The genetic landscape of ganglioglioma

Abstract

Ganglioglioma is the most common epilepsy-associated neoplasm that accounts for approximately 2% of all primary brain tumors. While a subset of gangliogliomas are known to harbor the activating p.V600E mutation in the BRAF oncogene, the genetic alterations responsible for the remainder are largely unknown, as is the spectrum of any additional cooperating gene mutations or copy number alterations. We performed targeted next-generation sequencing that provides comprehensive assessment of mutations, gene fusions, and copy number alterations on a cohort of 40 gangliogliomas. Thirty-six harbored mutations predicted to activate the MAP kinase signaling pathway, including 18 with BRAF p.V600E mutation, 5 with variant BRAF mutation (including 4 cases with novel in-frame insertions at p.R506 in the β3-αC loop of the kinase domain), 4 with BRAF fusion, 2 with KRAS mutation, 1 with RAF1 fusion, 1 with biallelic NF1 mutation, and 5 with FGFR1/2 alterations. Three gangliogliomas with BRAF p.V600E mutation had concurrent CDKN2A homozygous deletion and one additionally harbored a subclonal mutation in PTEN. Otherwise, no additional pathogenic mutations, fusions, amplifications, or deletions were identified in any of the other tumors. Amongst the 4 gangliogliomas without canonical MAP kinase pathway alterations identified, one epilepsy-associated tumor in the temporal lobe of a young child was found to harbor a novel ABL2-GAB2 gene fusion. The underlying genetic alterations did not show significant association with patient age or disease progression/recurrence in this cohort. Together, this study highlights that ganglioglioma is characterized by genetic alterations that activate the MAP kinase pathway, with only a small subset of cases that harbor additional pathogenic alterations such as CDKN2A deletion.

Keywords: ABL2; BRAF; Epilepsy; FGFR1; FGFR2; Ganglioglioma; Glioneuronal tumor; KRAS; MAP kinase signaling pathway; NF1; RAF1; Ras-Raf-MEK-ERK; Seizures; Targeted next-generation sequencing.

Fig. 1

Oncoprint summary table of the 40 patients with ganglioglioma including patient age, sex, tumor location, genetic alterations, and number of chromosomal gains/losses

Fig. 2

Histologic features of gangliogliomas with different genetic alterations in the MAP kinase signaling pathway. a Ganglioglioma in the temporal lobe of a 27 year old man with BRAF p.V600E mutation (SF-GG-08). b Ganglioglioma in the occipital lobe of a 14 year old boy with BRAF p.V600E mutation and CDKN2A homozygous deletion (SF-GG-03). c Ganglioglioma in the temporal lobe of a 23 year old woman with BRAF p.L505delinsLEYLS mutation (SF-GG-22). d Ganglioglioma in the spinal cord of a 5 year old girl with KIAA1549-BRAF gene fusion (SF-GG-24). e Ganglioglioma in the frontal lobe of a 48 year old man with ERC2-RAF1 gene fusion (SF-GG-28). f Ganglioglioma in the temporal lobe of a 7 year old boy with FGFR2-KIAA1598 gene fusion (SF-GG-34)

Fig. 3

Event-free survival of the 40 patients with ganglioglioma stratified by genetic alterations. a-d Shown are Kaplan-Meier curves of event-free survival (either recurrence after gross total resection or disease progression after subtotal resection) from the ganglioglioma cohort stratified by BRAF altered versus BRAF wildtype (a), BRAF V600E mutant versus other BRAF alteration (b), BRAF altered versus FGFR altered (c), and BRAF V600E mutant with CDKN2A intact versus BRAF V600E mutant with CDKN2A homozygous deletion (d). p values were calculated by Log-rank (Mantel-Cox) test