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Acta Neuropathol Commun. 2016 Aug 31;4(1):93. doi: 10.1186/s40478-016-0353-0.

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

Author information

1
Arthur and Sonia Labatt Brain Tumour Research Centre, Hospital for Sick Children, Toronto, ON, Canada.
2
Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada.
3
Division of Haematology/Oncology, Hospital for Sick Children, Toronto, ON, Canada.
4
Division of Pathology, Hospital for Sick Children, Toronto, ON, Canada.
5
Department of Paediatrics, Washington University School of Medicine in St. Louis, St. Louis, MO, USA.
6
Division of Neurology and Oncology, Department of Paediatrics, University of British Columbia & British Columbia Children's Hospital, Vancouver, BC, Canada.
7
Division of Paediatric Neurosurgery, Department of Surgery, University of British Columbia & British Columbia Children's Hospital, Vancouver, BC, Canada.
8
Institute of Medical Science, University of Toronto, Toronto, ON, Canada.
9
Arthur and Sonia Labatt Brain Tumour Research Centre, Hospital for Sick Children, Toronto, ON, Canada. cynthia.hawkins@sickkids.ca.
10
Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada. cynthia.hawkins@sickkids.ca.
11
Division of Pathology, Hospital for Sick Children, Toronto, ON, Canada. cynthia.hawkins@sickkids.ca.
12
The Hospital for Sick Children, 555 University Avenue, Toronto, ON, M5G 1X8, Canada. cynthia.hawkins@sickkids.ca.

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

PMID:
27577993
PMCID:
PMC5006436
DOI:
10.1186/s40478-016-0353-0
[Indexed for MEDLINE]
Free PMC Article

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