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.Electronic supplementary materialThe online version of this article (doi:10.1186/s40478-016-0353-0) contains supplementary material, which is available to authorized users.
Highlights
Brain tumours are the largest group of solid tumours and the leading cause of tumour-related death in children [4]
Clinical characteristics of patients with thalamic glioma Sixty-four patients treated at the Hospital for Sick Children from 1986 to 2014 were identified as thalamic tumour patients
Forty-two thalamic tumours were histologically diagnosed as low grade glioma (62 % grade I, 5 % grade II, and 33 % low grade glioma, NOS) whereas the remaining 22 were diagnosed as high grade glioma (41 % grade III, 50 % grade IV, and 9 % high grade, NOS)
Summary
Brain tumours are the largest group of solid tumours and the leading cause of tumour-related death in children [4]. Ryall et al Acta Neuropathologica Communications (2016) 4:93 are associated with worse clinical outcome as compared to grade I or II low grade tumours [23, 24]. Subsequent studies have identified H3K27M mutations in other high grade midline tumours, including those in the thalamus, but have not looked directly at its impact on patient survival [5, 31, 33]. A comprehensive study of genetic markers and their role relative to histologic and clinical risk factors has not been performed for thalamic glioma. To address this limitation, we assembled a cohort of concisely defined paediatric thalamic glioma. We investigated the diagnostic and prognostic roles of defined genetic, clinical and histologic markers
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