RESUMO
Hepatocellular carcinoma (HCC) rarely occurs in childhood. We describe a patient with new onset of pruritus at 8 months of age who at 17 months of age was found to have a 2.5 cm HCC. To delineate the possible genetic basis of this tumour, we performed whole exome sequencing (WES) of the germline DNA and identified two novel predictably deleterious missense mutations in ABCB11, encoding bile salt export pump (BSEP), confirmed in the parental DNA as bi-allelic and inherited. Although inherited ABCB11 mutations have previously been linked to HCC in a small number of cases, the molecular mechanisms of hepatocellular carcinogenesis in ABCB11 disease are unknown. WES of the HCC tissue uncovered somatic driver mutations in the beta-catenin (CTNNB1) and nuclear-factor-erythroid-2-related-factor-2 (NFE2L2) genes. Moreover, clonality analysis predicted that the CTNNB1 mutation was clonal and occurred earlier during carcinogenesis, whereas the NFE2L2 mutation was acquired later. Interestingly, background liver parenchyma showed no inflammation or fibrosis and BSEP expression was preserved. This is the first study to identify somatic CTNNB1 and NFE2L2 mutations in early childhood arisen in the setting of inherited bi-allelic ABCB11 mutations. Rapid WES analysis expedited this child's diagnosis and treatment, and likely improved her prognosis.
Assuntos
Transportadores de Cassetes de Ligação de ATP/genética , Carcinoma Hepatocelular/genética , Neoplasias Hepáticas/genética , Mutação , Fator 2 Relacionado a NF-E2/genética , beta Catenina/genética , Membro 11 da Subfamília B de Transportadores de Cassetes de Ligação de ATP , Sequência de Aminoácidos , Sequência de Bases , Carcinoma Hepatocelular/complicações , Carcinoma Hepatocelular/patologia , Colestase Intra-Hepática/complicações , Colestase Intra-Hepática/genética , DNA de Neoplasias/genética , Feminino , Mutação em Linhagem Germinativa , Humanos , Lactente , Neoplasias Hepáticas/complicações , Neoplasias Hepáticas/patologia , Dados de Sequência Molecular , Mutação de Sentido Incorreto , Homologia de Sequência de AminoácidosRESUMO
Adult patients with space-occupying hemispheric infarctions have a poor prognosis, with an associated fatality rate of 80%. Decompressive hemicraniectomy (DH) has been studied as a treatment option for patients with malignant cerebral infarction refractory to maximal medical therapy, with reasonable outcomes demonstrated in the adult population if the patient is decompressed within 48 h. However, there are no randomized controlled trials in the pediatric literature to make the same claims. In this study, we evaluated the current literature in regards to DH following malignant stroke in the pediatric population. We found that excellent recovery, with an acceptable quality of life, is possible, particularly in the pediatric patient. Our cohort suggests that pediatric intervention beyond the 48-h time interval may still lead to positive outcomes, unlike adult patients. Regardless, randomized controlled trials are needed to determine optimal timing of intervention following symptom onset, as well as to identify predictors for positive outcome in the pediatric population.
Assuntos
Isquemia Encefálica/cirurgia , Descompressão Cirúrgica/métodos , Procedimentos Neurocirúrgicos/métodos , Acidente Vascular Cerebral/cirurgia , Adolescente , Criança , Pré-Escolar , Estudos de Coortes , Dura-Máter/cirurgia , Humanos , Lactente , Infarto da Artéria Cerebral Média/complicações , Infarto da Artéria Cerebral Média/cirurgia , Cuidados Pós-Operatórios , Resultado do TratamentoRESUMO
This corrects the article DOI: 10.1038/ncomms14433.
RESUMO
Meningiomas are mostly benign brain tumours, with a potential for becoming atypical or malignant. On the basis of comprehensive genomic, transcriptomic and epigenomic analyses, we compared benign meningiomas to atypical ones. Here, we show that the majority of primary (de novo) atypical meningiomas display loss of NF2, which co-occurs either with genomic instability or recurrent SMARCB1 mutations. These tumours harbour increased H3K27me3 signal and a hypermethylated phenotype, mainly occupying the polycomb repressive complex 2 (PRC2) binding sites in human embryonic stem cells, thereby phenocopying a more primitive cellular state. Consistent with this observation, atypical meningiomas exhibit upregulation of EZH2, the catalytic subunit of the PRC2 complex, as well as the E2F2 and FOXM1 transcriptional networks. Importantly, these primary atypical meningiomas do not harbour TERT promoter mutations, which have been reported in atypical tumours that progressed from benign ones. Our results establish the genomic landscape of primary atypical meningiomas and potential therapeutic targets.
