Recurrent somatic alterations of FGFR1 and NTRK2 in pilocytic astrocytoma

Abstract

Pilocytic astrocytoma, the most common childhood brain tumor1, is typically associated with mitogen-activated protein kinase (MAPK) pathway alterations2. Surgically inaccessible midline tumors are therapeutically challenging, showing sustained tendency for progression3 and often becoming a chronic disease with substantial morbidities4. 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 NF15. Our findings thus identify new potential therapeutic targets in distinct subsets of pilocytic astrocytoma and childhood glioblastoma.

The landscape of genomic alterations across childhood cancers

“…Mutation calling. SNVs were called with the previously described samtools-based DKFZ pipeline adjusted for ICGC Pan-Cancer settings, and short indels were called using Platypus (v.0.7.4) 74,83 . Variants were first identified in the tumour sample and germline or somatic origin was determined based on their presence or absence in the matched control tissue.…”

NTRK gene amplification in patients with metastatic cancer

“…Subsequently, NTRK1 fusions have been detected at a frequency of 12% in papillary thyroid cancers, with TPM3-NTRK1 being the most common gene rearrangement [9][10][11]. In addition, TRKC and very recently TRKB have also been shown to form oncogenic chimeras in multiple tumor types [12,13]. Aside from gene fusions, only an in-frame deletion of NTRK1 in acute myeloid leukemia and a splice variant of NTRK1 in neuroblastoma have been functionally characterized as oncogenic to date [14][15][16][17][18].…”

Molecular classification of diffuse cerebral WHO grade II/III gliomas using genome- and transcriptome-wide profiling improves stratification of prognostically distinct patient groups

“…Combined classification approaches have resulted in a satisfactory segregation of WHO grade I pilocytic astrocytoma as a distinct entity characterized by a benign clinical course and almost universally driven by mitogen-activated protein kinase (MAPK) pathway activation, most commonly caused by fusion of the v-raf murine sarcoma viral oncogene homolog B1 (BRAF) proto-oncogene to other genes or activating BRAF point mutations [16]. On the other end of the glial tumor spectrum, primary glioblastoma has been delineated as a distinct entity of highly malignant tumors characterized by the absence of IDH1/2 mutation, gains on chromosome 7 and losses on chromosome arm 9p and chromosome 10, frequent mutations in the phosphatase and tensin homolog on chromosome 10 (PTEN) gene and the human telomerase (TERT) promoter, as well as activation of receptor tyrosine kinase pathways, in particular the epidermal growth factor receptor (EGFR) and platelet-derived growth factor receptor pathways [17,25].…”