Recurrent somatic alterations of FGFR1 and NTRK2 in pilocytic astrocytoma

Pilocytic astrocytoma, the most common childhood brain tumor(1), is typically associated with mitogen-activated protein kinase (MAPK) pathway alterations(2). Surgically inaccessible midline tumors are therapeutically challenging, showing sustained tendency for progression(3) and often becoming a chronic disease with substantial morbidities(4). 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 novel NTRK2 fusion genes in non-cerebellar tumors. New BRAF activating changes were also observed. MAPK pathway alterations affected 100% of tumors analyzed, with no other significant mutations, indicating pilocytic astrocytoma as predominantly a single-pathway disease. Notably, we identified the same FGFR1 mutations in a subset of H3F3A-mutated pediatric glioblastoma with additional alterations in NF1(5). Our findings thus identify new potential therapeutic targets in distinct subsets of pilocytic astrocytoma and childhood glioblastoma