Assuntos
Redes Reguladoras de Genes/genética , Redes Reguladoras de Genes/fisiologia , Genoma , Genômica/métodos , Neoplasias Meníngeas/genética , Neoplasias Meníngeas/metabolismo , Meningioma/genética , Meningioma/metabolismo , Sítios de Ligação , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/metabolismo , Transformação Celular Neoplásica/genética , Instabilidade Cromossômica , Análise por Conglomerados , Metilação de DNA , Fator de Transcrição E2F2/metabolismo , Proteína Potenciadora do Homólogo 2 de Zeste/metabolismo , Epigenômica/métodos , Exoma/genética , Proteína Forkhead Box M1/metabolismo , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Inativação Gênica , Genes da Neurofibromatose 2 , Técnicas de Genotipagem , Células-Tronco Embrionárias Humanas/metabolismo , Humanos , Histona Desmetilases com o Domínio Jumonji/genética , Técnicas de Sonda Molecular , Mutação , Fenótipo , Complexo Repressor Polycomb 2/genética , Complexo Repressor Polycomb 2/metabolismo , Regiões Promotoras Genéticas , RNA Mensageiro/metabolismo , Proteína SMARCB1/genética , Análise de Sequência , Transdução de Sinais/genética , TranscriptomaRESUMO
BACKGROUND: Glioblastoma multiforme (GBM) constitutes nearly half of all malignant brain tumors and has a median survival of 15 months. The standard treatment for these lesions includes maximal resection, radiotherapy, and chemotherapy; however, individual tumors display immense variability in their response to these approaches. Genomic techniques such as whole-exome sequencing (WES) provide an opportunity to understand the molecular basis of this variability. METHODS: Here, we report WES-guided treatment of a patient with a primary GBM and two subsequent recurrences, demonstrating the dynamic nature of treatment-induced molecular changes and their implications for clinical decision-making. We also analyze the Yale-Glioma cohort, composed of 110 whole exome- or whole genome-sequenced tumor-normal pairs, to assess the frequency of genomic events found in the presented case. RESULTS: Our longitudinal analysis revealed how the genomic profile evolved under the pressure of therapy. Specifically targeted approaches eradicated treatment-sensitive clones while enriching for resistant ones, generated due to chromothripsis, which we show to be a frequent event in GBMs based on our extended analysis of 110 gliomas in the Yale-Glioma cohort. Despite chromothripsis and the later acquired mismatch-repair deficiency, genomics-guided personalized treatment extended survival to over 5 years. Interestingly, the case displayed a favorable response to immune checkpoint inhibition after acquiring mismatch repair deficiency. CONCLUSIONS: Our study demonstrates the importance of longitudinal genomic profiling to adjust to the dynamic nature of treatment-induced molecular changes to improve the outcomes of precision therapies.
Assuntos
Aberrações Cromossômicas , Genômica , Glioblastoma/terapia , Recidiva Local de Neoplasia , Medicina de Precisão , Antineoplásicos/uso terapêutico , Terapia Combinada , Reparo de Erro de Pareamento de DNA , Análise Mutacional de DNA , DNA de Neoplasias , Progressão da Doença , Exoma , Feminino , Cirurgia Geral , Genoma Humano , Glioblastoma/genética , Glioblastoma/patologia , Humanos , Imunoterapia , Estudos Longitudinais , Pessoa de Meia-Idade , Mutação , Radioterapia , Resultado do TratamentoRESUMO
Gliomas represent approximately 30% of all central nervous system tumors and 80% of malignant brain tumors. To understand the molecular mechanisms underlying the malignant progression of low-grade gliomas with mutations in IDH1 (encoding isocitrate dehydrogenase 1), we studied paired tumor samples from 41 patients, comparing higher-grade, progressed samples to their lower-grade counterparts. Integrated genomic analyses, including whole-exome sequencing and copy number, gene expression and DNA methylation profiling, demonstrated nonlinear clonal expansion of the original tumors and identified oncogenic pathways driving progression. These include activation of the MYC and RTK-RAS-PI3K pathways and upregulation of the FOXM1- and E2F2-mediated cell cycle transitions, as well as epigenetic silencing of developmental transcription factor genes bound by Polycomb repressive complex 2 in human embryonic stem cells. Our results not only provide mechanistic insight into the genetic and epigenetic mechanisms driving glioma progression but also identify inhibition of the bromodomain and extraterminal (BET) family as a potential therapeutic approach.
