RESUMO
Glioblastoma multiforme (GBM) is an aggressive brain tumor for which current immunotherapy approaches have been unsuccessful. Here, we explore the mechanisms underlying immune evasion in GBM. By serially transplanting GBM stem cells (GSCs) into immunocompetent hosts, we uncover an acquired capability of GSCs to escape immune clearance by establishing an enhanced immunosuppressive tumor microenvironment. Mechanistically, this is not elicited via genetic selection of tumor subclones, but through an epigenetic immunoediting process wherein stable transcriptional and epigenetic changes in GSCs are enforced following immune attack. These changes launch a myeloid-affiliated transcriptional program, which leads to increased recruitment of tumor-associated macrophages. Furthermore, we identify similar epigenetic and transcriptional signatures in human mesenchymal subtype GSCs. We conclude that epigenetic immunoediting may drive an acquired immune evasion program in the most aggressive mesenchymal GBM subtype by reshaping the tumor immune microenvironment.
Assuntos
Neoplasias Encefálicas/imunologia , Epigênese Genética , Glioblastoma/imunologia , Evasão da Resposta Imune/imunologia , Células Mieloides/imunologia , Células-Tronco Neoplásicas/imunologia , Microambiente Tumoral/imunologia , Animais , Apoptose , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patologia , Proliferação de Células , Metilação de DNA , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Glioblastoma/genética , Glioblastoma/metabolismo , Glioblastoma/patologia , Humanos , Masculino , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Células Mieloides/metabolismo , Células Mieloides/patologia , Células-Tronco Neoplásicas/metabolismo , Células-Tronco Neoplásicas/patologia , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Histone H3.3 glycine 34 to arginine/valine (G34R/V) mutations drive deadly gliomas and show exquisite regional and temporal specificity, suggesting a developmental context permissive to their effects. Here we show that 50% of G34R/V tumors (n = 95) bear activating PDGFRA mutations that display strong selection pressure at recurrence. Although considered gliomas, G34R/V tumors actually arise in GSX2/DLX-expressing interneuron progenitors, where G34R/V mutations impair neuronal differentiation. The lineage of origin may facilitate PDGFRA co-option through a chromatin loop connecting PDGFRA to GSX2 regulatory elements, promoting PDGFRA overexpression and mutation. At the single-cell level, G34R/V tumors harbor dual neuronal/astroglial identity and lack oligodendroglial programs, actively repressed by GSX2/DLX-mediated cell fate specification. G34R/V may become dispensable for tumor maintenance, whereas mutant-PDGFRA is potently oncogenic. Collectively, our results open novel research avenues in deadly tumors. G34R/V gliomas are neuronal malignancies where interneuron progenitors are stalled in differentiation by G34R/V mutations and malignant gliogenesis is promoted by co-option of a potentially targetable pathway, PDGFRA signaling.
Assuntos
Neoplasias Encefálicas/genética , Carcinogênese/genética , Glioma/genética , Histonas/genética , Interneurônios/metabolismo , Mutação/genética , Células-Tronco Neurais/metabolismo , Receptor alfa de Fator de Crescimento Derivado de Plaquetas/genética , Animais , Astrócitos/metabolismo , Astrócitos/patologia , Neoplasias Encefálicas/patologia , Carcinogênese/patologia , Linhagem da Célula , Reprogramação Celular/genética , Cromatina/metabolismo , Embrião de Mamíferos/metabolismo , Epigênese Genética , Regulação Neoplásica da Expressão Gênica , Inativação Gênica , Glioma/patologia , Histonas/metabolismo , Lisina/metabolismo , Camundongos Endogâmicos C57BL , Modelos Biológicos , Gradação de Tumores , Oligodendroglia/metabolismo , Regiões Promotoras Genéticas/genética , Prosencéfalo/embriologia , Receptor alfa de Fator de Crescimento Derivado de Plaquetas/metabolismo , Transcrição Gênica , Transcriptoma/genéticaRESUMO
Interictal epileptiform discharges (IEDs) are transient abnormal electrophysiological events commonly observed in epilepsy patients but are also present in other neurological diseases, such as Alzheimer's disease (AD). Understanding the role IEDs have on the hippocampal circuit is important for our understanding of the cognitive deficits seen in epilepsy and AD. We characterize and compare the IEDs of human epilepsy patients from microwire hippocampal recording with those of AD transgenic mice with implanted multilayer hippocampal silicon probes. Both the local field potential features and firing patterns of pyramidal cells and interneurons were similar in the mouse and human. We found that as IEDs emerged from the CA3-1 circuits, they recruited pyramidal cells and silenced interneurons, followed by post-IED suppression. IEDs suppressed the incidence and altered the properties of physiological sharp-wave ripples, altered their physiological properties, and interfered with the replay of place field sequences in a maze. In addition, IEDs in AD mice inversely correlated with daily memory performance. Together, our work implies that IEDs may present a common and epilepsy-independent phenomenon in neurodegenerative diseases that perturbs hippocampal-cortical communication and interferes with memory.
