Abstract
Pilocytic astrocytoma (PA) is emerging as a tumor entity with dysregulated RAS/RAF/MEK/ERK signaling. In this study, we report the identification of a novel recurrent BRAF insertion (p.V504_R506dup) in five PA cases harboring exclusively this somatic tandem duplication. This recurrent alteration leads to an addition of three amino acids in the kinase domain of BRAF and has functional impact on activating MAPK phosphorylation. Importantly, we show that this mutation confers resistance to RAF inhibitors without changing effectiveness while downstream MEK inhibitors remain effective. Our results further emphasize the importance of BRAF alterations in PA and the need to characterize them in a given tumor as this can affect therapeutic strategies and their potential use as tumor marker in molecular diagnostics.
Highlights
Pilocytic astrocytoma (PA) is the most common pediatric brain tumor, accounting for ~20% of all brain tumors under the age of 20 [1,2,3,4,5,6]
We identified a novel recurrent BRAF tandem insertion (p.V504_R506dup), which has an impact on mitogen-activated protein kinase (MAPK) phosphorylation and confers resistance to RAF inhibitors
Whole-exome sequencing of the non-responding PA patient TC0011 led to the identification of three putative driver mutations in DTX1 (p.P331A), PAX3 (p.R270H) and BRAF (p.V504_R506dup)
Summary
Pilocytic astrocytoma (PA) is the most common pediatric brain tumor, accounting for ~20% of all brain tumors under the age of 20 [1,2,3,4,5,6]. The clinical course of the disease may be unpredictable with recurrence, progression or dissemination in 10–20% of cases [8,9,10,11]
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