Targeted detection of genetic alterations reveal the prognostic impact of H3K27M and MAPK pathway aberrations in paediatric thalamic glioma

Abstract

Paediatric brain tumours arising in the thalamus present significant diagnostic and therapeutic challenges to physicians due to their sensitive midline location. As such, genetic analysis for biomarkers to aid in the diagnosis, prognosis and treatment of these tumours is needed. Here, we identified 64 thalamic gliomas with clinical follow-up and characterized targeted genomic alterations using newly optimized droplet digital and NanoString-based assays. The median age at diagnosis was 9.25 years (range, 0.63-17.55) and median survival was 6.43 (range, 0.01-27.63) years. Our cohort contained 42 and 22 tumours reviewed as low and high grade gliomas, respectively. Five (12 %) low grade and 11 (50 %) high grade gliomas were positive for the H3F3A/HIST1H3B K27M (H3K27M) mutation. Kaplan-Meier survival analysis revealed significantly worse overall survival for patients harbouring the H3K27M mutation versus H3F3A/HIST1H3B wild type (H3WT) samples (log-rank p < 0.0001) with a median survival of 1.02 vs. 9.12 years. Mitogen-activated protein kinase (MAPK) pathway activation via BRAF or FGFR1 hotspot mutations or fusion events were detected in 44 % of patients, and was associated with long-term survival in the absence of H3K27M (log-rank p < 0.0001). Multivariate analysis demonstrated H3K27M status and high grade histology to be the most significant independent predictors of poor overall survival with hazard ratios of 6.945 and 7.721 (p < 0.0001), respectively. In contrast, MAPK pathway activation is a predictor of favourable patient outcome, although not independent of other clinical factors. Importantly, we show that low grade malignancies may harbour H3K27M mutations and that these tumours show a dismal survival compared to low grade H3WT cases. Our data strongly supports the inclusion of targeted genetic testing in childhood thalamic tumours to most accurately stratify patients into appropriate risk groups.

Keywords: BRAF; H3K27M; MAPK; Pediatric; Prognostic; Thalamic glioma.

Fig. 1

Genetic, molecular and clinical characteristics of paediatric thalamic glioma

Fig. 2

H3K27M is a negative prognostic marker in paediatric thalamic glioma. SickKids cohort (a) and )(b) Canadian cohort were tested for association between H3K27M-status and survival. Sample stratification based on histological grade showed H3K27M a significant prognostic marker in high grade (c) and low grade (d). Histology and H3K27M status combined (e) revealed clinical disease stratification

Fig. 3

MAPK pathway activation is a positive predictive marker. BRAFV600E in the absence of H3K27M in low grade tumours. a shows a survival advantage. BRAF fusion events in low grade tumours. b shows robust survival. MAPK activation combined. c shows reveals a positive prognosis throughout low and high grade tumours