Recurrent somatic alterations of FGFR1 and NTRK2 in pilocytic astrocytoma
David T W Jones1, Barbara Hutter, Natalie Jäger
1Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
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.
Insights
Pilocytic astrocytoma, a common pediatric brain tumor, is driven by the MAPK pathway. This study identified new genetic targets like FGFR1, PTPN11, NTRK2, and BRAF, offering hope for novel treatments.
Area of Science:
- Neuro-oncology
- Genomics
- Pediatric Cancer Research
Background:
- Pilocytic astrocytoma is the most frequent pediatric brain tumor, often affecting midline structures and posing therapeutic challenges.
- Tumor progression and chronicity lead to significant morbidity in affected children.
- Mitogen-activated protein kinase (MAPK) pathway alterations are characteristic of pilocytic astrocytoma.
Purpose of the Study:
- To comprehensively analyze the genomic landscape of pilocytic astrocytoma.
- To identify novel therapeutic targets in pediatric brain tumors.
- To investigate the role of MAPK pathway alterations in pilocytic astrocytoma pathogenesis.
Main Methods:
- Whole-genome sequencing of 96 pilocytic astrocytomas.
- Matched RNA sequencing of 73 pilocytic astrocytomas.
- Analysis conducted by the International Cancer Genome Consortium (ICGC) PedBrain Tumor Project.
Main Results:
- All analyzed pilocytic astrocytomas harbored MAPK pathway alterations, confirming it as a single-pathway disease.
- Recurrent activating mutations in FGFR1 and PTPN11 were identified.
- New NTRK2 fusion genes in non-cerebellar tumors and novel BRAF alterations were discovered.
- FGFR1 mutations were also found in a subset of H3F3A-mutated pediatric glioblastoma with NF1 alterations.
Conclusions:
- Pilocytic astrocytoma is predominantly driven by alterations in the MAPK pathway.
- FGFR1, PTPN11, NTRK2, and BRAF represent potential therapeutic targets for specific subsets of pilocytic astrocytoma.
- These findings may also inform therapeutic strategies for certain pediatric glioblastomas.
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