title: DNMTs as potential therapeutic targets in high-risk pediatric embryonal brain tumors.
abstract: Malignant brain tumors, which are the leading cause of cancer-related morbidity and mortality in children, span a wide spectrum of diseases with distinct clinical phenotypes but may share remarkably similar morphologic features. Until recently, few molecular markers of childhood brain tumors have been identified, which has limited therapeutic advances. Recent global genomic studies have enabled robust molecular classification of childhood brain tumors and the identification and consolidation of rare, seemingly disparate clinical entities. It is now increasingly evident that deregulation of epigenetic processes contributes substantially to heterogeneity in tumor phenotypes and comprise significant drivers of cancer initiation and progression. Specifically, DNA hypermethylation and silencing of critical tumor suppressor genes by DNA methyltransferases (DNMT) has emerged as an important and fundamental mechanism in brain tumor pathogenesis. These observations have been underscored by the recent discovery of TTYH1-C19MC gene fusions in an aggressive pediatric embryonal brain tumor, which results in deregulation and increased expression of a neural-specific DNMT3B isoform in C19MC-associated brain tumors. Our observations that pharmacological inhibitors of DNMTs and histone deacetylases significantly inhibit growth of cells derived from C19MC-associated tumors indicate targeting of epigenomic modifiers as a novel therapeutic approach for these highly treatment-resistant tumors.
authors.affiliation: The Hospital for Sick Children, Arthur and Sonia Labatt Brain Tumor Research Centre, Division of Hematology-Oncology, Department of Pediatrics, Program in Cell Biology , 555 University Avenue, Toronto, Ontario, M5G 1X8 , Canada annie.huang@sickkids.ca.
authors.forename: Patrick
authors.initials: P
authors.lastname: Sin-Chan
authors.forename: Annie
authors.initials: A
authors.lastname: Huang
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D002648:Child; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000235:genetics / Q000378:metabolism; D019175:DNA Methylation; D015195:Drug Design; D044127:Epigenesis, Genetic; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology; D006801:Humans; D058990:Molecular Targeted Therapy; D009373:Neoplasms, Germ Cell and Embryonal / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology
chemical_list: D000970:Antineoplastic Agents; D056572:Histone Deacetylase Inhibitors; D004248:DNA (Cytosine-5-)-Methyltransferases
keywords: C19MC; CNS-primitive neuroectodermal tumors; DNA methyltransferases; brain tumor; therapeutics