Assuntos
Doença de Alzheimer , Líquidos Corporais , Transtornos Cognitivos , Humanos , Animais , Camundongos , Doença de Alzheimer/genética , Cognição , Modelos Animais de Doenças , Camundongos TransgênicosRESUMO
Deep learning applied to whole-slide histopathology images (WSIs) has the potential to enhance precision oncology and alleviate the workload of experts. However, developing these models necessitates large amounts of data with ground truth labels, which can be both time-consuming and expensive to obtain. Pathology reports are typically unstructured or poorly structured texts, and efforts to implement structured reporting templates have been unsuccessful, as these efforts lead to perceived extra workload. In this study, we hypothesised that large language models (LLMs), such as the generative pre-trained transformer 4 (GPT-4), can extract structured data from unstructured plain language reports using a zero-shot approach without requiring any re-training. We tested this hypothesis by utilising GPT-4 to extract information from histopathological reports, focusing on two extensive sets of pathology reports for colorectal cancer and glioblastoma. We found a high concordance between LLM-generated structured data and human-generated structured data. Consequently, LLMs could potentially be employed routinely to extract ground truth data for machine learning from unstructured pathology reports in the future. © 2023 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.
Assuntos
Glioblastoma , Medicina de Precisão , Humanos , Aprendizado de Máquina , Reino UnidoRESUMO
Sporadic Creutzfeldt-Jakob disease (sCJD), the most common human prion disease, is thought to occur when the cellular prion protein (PrPC) spontaneously misfolds and assembles into prion fibrils, culminating in fatal neurodegeneration. In a genome-wide association study of sCJD, we recently identified risk variants in and around the gene STX6, with evidence to suggest a causal increase of STX6 expression in disease-relevant brain regions. STX6 encodes syntaxin-6, a SNARE protein primarily involved in early endosome to trans-Golgi network retrograde transport. Here we developed and characterised a mouse model with genetic depletion of Stx6 and investigated a causal role of Stx6 expression in mouse prion disease through a classical prion transmission study, assessing the impact of homozygous and heterozygous syntaxin-6 knockout on disease incubation periods and prion-related neuropathology. Following inoculation with RML prions, incubation periods in Stx6-/- and Stx6+/- mice differed by 12 days relative to wildtype. Similarly, in Stx6-/- mice, disease incubation periods following inoculation with ME7 prions also differed by 12 days. Histopathological analysis revealed a modest increase in astrogliosis in ME7-inoculated Stx6-/- animals and a variable effect of Stx6 expression on microglia activation, however no differences in neuronal loss, spongiform change or PrP deposition were observed at endpoint. Importantly, Stx6-/- mice are viable and fertile with no gross impairments on a range of neurological, biochemical, histological and skeletal structure tests. Our results provide some support for a pathological role of Stx6 expression in prion disease, which warrants further investigation in the context of prion disease but also other neurodegenerative diseases considering syntaxin-6 appears to have pleiotropic risk effects in progressive supranuclear palsy and Alzheimer's disease.
Assuntos
Síndrome de Creutzfeldt-Jakob , Doenças Priônicas , Príons , Camundongos , Humanos , Animais , Síndrome de Creutzfeldt-Jakob/genética , Síndrome de Creutzfeldt-Jakob/patologia , Príons/genética , Príons/metabolismo , Estudo de Associação Genômica Ampla , Camundongos Transgênicos , Encéfalo/metabolismo , Doenças Priônicas/genética , Doenças Priônicas/patologia , Proteínas Qa-SNARE/genética , Proteínas Qa-SNARE/metabolismoRESUMO
Tumour-associated microglia/macrophages (TAM) are the most numerous non-neoplastic populations in the tumour microenvironment in glioblastoma multiforme (GBM), the most common malignant brain tumour in adulthood. The mTOR pathway, an important regulator of cell survival/proliferation, is upregulated in GBM, but little is known about the potential role of this pathway in TAM. Here, we show that GBM-initiating cells induce mTOR signalling in the microglia but not bone marrow-derived macrophages in both in vitro and in vivo GBM mouse models. mTOR-dependent regulation of STAT3 and NF-κB activity promotes an immunosuppressive microglial phenotype. This hinders effector T-cell infiltration, proliferation and immune reactivity, thereby contributing to tumour immune evasion and promoting tumour growth in mouse models. The translational value of our results is demonstrated in whole transcriptome datasets of human GBM and in a novel in vitro model, whereby expanded-potential stem cells (EPSC)-derived microglia-like cells are conditioned by syngeneic patient-derived GBM-initiating cells. These results raise the possibility that microglia could be the primary target of mTOR inhibition, rather than the intrinsic tumour cells in GBM.
