BRAF V600E Mutation in Ganglioglioma: Impact on Epileptogenicity and Implications for Surgical Strategy

Abstract

Objective: Gangliogliomas are commonly found pathologies in patients undergoing epilepsy surgery. While resections can be curative, seizure relapses occur. Expression of CD34 and the BRAF V600E mutation are the most common molecular biomarkers found in gangliogliomas, but their influence on seizure outcomes is unclear. We therefore reviewed our experience over two decades to better describe prognostic factors.

Methods: We performed a retrospective chart review of all patients operated on for ganglioglioma at our institution since the year 2000. We included patients with preoperative epilepsy and a minimum follow-up of 1 year. Available tumor specimens were immunohistochemically stained for CD34 and BRAF V600E.

Results: We included 62 patients with epilepsy operated for ganglioglioma. Lesionectomies were performed in 32 (51.6%), extended resections in 21 (33.9%), and partial resections in 9 cases (14.5%). Residual tumor mass on postoperative MRI was diagnosed in 21 patients (33.9%). CD34 reactivity was found in 57 patients (91.9%) and the BRAF V600E mutation was detected in 30 patients (48.4%). Patients with a BRAF V600E mutation were younger at the time of epilepsy onset (9.1 years vs. 15.2 years) and surgery (14.5 years vs. 23.7 years). Residual tumor was the largest risk factor for seizure relapses (hazard ratio 8.45) and the BRAF V600E mutation also increased this risk (hazard ratio 3.94).

Conclusions: BRAF V600E status in patients with ganglioglioma-associated epilepsy is a potential biomarker to stratify the risk for seizure relapse after surgery. BRAF V600E-positive patients might benefit from a more aggressive surgical strategy.

Keywords: BRAF V600E mutation; biomarkers; epilepsy surgery; ganglioglioma; seizure outcome.

FIGURE 1

Kaplan–Meier plots of seizure‐free survival after the initial surgery. (A) Patients with residual tumor tissue experienced earlier seizure relapses. (B) Considering the entire cohort (n = 62), no significant effect of the BRAF V600E mutation could be demonstrated, likely because residual tumor led to early relapses regardless of mutation status. (C) In patients with a radiologically gross total resection (n = 41), the BRAF V600E mutation was associated with early seizure relapses, while patients without it had only a few relapses.

FIGURE 2

Interaction plot showing the difference in median time to seizure relapse dependent on the residual tumor and BRAF mutation. When residual tumor is present, BRAF V600E positive and negative cases have a similar seizure‐free interval of 31 and 42 days, respectively. In patients without radiologically detectable residual tumors, the difference is greatly increased to 182 days in BRAF V600E positive and 556 days in BRAF V600E negative cases.