis on 44 formalin-fixed, paraffin-embedded diffuse PLGGs to identify recurrent alterations. Diffuse PLGGs exhibited fewer such alterations than adult low-grade gliomas, but we identified several significantly recurrent events. The most significant event, 8q13.1 gain, was observed in 28% of diffuse astrocytoma grade IIs and resulted in partial duplication of the transcription factor MYBL1 with truncation of its C-terminal negative-regulatory domain. A similar recurrent deletion-truncation breakpoint was identified in two angiocentric gliomas in the related gene v-myb avian myeloblastosis viral oncogene homolog (MYB) on 6q23.3. Whole-genome sequencing of a MYBL1-rearranged diffuse astrocytoma grade II demonstrated MYBL1 tandem duplication and few other events. Truncated MYBL1 transcripts identified in this tumor induced anchorage-independent growth in 3T3 cells and tumor formation in nude mice. Truncated transcripts were also expressed in two additional tumors with MYBL1 partial duplication. Our results define clinically relevant molecular subclasses of diffuse PLGGs and highlight a potential role for the MYB family in the biology of low-grade gliomas.
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Neoplasias Encefálicas/genética , Glioma/genética , Proteínas Proto-Oncogénicas/genética , Transactivadores/genética , Células 3T3 , Alelos , Animales , Neoplasias Encefálicas/patología , Línea Celular Tumoral , Niño , Preescolar , Estudios de Cohortes , Hibridación Genómica Comparativa , Glioma/patología , Humanos , Masculino , Ratones , Ratones Desnudos , Familia de Multigenes , Mutación , Estructura Terciaria de Proteína , Análisis de Secuencia de ADNRESUMEN
OBJECTIVE: Seizures are common during and after treatment for a primary brain tumor. Our objective was to describe the incidence and risk factors for seizures in long-term survivors of pediatric brain tumors. METHODS: In a retrospective, longitudinal study, we reviewed all consecutive patients during a 12-month period who were at least 2 years post initial diagnosis of a brain tumor. Data collection included age at diagnosis, length of follow-up, extent of initial resection, tumor histology, and treatment modalities. For patients who had experienced seizures at any time, the timing and frequency of seizures, seizure semiology, electroencephalography results, and anticonvulsant use were recorded. Univariate analyses and logistic regression were performed to assess risk factors. RESULTS: The cohort included 298 patients (140 female). Average duration of follow-up was 7.6 years. Initial surgical resection was gross-total in 109 patients, and subtotal for 143. Twenty-nine patients underwent biopsy alone and 17 had no surgical intervention. Tumor location included posterior fossa (104; 36%), midline (98; 34%), cortical (85; 29%), and other (11; 3%). Most frequent diagnoses were low grade glioma, medulloblastoma, and ependymoma. Other treatments included cranial irradiation (N = 163) and chemotherapy (n = 127). Tumor recurrence occurred in 92 patients (30%). Seventy-one patients had seizures (24%). Ongoing seizures at the time of most recent follow-up were present in 42 patients. Risk factors for seizures included tumor location, tumor histology, tumor recurrence, and incomplete resection at time of initial presentation. SIGNIFICANCE: Seizures are a frequent comorbidity in pediatric brain tumor survivors, seen at presentation in 24% of patients and ongoing in 14%. Factors predisposing to seizures include tumor pathology (low/high grade glioma, glioneuronal tumor), cortical location, and subtotal resection. These data may assist in identification and management of patients at highest risk for seizures as well as identification of patients for potential treatment trials with antiepileptogenic agents.
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Neoplasias Encefálicas , Epilepsia/epidemiología , Epilepsia/etiología , Adolescente , Neoplasias Encefálicas/complicaciones , Neoplasias Encefálicas/epidemiología , Neoplasias Encefálicas/mortalidad , Niño , Estudios de Cohortes , Femenino , Humanos , Incidencia , Masculino , Pediatría , Factores de RiesgoRESUMEN
WTX is a tumor suppressor gene expressed during embryonic development and inactivated in 20-30% of cases of Wilms tumor, the most common pediatric kidney cancer. WTX has been implicated in several cellular processes including Wnt signaling, WT1 transcription, NRF2 degradation, and p53 function. Given that WTX is widely expressed during embryonic development and has been recently shown to regulate mesenchymal precursor cells in several organs, we tested for the potential involvement of WTX in a panel of pediatric tumors and adult sarcomas. A total of 353 tumors were screened for WTX deletions by fluorescence in situ hybridization (FISH). Discrete somatic WTX deletions were identified in two cases, one hepatoblastoma and one embryonal rhabdomyosarcoma, and confirmed by array comparative genomic hybridization. Direct sequencing of the full WTX open reading frame in 24 hepatoblastomas and 21 embryonal rhabdomyosarcomas did not identify additional mutations in these tumor types. The presence of WTX mRNA was confirmed in hepatoblastomas and embryonal rhabdomyosarcomas without WTX deletions by RNA-in situ hybridization. Notably, tumors with evidence of WTX inactivation, Wilms tumor, hepatoblastoma and rhabdomyosarcoma, are primitive tumors that resemble undifferentiated precursor cells and are linked to overgrowth syndromes. These results indicate that WTX inactivation occurs in a wider variety of tumor types than previously appreciated and point to shared pathogenic mechanisms between a subset of pediatric malignancies.