Assuntos
Neoplasias Encefálicas/imunologia , Glioblastoma/imunologia , Tolerância Imunológica , Microglia/imunologia , Proteínas de Neoplasias/imunologia , Serina-Treonina Quinases TOR/imunologia , Microambiente Tumoral/imunologia , Animais , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patologia , Linhagem Celular Tumoral , Glioblastoma/genética , Glioblastoma/patologia , Humanos , Camundongos , Camundongos Knockout , Microglia/patologia , Proteínas de Neoplasias/genética , Serina-Treonina Quinases TOR/genética , Microambiente Tumoral/genéticaRESUMO
The convergence of digital pathology and artificial intelligence could assist histopathology image analysis by providing tools for rapid, automated morphological analysis. This systematic review explores the use of artificial intelligence for histopathological image analysis of digitised central nervous system (CNS) tumour slides. Comprehensive searches were conducted across EMBASE, Medline and the Cochrane Library up to June 2023 using relevant keywords. Sixty-eight suitable studies were identified and qualitatively analysed. The risk of bias was evaluated using the Prediction model Risk of Bias Assessment Tool (PROBAST) criteria. All the studies were retrospective and preclinical. Gliomas were the most frequently analysed tumour type. The majority of studies used convolutional neural networks or support vector machines, and the most common goal of the model was for tumour classification and/or grading from haematoxylin and eosin-stained slides. The majority of studies were conducted when legacy World Health Organisation (WHO) classifications were in place, which at the time relied predominantly on histological (morphological) features but have since been superseded by molecular advances. Overall, there was a high risk of bias in all studies analysed. Persistent issues included inadequate transparency in reporting the number of patients and/or images within the model development and testing cohorts, absence of external validation, and insufficient recognition of batch effects in multi-institutional datasets. Based on these findings, we outline practical recommendations for future work including a framework for clinical implementation, in particular, better informing the artificial intelligence community of the needs of the neuropathologist.
Assuntos
Inteligência Artificial , Neoplasias do Sistema Nervoso Central , Humanos , Neoplasias do Sistema Nervoso Central/patologia , Processamento de Imagem Assistida por Computador/métodosRESUMO
OBJECTIVE: Benchmarking has been proposed to reflect surgical quality and represents the highest standard reference values for desirable results. We sought to determine benchmark outcomes in patients after surgery for drug-resistant mesial temporal lobe epilepsy (MTLE). METHODS: This retrospective multicenter study included patients who underwent MTLE surgery at 19 expert centers on five continents. Benchmarks were defined for 15 endpoints covering surgery and epilepsy outcome at discharge, 1 year after surgery, and the last available follow-up. Patients were risk-stratified by applying outcome-relevant comorbidities, and benchmarks were calculated for low-risk ("benchmark") cases. Respective measures were derived from the median value at each center, and the 75th percentile was considered the benchmark cutoff. RESULTS: A total of 1119 patients with a mean age (range) of 36.7 (1-74) years and a male-to-female ratio of 1:1.1 were included. Most patients (59.2%) underwent anterior temporal lobe resection with amygdalohippocampectomy. The overall rate of complications or neurological deficits was 14.4%, with no in-hospital death. After risk stratification, 377 (33.7%) benchmark cases of 1119 patients were identified, representing 13.6%-72.9% of cases per center and leaving 742 patients in the high-risk cohort. Benchmark cutoffs for any complication, clinically apparent stroke, and reoperation rate at discharge were ≤24.6%, ≤.5%, and ≤3.9%, respectively. A favorable seizure outcome (defined as International League Against Epilepsy class I and II) was reached in 83.6% at 1 year and 79.0% at the last follow-up in benchmark cases, leading to benchmark cutoffs of ≥75.2% (1-year follow-up) and ≥69.5% (mean follow-up of 39.0 months). SIGNIFICANCE: This study presents internationally applicable benchmark outcomes for the efficacy and safety of MTLE surgery. It may allow for comparison between centers, patient registries, and novel surgical and interventional techniques.
Assuntos
Benchmarking , Epilepsia do Lobo Temporal , Humanos , Epilepsia do Lobo Temporal/cirurgia , Masculino , Feminino , Adulto , Pessoa de Meia-Idade , Adolescente , Adulto Jovem , Estudos Retrospectivos , Idoso , Resultado do Tratamento , Criança , Pré-Escolar , Lactente , Complicações Pós-Operatórias/epidemiologia , Procedimentos Neurocirúrgicos/normas , Procedimentos Neurocirúrgicos/métodos , Epilepsia Resistente a Medicamentos/cirurgia , Lobectomia Temporal Anterior/métodosRESUMO
Tumour heterogeneity is increasingly recognized as a major obstacle to therapeutic success across neuro-oncology. Gliomas are characterized by distinct combinations of genetic and epigenetic alterations, resulting in complex interactions across multiple molecular pathways. Predicting disease evolution and prescribing individually optimal treatment requires statistical models complex enough to capture the intricate (epi)genetic structure underpinning oncogenesis. Here, we formalize this task as the inference of distinct patterns of connectivity within hierarchical latent representations of genetic networks. Evaluating multi-institutional clinical, genetic and outcome data from 4023 glioma patients over 14 years, across 12 countries, we employ Bayesian generative stochastic block modelling to reveal a hierarchical network structure of tumour genetics spanning molecularly confirmed glioblastoma, IDH-wildtype; oligodendroglioma, IDH-mutant and 1p/19q codeleted; and astrocytoma, IDH-mutant. Our findings illuminate the complex dependence between features across the genetic landscape of brain tumours and show that generative network models reveal distinct signatures of survival with better prognostic fidelity than current gold standard diagnostic categories.
