ABSTRACT
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.
Subject(s)
Choline Kinase , Hepatoblastoma , Liver Neoplasms , beta Catenin/genetics , Biomarkers, Tumor/analysis , Calcium-Binding Proteins/genetics , Choline Kinase/antagonists & inhibitors , Choline Kinase/metabolism , DNA Methylation , Drug Discovery/methods , Epigenesis, Genetic , Female , Gene Expression Profiling , Hepatoblastoma/genetics , Hepatoblastoma/metabolism , Hepatoblastoma/mortality , Hepatoblastoma/pathology , High-Throughput Screening Assays , Humans , Infant , Liver Neoplasms/genetics , Liver Neoplasms/metabolism , Liver Neoplasms/mortality , Liver Neoplasms/pathology , Male , Membrane Proteins/genetics , Neoplasm Proteins/genetics , Prognosis , Risk Assessment/methodsSubject(s)
Antineoplastic Agents/therapeutic use , Everolimus/therapeutic use , Neurofibroma, Plexiform/drug therapy , Neurofibromatosis 1/drug therapy , Child , Female , Humans , Magnetic Resonance Imaging/methods , Neurofibroma, Plexiform/complications , Neurofibromatosis 1/complications , TOR Serine-Threonine Kinases/metabolism , Treatment OutcomeABSTRACT
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.
Subject(s)
Arrhythmias, Cardiac/genetics , Genetic Diseases, X-Linked/genetics , Gigantism/genetics , Glypicans/genetics , Heart Defects, Congenital/genetics , Hepatoblastoma/genetics , Intellectual Disability/genetics , Liver Neoplasms/genetics , Arrhythmias, Cardiac/diagnosis , Exons , Genetic Diseases, X-Linked/diagnosis , Gigantism/diagnosis , Heart Defects, Congenital/diagnosis , Hepatoblastoma/diagnosis , Humans , Infant, Newborn , Intellectual Disability/diagnosis , Liver Neoplasms/diagnosis , Male , Multiplex Polymerase Chain Reaction , Mutation , Polymerase Chain Reaction , Sequence Analysis, DNASubject(s)
Antibodies, Monoclonal/therapeutic use , Antineoplastic Agents, Alkylating/therapeutic use , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Brain Stem Neoplasms/drug therapy , Dacarbazine/analogs & derivatives , Pons , Antibodies, Monoclonal/administration & dosage , Antibodies, Monoclonal, Humanized , Antineoplastic Agents, Alkylating/administration & dosage , Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Brain Stem Neoplasms/metabolism , Brain Stem Neoplasms/radiotherapy , Child , Dacarbazine/administration & dosage , Dacarbazine/therapeutic use , Disease Progression , ErbB Receptors/metabolism , Humans , Infusions, Intravenous , Magnetic Resonance Imaging , Male , TemozolomideABSTRACT
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.
Subject(s)
Anemia, Iron-Deficiency/diagnosis , Hemoglobinometry/methods , Hemoglobins/analysis , Iron Deficiencies , Reticulocytes/chemistry , Adolescent , Anemia, Iron-Deficiency/blood , Anemia, Iron-Deficiency/prevention & control , Child , Child, Preschool , Early Diagnosis , Erythrocyte Indices , Female , Ferritins/blood , Humans , Infant , Iron/blood , Male , Mass Screening , Sensitivity and Specificity , Transferrin/analysisABSTRACT
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.
Subject(s)
Antiparkinson Agents/adverse effects , GTP Cyclohydrolase/deficiency , Hypokinesia/chemically induced , Levodopa/adverse effects , Muscle Rigidity , Family Health , Female , Humans , Hypokinesia/physiopathology , Infant , Male , Retrospective StudiesABSTRACT
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.
