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Free keywords:
Animals
Astrocytoma/*genetics/metabolism
Base Sequence
Brain Neoplasms/*genetics/metabolism
Cell Line
Cell Transformation, Neoplastic/genetics/metabolism
Chromosome Breakpoints
Chromosomes, Human, Pair 6
Chromosomes, Human, Pair 9
Fibroblast Growth Factors/metabolism
Humans
MAP Kinase Signaling System
Mice
Models, Molecular
*Mutation
Oncogene Proteins, Fusion/chemistry/genetics
Protein Conformation
Proto-Oncogene Proteins B-raf/chemistry/genetics
Receptor, Fibroblast Growth Factor, Type 1/*genetics/metabolism
Receptor, trkB/*genetics/metabolism
Abstract:
Pilocytic astrocytoma, the most common childhood brain tumor, is typically associated with mitogen-activated protein kinase (MAPK) pathway alterations. Surgically inaccessible midline tumors are therapeutically challenging, showing sustained tendency for progression and often becoming a chronic disease with substantial morbidities. Here we describe whole-genome sequencing of 96 pilocytic astrocytomas, with matched RNA sequencing (n = 73), conducted by the International Cancer Genome Consortium (ICGC) PedBrain Tumor Project. We identified recurrent activating mutations in FGFR1 and PTPN11 and new NTRK2 fusion genes in non-cerebellar tumors. New BRAF-activating changes were also observed. MAPK pathway alterations affected all tumors analyzed, with no other significant mutations identified, indicating that pilocytic astrocytoma is predominantly a single-pathway disease. Notably, we identified the same FGFR1 mutations in a subset of H3F3A-mutated pediatric glioblastoma with additional alterations in the NF1 gene. Our findings thus identify new potential therapeutic targets in distinct subsets of pilocytic astrocytoma and childhood glioblastoma.