Assuntos
Neoplasias Encefálicas , Glioma , Humanos , Teorema de Bayes , Redes Reguladoras de Genes/genética , Mutação/genética , Isocitrato Desidrogenase/genética , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patologia , Glioma/genéticaRESUMO
Understanding the exact molecular mechanisms involved in the aetiology of epileptogenic pathologies with or without tumour activity is essential for improving treatment of drug-resistant focal epilepsy. Here, we characterize the landscape of somatic genetic variants in resected brain specimens from 474 individuals with drug-resistant focal epilepsy using deep whole-exome sequencing (>350×) and whole-genome genotyping. Across the exome, we observe a greater number of somatic single-nucleotide variants in low-grade epilepsy-associated tumours (7.92 ± 5.65 single-nucleotide variants) than in brain tissue from malformations of cortical development (6.11 ± 4 single-nucleotide variants) or hippocampal sclerosis (5.1 ± 3.04 single-nucleotide variants). Tumour tissues also had the largest number of likely pathogenic variant carrying cells. low-grade epilepsy-associated tumours had the highest proportion of samples with one or more somatic copy-number variants (24.7%), followed by malformations of cortical development (5.4%) and hippocampal sclerosis (4.1%). Recurring somatic whole chromosome duplications affecting Chromosome 7 (16.8%), chromosome 5 (10.9%), and chromosome 20 (9.9%) were observed among low-grade epilepsy-associated tumours. For germline variant-associated malformations of cortical development genes such as TSC2, DEPDC5 and PTEN, germline single-nucleotide variants were frequently identified within large loss of heterozygosity regions, supporting the recently proposed 'second hit' disease mechanism in these genes. We detect somatic variants in 12 established lesional epilepsy genes and demonstrate exome-wide statistical support for three of these in the aetiology of low-grade epilepsy-associated tumours (e.g. BRAF) and malformations of cortical development (e.g. SLC35A2 and MTOR). We also identify novel significant associations for PTPN11 with low-grade epilepsy-associated tumours and NRAS Q61 mutated protein with a complex malformation of cortical development characterized by polymicrogyria and nodular heterotopia. The variants identified in NRAS are known from cancer studies to lead to hyperactivation of NRAS, which can be targeted pharmacologically. We identify large recurrent 1q21-q44 duplication including AKT3 in association with focal cortical dysplasia type 2a with hyaline astrocytic inclusions, another rare and possibly under-recognized brain lesion. The clinical-genetic analyses showed that the numbers of somatic single-nucleotide variant across the exome and the fraction of affected cells were positively correlated with the age at seizure onset and surgery in individuals with low-grade epilepsy-associated tumours. In summary, our comprehensive genetic screen sheds light on the genome-scale landscape of genetic variants in epileptic brain lesions, informs the design of gene panels for clinical diagnostic screening and guides future directions for clinical implementation of epilepsy surgery genetics.
Assuntos
Epilepsia Resistente a Medicamentos , Epilepsias Parciais , Epilepsia , Malformações do Desenvolvimento Cortical , Humanos , Epilepsia/patologia , Encéfalo/patologia , Epilepsia Resistente a Medicamentos/genética , Epilepsia Resistente a Medicamentos/cirurgia , Epilepsia Resistente a Medicamentos/metabolismo , Genômica , Malformações do Desenvolvimento Cortical/complicações , Malformações do Desenvolvimento Cortical/genética , Malformações do Desenvolvimento Cortical/metabolismo , Epilepsias Parciais/metabolismo , Nucleotídeos/metabolismoRESUMO
PURPOSE: Many patients with glioblastoma suffer from tumor-related seizures. However, there is limited data on the characteristics of tumor-related epilepsy achieving seizure freedom. The aim of this study was to characterize the course of epilepsy in patients with glioblastoma and the factors that influence it. METHODS: We retrospectively analyzed the medical records of glioblastoma patients treated at the University Hospital Erlangen between 01/2006 and 01/2020. RESULTS: In the final cohort of patients with glioblastoma (n = 520), 292 patients (56.2 %) suffered from tumor-related epilepsy (persons with epilepsy, PWE). Levetiracetam was the most commonly used first-line antiseizure medication (n = 245, 83.9 % of PWE). The onset of epilepsy was preoperative in 154/292 patients (52.7 %). 136 PWE (46.6 %) experienced only one single seizure while 27/292 PWE (9.2 %) developed drug-resistant epilepsy. Status epilepticus occurred in 48/292 patients (16.4 %). Early postoperative onset (within 30 days of surgery) of epilepsy and total gross resection (compared with debulking) were independently associated with a lower risk of further seizures. We did not detect dose-dependent pro- or antiseizure effects of radiochemotherapy. CONCLUSION: Tumor-related epilepsy occurred in more than 50% of our cohort, but drug-resistant epilepsy developed in less than 10% of cases. Epilepsy usually started before tumor surgery.
