Potential Targets Are Identified in Diffuse Low-Grade Pediatric Gliomas

Low-grade gliomas are the most common cancers of the central nervous system in children and young adults. Despite their relatively slow growth, low-grade gliomas that cannot be completely resected owing to their diffuse nature or proximity to vital brain structures ultimately cause significant morbidity and early death. Driving mutations in NF1 and BRAF have been identified in hereditary and sporadic forms of cerebellar pilocytic astrocytoma, the most common type of pediatric low-grade glioma, but little is known about the underlying genetic causes of other rarer, less frequently resectable low-grade gliomas. Zhang and colleagues performed whole-genome sequencing of 39 low-grade gliomas and discovered a median of only 1 nonsilent somatic mutation or structural alteration per tumor, indicating that these tumors are driven by few genetic alterations. Analysis of an expanded cohort to determine the frequency and clinicopathologic associations of the identified mutations revealed that intragenic duplications of FGFR1 affecting the tyrosine kinase domain (TKD) and MYB rearrangements were mutually exclusive and occurred in 53% of grade 2 diffuse low-grade gliomas. TKD-duplicated FGFR1 was capable of transforming glial cells, as expression of this mutant in Tp53-null murine astrocytes transplanted in the brains of nude mice rapidly induced high-grade astrocytomas in all mice, whereas cells with empty vector or wild-type FGFR1 did not form tumors. Duplication of the TKD resulted in autophosphorylation of FGFR1 and downstream activation of the MAPK/ERK and PI3K pathways, which could be blocked in FGFR1 TKD duplication-expressing cells by FGFR1-specific inhibitors. Additionally, tumors with MYB rearrangement also showed evidence of MAPK/ERK and PI3K pathway activation compared with normal brain. These findings provide a rationale for targeting FGFR1 or its downstream effectors in unresectable pediatric low-grade gliomas.

Zhang J, Wu G, Miller CP, Tatevossian RG, Dalton JD, Tang B, et al. Whole-genome sequencing identifies genetic alterations in pediatric low-grade gliomas. Nat Genet 2013 Apr 14 [Epub ahead of print].