RESUMO
BACKGROUND & AIMS: Hepatoblastoma (HB) is a rare disease. Nevertheless, it is the predominant pediatric liver cancer, with limited therapeutic options for patients with aggressive tumors. Herein, we aimed to uncover the mechanisms of HB pathobiology and to identify new biomarkers and therapeutic targets in a move towards precision medicine for patients with advanced HB. METHODS: We performed a comprehensive genomic, transcriptomic and epigenomic characterization of 159 clinically annotated samples from 113 patients with HB, using high-throughput technologies. RESULTS: We discovered a widespread epigenetic footprint of HB that includes hyperediting of the tumor suppressor BLCAP concomitant with a genome-wide dysregulation of RNA editing and the overexpression of mainly non-coding genes of the oncogenic 14q32 DLK1-DIO3 locus. By unsupervised analysis, we identified 2 epigenomic clusters (Epi-CA, Epi-CB) with distinct degrees of DNA hypomethylation and CpG island hypermethylation that are associated with the C1/C2/C2B transcriptomic subtypes. Based on these findings, we defined the first molecular risk stratification of HB (MRS-HB), which encompasses 3 main prognostic categories and improves the current clinical risk stratification approach. The MRS-3 category (28%), defined by strong 14q32 locus expression and Epi-CB methylation features, was characterized by CTNNB1 and NFE2L2 mutations, a progenitor-like phenotype and clinical aggressiveness. Finally, we identified choline kinase alpha as a promising therapeutic target for intermediate and high-risk HBs, as its inhibition in HB cell lines and patient-derived xenografts strongly abrogated tumor growth. CONCLUSIONS: These findings provide a detailed insight into the molecular features of HB and could be used to improve current clinical stratification approaches and to develop treatments for patients with HB. LAY SUMMARY: Hepatoblastoma is a rare childhood liver cancer that has been understudied. We have used cutting-edge technologies to expand our molecular knowledge of this cancer. Our biological findings can be used to improve clinical management and pave the way for the development of novel therapies for this cancer.
Assuntos
Colina Quinase , Hepatoblastoma , Neoplasias Hepáticas , beta Catenina/genética , Biomarcadores Tumorais/análise , Proteínas de Ligação ao Cálcio/genética , Colina Quinase/antagonistas & inibidores , Colina Quinase/metabolismo , Metilação de DNA , Descoberta de Drogas/métodos , Epigênese Genética , Feminino , Perfilação da Expressão Gênica , Hepatoblastoma/genética , Hepatoblastoma/metabolismo , Hepatoblastoma/mortalidade , Hepatoblastoma/patologia , Ensaios de Triagem em Larga Escala , Humanos , Lactente , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/mortalidade , Neoplasias Hepáticas/patologia , Masculino , Proteínas de Membrana/genética , Proteínas de Neoplasias/genética , Prognóstico , Medição de Risco/métodosAssuntos
Antineoplásicos/uso terapêutico , Everolimo/uso terapêutico , Neurofibroma Plexiforme/tratamento farmacológico , Neurofibromatose 1/tratamento farmacológico , Criança , Feminino , Humanos , Imageamento por Ressonância Magnética/métodos , Neurofibroma Plexiforme/complicações , Neurofibromatose 1/complicações , Serina-Treonina Quinases TOR/metabolismo , Resultado do TratamentoRESUMO
Mutations in the gene encoding glypican (GPC) 3 appear to be responsible for most cases of Simpson-Golabi-Behmel syndrome type 1. Duplication of the GPC4 gene has also been associated to this syndrome; however, no duplications involving GPC3 have been related. We describe a family that harbors a novel exon 2-4 duplication event leading to a truncating germline mutation of the GPC3 gene that, to our knowledge, has not been previously reported. GPC3 transcripts that carry this duplication bear non-functional proteins making its pathogenic role highly probable. The absence of a functional GPC3 may alter the normal differentiation of embryonal mesodermal tissues predisposing to the development of embryonal tumors, as the index case studied who developed a hepatoblastoma at age 9 months.