RESUMO
We previously reported1 the presence of amyloid-ß protein (Aß) deposits in individuals with Creutzfeldt-Jakob disease (CJD) who had been treated during childhood with human cadaveric pituitary-derived growth hormone (c-hGH) contaminated with prions. The marked deposition of parenchymal and vascular Aß in these relatively young individuals with treatment-induced (iatrogenic) CJD (iCJD), in contrast to other prion-disease patients and population controls, allied with the ability of Alzheimer's disease brain homogenates to seed Aß deposition in laboratory animals, led us to argue that the implicated c-hGH batches might have been contaminated with Aß seeds as well as with prions. However, this was necessarily an association, and not an experimental, study in humans and causality could not be concluded. Given the public health importance of our hypothesis, we proceeded to identify and biochemically analyse archived vials of c-hGH. Here we show that certain c-hGH batches to which patients with iCJD and Aß pathology were exposed have substantial levels of Aß40, Aß42 and tau proteins, and that this material can seed the formation of Aß plaques and cerebral Aß-amyloid angiopathy in intracerebrally inoculated mice expressing a mutant, humanized amyloid precursor protein. These results confirm the presence of Aß seeds in archived c-hGH vials and are consistent with the hypothesized iatrogenic human transmission of Aß pathology. This experimental confirmation has implications for both the prevention and the treatment of Alzheimer's disease, and should prompt a review of the risk of iatrogenic transmission of Aß seeds by medical and surgical procedures long recognized to pose a risk of accidental prion transmission2,3.
Assuntos
Doença de Alzheimer/induzido quimicamente , Peptídeos beta-Amiloides/metabolismo , Cadáver , Síndrome de Creutzfeldt-Jakob/induzido quimicamente , Contaminação de Medicamentos , Hormônio do Crescimento/farmacologia , Doença Iatrogênica , Doença de Alzheimer/etiologia , Peptídeos beta-Amiloides/análise , Precursor de Proteína beta-Amiloide/administração & dosagem , Precursor de Proteína beta-Amiloide/efeitos adversos , Animais , Estudos de Casos e Controles , Síndrome de Creutzfeldt-Jakob/etiologia , Modelos Animais de Doenças , Transmissão de Doença Infecciosa/prevenção & controle , Transmissão de Doença Infecciosa/estatística & dados numéricos , Contaminação de Medicamentos/prevenção & controle , Contaminação de Medicamentos/estatística & dados numéricos , Feminino , Hormônio do Crescimento/administração & dosagem , Humanos , Masculino , Camundongos , Modelos Biológicos , Príons/metabolismo , Proteínas Recombinantes/administração & dosagem , Proteínas Recombinantes/farmacologia , Reprodutibilidade dos Testes , Proteínas tau/análise , Proteínas tau/metabolismoRESUMO
BACKGROUND: The role of isocitrate dehydrogenase (IDH) mutation status for glioma stratification and prognosis is established. While structural magnetic resonance image (MRI) is a promising biomarker, it may not be sufficient for non-invasive characterisation of IDH mutation status. We investigated the diagnostic value of combined diffusion tensor imaging (DTI) and structural MRI enhanced by a deep radiomics approach based on convolutional neural networks (CNNs) and support vector machine (SVM), to determine the IDH mutation status in Central Nervous System World Health Organization (CNS WHO) grade 2-4 gliomas. METHODS: This retrospective study analyzed the DTI-derived fractional anisotropy (FA) and mean diffusivity (MD) images and structural images including fluid attenuated inversion recovery (FLAIR), non-enhanced T1-, and T2-weighted images of 206 treatment-naïve gliomas, including 146 IDH mutant and 60 IDH-wildtype ones. The lesions were manually segmented by experienced neuroradiologists and the masks were applied to the FA and MD maps. Deep radiomics features were extracted from each subject by applying a pre-trained CNN and statistical description. An SVM classifier was applied to predict IDH status using imaging features in combination with demographic data. RESULTS: We comparatively assessed the CNN-SVM classifier performance in predicting IDH mutation status using standalone and combined structural and DTI-based imaging features. Combined imaging features surpassed stand-alone modalities for the prediction of IDH mutation status [area under the curve (AUC) = 0.846; sensitivity = 0.925; and specificity = 0.567]. Importantly, optimal model performance was noted following the addition of demographic data (patients' age) to structural and DTI imaging features [area under the curve (AUC) = 0.847; sensitivity = 0.911; and specificity = 0.617]. CONCLUSIONS: Imaging features derived from DTI-based FA and MD maps combined with structural MRI, have superior diagnostic value to that provided by standalone structural or DTI sequences. In combination with demographic information, this CNN-SVM model offers a further enhanced non-invasive prediction of IDH mutation status in gliomas.