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Proteínas Adaptadoras Transductoras de Señales/genética , Hepatoblastoma/genética , Neoplasias Hepáticas/genética , Rabdomiosarcoma Embrionario/genética , Proteínas Supresoras de Tumor/genética , Tumor de Wilms/genética , Adulto , Preescolar , Femenino , Regulación de la Expresión Génica , Humanos , Masculino , Eliminación de SecuenciaRESUMEN
Neural tumors often express neurotransmitter receptors as markers of their developmental lineage. Although these receptors have been well characterized in electrophysiological, developmental and pharmacological settings, their importance in the maintenance and progression of brain tumors and, importantly, the effect of their targeting in brain cancers remains obscure. Here, we demonstrate high levels of GABRA5, which encodes the α5-subunit of the GABAA receptor complex, in aggressive MYC-driven, "Group 3" medulloblastomas. We hypothesized that modulation of α5-GABAA receptors alters medulloblastoma cell survival and monitored biological and electrophysiological responses of GABRA5-expressing medulloblastoma cells upon pharmacological targeting of the GABAA receptor. While antagonists, inverse agonists and non-specific positive allosteric modulators had limited effects on medulloblastoma cells, a highly specific and potent α5-GABAA receptor agonist, QHii066, resulted in marked membrane depolarization and a significant decrease in cell survival. This effect was GABRA5 dependent and mediated through the induction of apoptosis as well as accumulation of cells in S and G2 phases of the cell cycle. Chemical genomic profiling of QHii066-treated medulloblastoma cells confirmed inhibition of MYC-related transcriptional activity and revealed an enrichment of HOXA5 target gene expression. siRNA-mediated knockdown of HOXA5 markedly blunted the response of medulloblastoma cells to QHii066. Furthermore, QHii066 sensitized GABRA5 positive medulloblastoma cells to radiation and chemotherapy consistent with the role of HOXA5 in directly regulating p53 expression and inducing apoptosis. Thus, our results provide novel insights into the synthetic lethal nature of α5-GABAA receptor activation in MYC-driven/Group 3 medulloblastomas and propose its targeting as a novel strategy for the management of this highly aggressive tumor.
Asunto(s)
Neoplasias Cerebelosas/metabolismo , Regulación Neoplásica de la Expresión Génica/fisiología , Meduloblastoma/metabolismo , Proteínas Proto-Oncogénicas c-myc/metabolismo , Receptores Nicotínicos/metabolismo , Animales , Benzodiazepinas/farmacología , Ciclo Celular/genética , Línea Celular Tumoral , Proliferación Celular , Neoplasias Cerebelosas/patología , Cisplatino/farmacología , Ensayo de Unidades Formadoras de Colonias , Agonistas del GABA/farmacología , Proteínas de Homeodominio/genética , Proteínas de Homeodominio/metabolismo , Humanos , Meduloblastoma/patología , Potenciales de la Membrana/efectos de los fármacos , Potenciales de la Membrana/genética , Ratones , Técnicas de Placa-Clamp , Receptores Nicotínicos/genética , Proteína p53 Supresora de Tumor/genética , Proteína p53 Supresora de Tumor/metabolismo , Ensayos Antitumor por Modelo de Xenoinjerto , Ácido gamma-Aminobutírico/farmacologíaRESUMEN
Amplification of the C19MC oncogenic miRNA cluster and high LIN28 expression has been linked to a distinctly aggressive group of cerebral CNS-PNETs (group 1 CNS-PNETs) arising in young children. In this study, we sought to evaluate the diagnostic specificity of C19MC and LIN28, and the clinical and biological spectra of C19MC amplified and/or LIN28+ CNS-PNETs. We interrogated 450 pediatric brain tumors using FISH and IHC analyses and demonstrate that C19MC alteration is restricted to a sub-group of CNS-PNETs with high LIN28 expression; however, LIN28 immunopositivity was not exclusive to CNS-PNETs but was also detected in a proportion of other malignant pediatric brain tumors including rhabdoid brain tumors and malignant gliomas. C19MC amplified/LIN28+ group 1 CNS-PNETs arose predominantly in children <4 years old; a majority arose in the cerebrum but 24 % (13/54) of tumors had extra-cerebral origins. Notably, group 1 CNS-PNETs encompassed several histologic classes including embryonal tumor with abundant neuropil and true rosettes (ETANTR), medulloepithelioma, ependymoblastoma and CNS-PNETs with variable differentiation. Strikingly, gene expression and methylation profiling analyses revealed a common molecular signature enriched for primitive neural features, high LIN28/LIN28B and DNMT3B expression for all group 1 CNS-PNETs regardless of location or tumor histology. Our collective findings suggest that current known histologic categories of CNS-PNETs which include ETANTRs, medulloepitheliomas, ependymoblastomas in various CNS locations, comprise a common molecular and diagnostic entity and identify inhibitors of the LIN28/let7/PI3K/mTOR axis and DNMT3B as promising therapeutics for this distinct histogenetic entity.