Assuntos
Arritmias Cardíacas/genética , Doenças Genéticas Ligadas ao Cromossomo X/genética , Gigantismo/genética , Glipicanas/genética , Cardiopatias Congênitas/genética , Hepatoblastoma/genética , Deficiência Intelectual/genética , Neoplasias Hepáticas/genética , Arritmias Cardíacas/diagnóstico , Éxons , Doenças Genéticas Ligadas ao Cromossomo X/diagnóstico , Gigantismo/diagnóstico , Cardiopatias Congênitas/diagnóstico , Hepatoblastoma/diagnóstico , Humanos , Recém-Nascido , Deficiência Intelectual/diagnóstico , Neoplasias Hepáticas/diagnóstico , Masculino , Reação em Cadeia da Polimerase Multiplex , Mutação , Reação em Cadeia da Polimerase , Análise de Sequência de DNAAssuntos
Neoplasias das Glândulas Suprarrenais/complicações , Síndrome de Klinefelter/complicações , Neuroblastoma/complicações , Neoplasias das Glândulas Suprarrenais/patologia , Neoplasias das Glândulas Suprarrenais/cirurgia , Adrenalectomia , Humanos , Lactente , Masculino , Neuroblastoma/patologia , Neuroblastoma/cirurgiaAssuntos
Anticorpos Monoclonais/uso terapêutico , Antineoplásicos Alquilantes/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias do Tronco Encefálico/tratamento farmacológico , Dacarbazina/análogos & derivados , Ponte , Anticorpos Monoclonais/administração & dosagem , Anticorpos Monoclonais Humanizados , Antineoplásicos Alquilantes/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Neoplasias do Tronco Encefálico/metabolismo , Neoplasias do Tronco Encefálico/radioterapia , Criança , Dacarbazina/administração & dosagem , Dacarbazina/uso terapêutico , Progressão da Doença , Receptores ErbB/metabolismo , Humanos , Infusões Intravenosas , Imageamento por Ressonância Magnética , Masculino , TemozolomidaRESUMO
SUMMARY: Identification of iron deficiency (ID) is essential to initiate early treatment to prevent long-term systemic complications of ID anemia. This study was undertaken to evaluate the efficiency of the parameter reticulocyte hemoglobin content (CHr) compared with other laboratory parameters in the assessment of ID in a pediatric population. Blood samples were obtained for 237 children who received routine pediatric care visits in a primary care clinic (mean age: 63.7 mo; male:female ratio: 1.08:1). A multiple stepwise logistic regression analysis identified CHr as the most accurate marker independently associated to ID. A CHr cutoff value of 25 pg (sensitivity: 94%; specificity: 80%) proved an optimal performance predicting ID. Therefore, we conclude that the hematologic parameter CHr constitutes a valuable screening tool for the identification of ID with or without anemia in childhood.
Assuntos
Anemia Ferropriva/diagnóstico , Hemoglobinometria/métodos , Hemoglobinas/análise , Deficiências de Ferro , Reticulócitos/química , Adolescente , Anemia Ferropriva/sangue , Anemia Ferropriva/prevenção & controle , Criança , Pré-Escolar , Diagnóstico Precoce , Índices de Eritrócitos , Feminino , Ferritinas/sangue , Humanos , Lactente , Ferro/sangue , Masculino , Programas de Rastreamento , Sensibilidade e Especificidade , Transferrina/análiseRESUMO
We report on a GTP cyclohydrolase 1 mutation-confirmed heterozygous case presenting with an infantile hypokinetic rigid syndrome and delay in attainment of motor milestones starting from the first year of life. He had a family history of dopa-responsive dystonia-parkinsonism. CSF neopterin, biopterin and HVA values were decreased. Molecular study of GCH-1 gene showed the Q89X mutation in exon 1. Treatment with l-dopa resulted in a complete remission of symptoms.
Assuntos
Antiparkinsonianos/efeitos adversos , GTP Cicloidrolase/deficiência , Hipocinesia/induzido quimicamente , Levodopa/efeitos adversos , Rigidez Muscular , Saúde da Família , Feminino , Humanos , Hipocinesia/fisiopatologia , Lactente , Masculino , Estudos RetrospectivosRESUMO
Juvenile granulosa cell tumor of the testis is an infrequent tumor of the gonadal stroma characteristic of the pediatric age. It usually appears as a scrotal mass and less frequently as an abdominal or inguinal mass. It may be associated with ambiguous genitalia and/or abnormal sex chromosomes. The recommended treatment is orchiectomy alone because local recurrence or metastasis have never been observed. We describe a patient with a juvenile granulosa cell tumor of the testis and review the literature.