Assuntos
Neoplasias Encefálicas , Imagem de Tensor de Difusão , Glioma , Isocitrato Desidrogenase , Mutação , Humanos , Isocitrato Desidrogenase/genética , Glioma/diagnóstico por imagem , Glioma/genética , Glioma/patologia , Imagem de Tensor de Difusão/métodos , Estudos Retrospectivos , Masculino , Feminino , Pessoa de Meia-Idade , Neoplasias Encefálicas/diagnóstico por imagem , Neoplasias Encefálicas/genética , Adulto , Idoso , Gradação de Tumores , Máquina de Vetores de Suporte , Imageamento por Ressonância Magnética/métodos , Redes Neurais de Computação , RadiômicaRESUMO
Peripheral T-cell lymphomas are rare heterogeneous haematological malignancies that may also involve peripheral nerves in a very small subset of cases. We report a patient with a diagnostically challenging cutaneous T-cell lymphoma and multifocal mononeuropathies in whom a targeted nerve biopsy identified lymphomatous infiltration of nerves and expedited combination treatment with chemotherapy and an autologous stem cell transplant. She showed an excellent response with a complete metabolic response on positron emission tomography imaging and significant clinical improvement, maintained 5 years post-treatment.
Assuntos
Neurolinfomatose , Humanos , Neurolinfomatose/diagnóstico por imagem , Neurolinfomatose/patologia , Feminino , Biópsia/métodos , Pessoa de Meia-Idade , Linfoma de Células T/patologia , Linfoma de Células T/diagnóstico por imagem , Linfoma de Células T/diagnóstico , Tomografia por Emissão de PósitronsRESUMO
Primary familial brain calcification (PFBC) is a rare neurodegenerative disorder characterized by a combination of neurological, psychiatric, and cognitive decline associated with calcium deposition on brain imaging. To date, mutations in five genes have been linked to PFBC. However, more than 50% of individuals affected by PFBC have no molecular diagnosis. We report four unrelated families presenting with initial learning difficulties and seizures and later psychiatric symptoms, cerebellar ataxia, extrapyramidal signs, and extensive calcifications on brain imaging. Through a combination of homozygosity mapping and exome sequencing, we mapped this phenotype to chromosome 21q21.3 and identified bi-allelic variants in JAM2. JAM2 encodes for the junctional-adhesion-molecule-2, a key tight-junction protein in blood-brain-barrier permeability. We show that JAM2 variants lead to reduction of JAM2 mRNA expression and absence of JAM2 protein in patient's fibroblasts, consistent with a loss-of-function mechanism. We show that the human phenotype is replicated in the jam2 complete knockout mouse (jam2 KO). Furthermore, neuropathology of jam2 KO mouse showed prominent vacuolation in the cerebral cortex, thalamus, and cerebellum and particularly widespread vacuolation in the midbrain with reactive astrogliosis and neuronal density reduction. The regions of the human brain affected on neuroimaging are similar to the affected brain areas in the myorg PFBC null mouse. Along with JAM3 and OCLN, JAM2 is the third tight-junction gene in which bi-allelic variants are associated with brain calcification, suggesting that defective cell-to-cell adhesion and dysfunction of the movement of solutes through the paracellular spaces in the neurovascular unit is a key mechanism in CNS calcification.
Assuntos
Idade de Início , Alelos , Encefalopatias/genética , Calcinose/genética , Moléculas de Adesão Celular/genética , Genes Recessivos , Adolescente , Adulto , Animais , Encefalopatias/diagnóstico por imagem , Calcinose/diagnóstico por imagem , Criança , Feminino , Humanos , Masculino , Camundongos , Pessoa de Meia-Idade , LinhagemRESUMO
Exome-wide sequencing studies recently described PTPN11 as a novel brain somatic epilepsy gene. In contrast, germline mutations of PTPN11 are known to cause Noonan syndrome, a multisystem disorder characterized by abnormal facial features, developmental delay, and sporadically, also brain tumors. Herein, we performed a deep phenotype-genotype analysis of a comprehensive series of ganglioglioma (GG) with brain somatic alterations of the PTPN11/KRAS/NF1 genes compared to GG with common MAP-Kinase signaling pathway alterations, i.e., BRAFV600E. Seventy-two GG were submitted to whole exome sequencing and genotyping and 84 low grade epilepsy associated tumors (LEAT) to DNA-methylation analysis. In 28 tumours, both analyses were available from the same sample. Clinical data were retrieved from hospital files including disease onset, age at surgery, brain localization, and seizure outcome. A comprehensive histopathology staining panel was available in all cases. We identified eight GG with PTPN11 alterations, copy number variant (CNV) gains of chromosome 12, and the commonality of additional CNV gains in NF1, KRAS, FGFR4 and RHEB, as well as BRAFV600E alterations. Histopathology revealed an atypical glio-neuronal phenotype with subarachnoidal tumor spread and large, pleomorphic, and multinuclear cellular features. Only three out of eight patients with GG and PTPN11/KRAS/NF1 alterations were free of disabling-seizures 2 years after surgery (38% had Engel I). This was remarkably different from our series of GG with only BRAFV600E mutations (85% had Engel I). Unsupervised cluster analysis of DNA methylation arrays separated these tumours from well-established LEAT categories. Our data point to a subgroup of GG with cellular atypia in glial and neuronal cell components, adverse postsurgical outcome, and genetically characterized by complex alterations in PTPN11 and other RAS-/MAP-Kinase and/or mTOR signaling pathways. These findings need prospective validation in clinical practice as they argue for an adaptation of the WHO grading system in developmental, glio-neuronal tumors associated with early onset focal epilepsy.
