Pediatric brainstem gangliogliomas show BRAF^V600E mutation in a high percentage of cases

Brainstem gangliogliomas (GGs), often cannot be resected, have a much poorer prognosis than those located in more common supratentorial sites and may benefit from novel therapeutic approaches. Therapeutically targetable BRAF c.1799T>A (p.V600E) (BRAF^V600E) mutations are harbored in roughly 50% of collective GGs taken from all anatomical sites. Large numbers of pediatric brainstem GGs, however, have not been specifically assessed and anatomic - and age-restricted assessment of genetic and biological factors are becoming increasingly important. Pediatric brainstem GGs (n = 13), non-brainstem GGs (n = 11) and brainstem pilocytic astrocytomas (PAs) (n = 8) were screened by standard Sanger DNA sequencing of BRAF exon 15. Five of 13 (38%) pediatric GG harbored a definitive BRAF^V600E mutation, with two others exhibiting an equivocal result by this method. BRAF^V600E was also seen in five of 11 (45%) non-brainstem GGs and one of eight (13%) brainstem PAs. VE1 immunostaining for BRAF^V600E showed concordance with sequencing in nine of nine brainstem GGs including the two cases equivocal by Sanger. The equivocal brainstem GGs were subsequently shown to harbor BRAF^V600E using a novel, more sensitive, RNA-sequencing approach, yielding a final BRAF^V600E mutation frequency of 54% (seven of 13) in brainstem GGs. BRAF^V600E-targeted therapeutics should be a consideration for the high percentage of pediatric brainstem GGs refractory to conventional therapies.