Assuntos
Neoplasias do Sistema Nervoso Central/genética , Glioma/genética , Isocitrato Desidrogenase/genética , Mutação , Neoplasias do Sistema Nervoso Central/patologia , Metilação de DNA , Células-Tronco Embrionárias/metabolismo , Proteína Forkhead Box M1 , Fatores de Transcrição Forkhead/genética , Fatores de Transcrição Forkhead/metabolismo , Dosagem de Genes , Regulação Neoplásica da Expressão Gênica , Genes myc , Glioma/patologia , Humanos , Isocitrato Desidrogenase/metabolismo , Fosfatidilinositol 3-Quinases/genética , Fosfatidilinositol 3-Quinases/metabolismo , Receptor Notch1/genética , Receptor Notch1/metabolismoRESUMO
RNA polymerase II mediates the transcription of all protein-coding genes in eukaryotic cells, a process that is fundamental to life. Genomic mutations altering this enzyme have not previously been linked to any pathology in humans, which is a testament to its indispensable role in cell biology. On the basis of a combination of next-generation genomic analyses of 775 meningiomas, we report that recurrent somatic p.Gln403Lys or p.Leu438_His439del mutations in POLR2A, which encodes the catalytic subunit of RNA polymerase II (ref. 1), hijack this essential enzyme and drive neoplasia. POLR2A mutant tumors show dysregulation of key meningeal identity genes, including WNT6 and ZIC1/ZIC4. In addition to mutations in POLR2A, NF2, SMARCB1, TRAF7, KLF4, AKT1, PIK3CA, and SMO, we also report somatic mutations in AKT3, PIK3R1, PRKAR1A, and SUFU in meningiomas. Our results identify a role for essential transcriptional machinery in driving tumorigenesis and define mutually exclusive meningioma subgroups with distinct clinical and pathological features.
Assuntos
Neoplasias Meníngeas/genética , Meningioma/genética , Mutação , RNA Polimerase II/genética , Domínio Catalítico/genética , Cromossomos Humanos Par 22 , Estudos de Coortes , Análise Mutacional de DNA , Elementos Facilitadores Genéticos , Exoma , Regulação Neoplásica da Expressão Gênica , Genótipo , Humanos , Fator 4 Semelhante a Kruppel , Fatores de Transcrição Kruppel-Like/genética , Neoplasias Meníngeas/classificação , Meningioma/classificação , Neurofibromina 2/genética , Peptídeos e Proteínas Associados a Receptores de Fatores de Necrose Tumoral/genéticaRESUMO
BACKGROUND: Malignant high-grade gliomas (HGGs), including the most aggressive form, glioblastoma multiforme, show significant clinical and genomic heterogeneity. Despite recent advances, the overall survival of HGGs and their response to treatment remain poor. In order to gain further insight into disease pathophysiology by correlating genomic landscape with clinical behavior, thereby identifying distinct HGG molecular subgroups associated with improved prognosis, we performed a comprehensive genomic analysis. METHODS: We analyzed and compared 720 exome-sequenced gliomas (136 from Yale, 584 from The Cancer Genome Atlas) based on their genomic, histological, and clinical features. RESULTS: We identified a subgroup of HGGs (6 total, 4 adults and 2 children) that harbored a statistically significantly increased number of somatic mutations (mean = 9257.3 vs 76.2, P = .002). All of these "ultramutated" tumors harbored somatic mutations in the exonuclease domain of the polymerase epsilon gene (POLE), displaying a distinctive genetic profile, characterized by genomic stability and increased C-to-A transversions. Histologically, they all harbored multinucleated giant or bizarre cells, some with predominant infiltrating immune cells. One adult and both pediatric patients carried homozygous germline mutations in the mutS homolog 6 (MSH6) gene. In adults, POLE mutations were observed in patients younger than 40 years and were associated with a longer progression-free survival. CONCLUSIONS: We identified a genomically, histologically, and clinically distinct subgroup of HGGs that harbored somatic POLE mutations and carried an improved prognosis. Identification of distinctive molecular and pathological HGG phenotypes has implications not only for improved classification but also for potential targeted treatments.
Assuntos
Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patologia , DNA Polimerase II/genética , Glioma/genética , Glioma/patologia , Mutação , Adulto , Neoplasias Encefálicas/classificação , Neoplasias Encefálicas/diagnóstico , Criança , Pré-Escolar , Variações do Número de Cópias de DNA , Análise Mutacional de DNA , Intervalo Livre de Doença , Glioma/classificação , Glioma/diagnóstico , Humanos , Fenótipo , Proteínas de Ligação a Poli-ADP-Ribose , Prognóstico , Adulto JovemRESUMO
We report genomic analysis of 300 meningiomas, the most common primary brain tumors, leading to the discovery of mutations in TRAF7, a proapoptotic E3 ubiquitin ligase, in nearly one-fourth of all meningiomas. Mutations in TRAF7 commonly occurred with a recurrent mutation (K409Q) in KLF4, a transcription factor known for its role in inducing pluripotency, or with AKT1(E17K), a mutation known to activate the PI3K pathway. SMO mutations, which activate Hedgehog signaling, were identified in ~5% of non-NF2 mutant meningiomas. These non-NF2 meningiomas were clinically distinctive-nearly always benign, with chromosomal stability, and originating from the medial skull base. In contrast, meningiomas with mutant NF2 and/or chromosome 22 loss were more likely to be atypical, showing genomic instability, and localizing to the cerebral and cerebellar hemispheres. Collectively, these findings identify distinct meningioma subtypes, suggesting avenues for targeted therapeutics.