Assuntos
Epilepsia , Ganglioglioma , Humanos , Epilepsia/patologia , Ganglioglioma/genética , Ganglioglioma/patologia , Mutação/genética , Fenótipo , Proteína Tirosina Fosfatase não Receptora Tipo 11/genética , Proteínas Proto-Oncogênicas p21(ras)/genética , Genes ras , Sistema de Sinalização das MAP QuinasesRESUMO
Homozygous deletion of CDKN2A/B was recently incorporated into the World Health Organization classification for grade 3 meningiomas. While this marker is overall rare in meningiomas, its relationship to other CDKN2A alterations on a transcriptomic, epigenomic, and copy number level has not yet been determined. We therefore utilized multidimensional molecular data of 1577 meningioma samples from 6 independent cohorts enriched for clinically aggressive meningiomas to comprehensively interrogate the spectrum of CDKN2A alterations through DNA methylation, copy number variation, transcriptomics, and proteomics using an integrated molecular approach. Homozygous CDKN2A/B deletions were identified in only 7.1% of cases but were associated with significantly poorer outcomes compared to tumors without these deletions. Heterozygous CDKN2A/B deletions were identified in 2.6% of cases and had similarly poor outcomes as those with homozygous deletions. Among tumors with intact CDKN2A/B (without a homozygous or heterozygous deletion), we found a distinct difference in outcome based on mRNA expression of CDKN2A, with meningiomas that had elevated mRNA expression (CDKN2Ahigh) having a significantly shorter time to recurrence. The expression of CDKN2A was independently prognostic after accounting for copy number loss and consistently increased with WHO grade and more aggressive molecular and methylation groups irrespective of cohort. Despite the discordant and mutually exclusive status of the CDKN2A gene in these groups, both CDKN2Ahigh meningiomas and meningiomas with CDKN2A deletions were enriched for similar cell cycle pathways but at different checkpoints. High mRNA expression of CDKN2A was also associated with gene hypermethylation, Rb-deficiency, and lack of response to CDK inhibition. p16 immunohistochemistry could not reliably differentiate between meningiomas with and without CDKN2A deletions but appeared to correlate better with mRNA expression. These findings support the role of CDKN2A mRNA expression as a biomarker of clinically aggressive meningiomas with potential therapeutic implications.
Assuntos
Neoplasias Meníngeas , Meningioma , Humanos , Genes p16 , Meningioma/genética , Inibidor p16 de Quinase Dependente de Ciclina/genética , Transcriptoma , Variações do Número de Cópias de DNA , Homozigoto , Deleção de Sequência , Neoplasias Meníngeas/genéticaRESUMO
Pediatric central nervous system (CNS) tumors represent the most common cause of cancer-related death in children aged 0-14 years. They differ from their adult counterparts, showing extensive clinical and molecular heterogeneity as well as a challenging histopathological spectrum that often impairs accurate diagnosis. Here, we use DNA methylation-based CNS tumor classification in combination with copy number, RNA-seq, and ChIP-seq analysis to characterize a newly identified CNS tumor type. In addition, we report histology, patient characteristics, and survival data in this tumor type. We describe a biologically distinct pediatric CNS tumor type (n = 31 cases) that is characterized by focal high-level amplification and resultant overexpression of either PLAGL1 or PLAGL2, and an absence of recurrent genetic alterations characteristic of other pediatric CNS tumor types. Both genes act as transcription factors for a regulatory subset of imprinted genes (IGs), components of the Wnt/ß-Catenin pathway, and the potential drug targets RET and CYP2W1, which are also specifically overexpressed in this tumor type. A derived PLAGL-specific gene expression signature indicates dysregulation of imprinting control and differentiation/development. These tumors occurred throughout the neuroaxis including the cerebral hemispheres, cerebellum, and brainstem, and were predominantly composed of primitive embryonal-like cells lacking robust expression of markers of glial or neuronal differentiation (e.g., GFAP, OLIG2, and synaptophysin). Tumors with PLAGL1 amplification were typically diagnosed during adolescence (median age 10.5 years), whereas those with PLAGL2 amplification were diagnosed during early childhood (median age 2 years). The 10-year overall survival was 66% for PLAGL1-amplified tumors, 25% for PLAGL2-amplified tumors, 18% for male patients, and 82% for female patients. In summary, we describe a new type of biologically distinct CNS tumor characterized by PLAGL1/2 amplification that occurs predominantly in infants and toddlers (PLAGL2) or adolescents (PLAGL1) which we consider best classified as a CNS embryonal tumor and which is associated with intermediate survival. The cell of origin and optimal treatment strategies remain to be defined.
Assuntos
Neoplasias do Sistema Nervoso Central , Tumores Neuroectodérmicos Primitivos , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Masculino , Proteínas de Ciclo Celular/genética , Neoplasias do Sistema Nervoso Central/genética , Metilação de DNA , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Tumores Neuroectodérmicos Primitivos/genética , Proteínas de Ligação a RNA/genética , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Proteínas Supressoras de Tumor/genética , Via de Sinalização Wnt/genéticaRESUMO
Glioneuronal tumors are a heterogenous group of CNS neoplasms that can be challenging to accurately diagnose. Molecular methods are highly useful in classifying these tumors-distinguishing precise classes from their histological mimics and identifying previously unrecognized types of tumors. Using an unsupervised visualization approach of DNA methylation data, we identified a novel group of tumors (n = 20) that formed a cluster separate from all established CNS tumor types. Molecular analyses revealed ATRX alterations (in 16/16 cases by DNA sequencing and/or immunohistochemistry) as well as potentially targetable gene fusions involving receptor tyrosine-kinases (RTK; mostly NTRK1-3) in all of these tumors (16/16; 100%). In addition, copy number profiling showed homozygous deletions of CDKN2A/B in 55% of cases. Histological and immunohistochemical investigations revealed glioneuronal tumors with isomorphic, round and often condensed nuclei, perinuclear clearing, high mitotic activity and microvascular proliferation. Tumors were mainly located supratentorially (84%) and occurred in patients with a median age of 19 years. Survival data were limited (n = 18) but point towards a more aggressive biology as compared to other glioneuronal tumors (median progression-free survival 12.5 months). Given their molecular characteristics in addition to anaplastic features, we suggest the term glioneuronal tumor with ATRX alteration, kinase fusion and anaplastic features (GTAKA) to describe these tumors. In summary, our findings highlight a novel type of glioneuronal tumor driven by different RTK fusions accompanied by recurrent alterations in ATRX and homozygous deletions of CDKN2A/B. Targeted approaches such as NTRK inhibition might represent a therapeutic option for patients suffering from these tumors.
Assuntos
Neoplasias Encefálicas , Neoplasias do Sistema Nervoso Central , Neoplasias Neuroepiteliomatosas , Humanos , Adulto Jovem , Biomarcadores Tumorais/genética , Encéfalo/patologia , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patologia , Fusão Gênica , Neoplasias Neuroepiteliomatosas/genética , Neoplasias Neuroepiteliomatosas/patologia , Receptores Proteína Tirosina Quinases/genética , Proteína Nuclear Ligada ao X/genéticaRESUMO
OBJECTIVE: Epilepsy is a common comorbidity of glioblastoma. Seizures may occur in various phases of the disease. We aimed to assess potential risk factors for seizures in accordance with the point in time at which they occurred. METHODS: We retrospectively analyzed medical files of adult patients with de novo glioblastoma treated at our institution between January 2006 and January 2020. We categorized seizures as preoperative seizures (POS), early postoperative seizures (EPS; before initiation of radio[chemo]therapy [RCT]), seizures during radiotherapy (SDR; during or <30 days after RCT), and posttherapeutic seizures (PTS; ≥30 days after completion of RCT). We addressed associations between patients' characteristics and their seizures. RESULTS: In the final cohort (N = 520), 292 patients experienced seizures. POS, EPS, SDR, and/or PTS occurred in 29.6% (154/520), 6.0% (31/520), 13.8% (70/509), and 36.1% (152/421) of patients, respectively. POS occurred more frequently in patients with higher Karnofsky Performance Scale scores (odds ratio [OR] = 3.27, p = .001) and tumor location in the temporal lobe (OR = 1.51, p = .034). None of the parameters we analyzed was related to the occurrence of EPS. SDR were independently associated with tumor location (parietal lobe, OR = 1.86, p = .027) and POS, but not EPS, and were independent of RCT. PTS were independently associated with tumor progression (OR = 2.32, p < .001) and with occurrence of SDR (OR = 3.36, p < .001), and negatively correlated with temporal lobe location (OR = .58, p < .014). In patients with tumors exclusively located in the temporal lobe, complete tumor resection was associated with a decreased risk of postoperative seizures. SIGNIFICANCE: Seizures in glioblastoma patients have various, time-dependent risk factors. Temporal lobe localization was a risk factor for preoperative seizures; surgery may have had a protective effect in these patients. RCT did not have dose-dependent pro- or anticonvulsive effects. PTS were associated with tumor progression.