Comprehensive molecular characterisation of epilepsy-associated glioneuronal tumours

• Published in: Acta neuropathologica 2018-01, Vol.135 (1), p.115-129
• Main Authors: Stone, Thomas J., Keeley, Angus, Virasami, Alex, Harkness, William, Tisdall, Martin, Izquierdo Delgado, Elisa, Gutteridge, Alice, Brooks, Tony, Kristiansen, Mark, Chalker, Jane, Wilkhu, Lisa, Mifsud, William, Apps, John, Thom, Maria, Hubank, Mike, Forshew, Tim, Cross, J. Helen, Hargrave, Darren, Ham, Jonathan, Jacques, Thomas S.
• Format: Article
• Language: English
• Subjects: Adolescent; Analysis; Brain Neoplasms - genetics; Brain Neoplasms - metabolism; Brain Neoplasms - pathology; Brain Neoplasms - surgery; Child; Child, Preschool; Cohort Studies; DNA Methylation; DNA sequencing; Epilepsy; Epilepsy - genetics; Epilepsy - metabolism; Epilepsy - pathology; Epilepsy - surgery; Female; Fibroblast growth factor receptor 1; Ganglioglioma - genetics; Ganglioglioma - metabolism; Ganglioglioma - pathology; Ganglioglioma - surgery; Gene Expression; Gene mutation; Humans; Infant; Male; Medicine; Medicine & Public Health; Methylation; Mutation; Neoplasms, Neuroepithelial - genetics; Neoplasms, Neuroepithelial - metabolism; Neoplasms, Neuroepithelial - pathology; Neoplasms, Neuroepithelial - surgery; Neurosciences; Original Paper; Pathology; Phenotype; Platelet-derived growth factor; Proto-Oncogene Proteins B-raf - genetics; Proto-Oncogene Proteins B-raf - metabolism; Receptor, Fibroblast Growth Factor, Type 1 - metabolism; Ribonucleic acid; RNA; RNA sequencing; Tumors
• ISSN: 0001-6322; 1432-0533
• DOI: 10.1007/s00401-017-1773-z

Glioneuronal tumours are an important cause of treatment-resistant epilepsy. Subtypes of tumour are often poorly discriminated by histological features and may be difficult to diagnose due to a lack of robust diagnostic tools. This is illustrated by marked variability in the reported frequencies across different epilepsy surgical series. To address this, we used DNA methylation arrays and RNA sequencing to assay the methylation and expression profiles within a large cohort of glioneuronal tumours. By adopting a class discovery approach, we were able to identify two distinct groups of glioneuronal tumour, which only partially corresponded to the existing histological classification. Furthermore, by additional molecular analyses, we were able to identify pathogenic mutations in BRAF and FGFR1 , specific to each group, in a high proportion of cases. Finally, by interrogating our expression data, we were able to show that each molecular group possessed expression phenotypes suggesting different cellular differentiation: astrocytic in one group and oligodendroglial in the second. Informed by this, we were able to identify CCND1, CSPG4, and PDGFRA as immunohistochemical targets which could distinguish between molecular groups. Our data suggest that the current histological classification of glioneuronal tumours does not adequately represent their underlying biology. Instead, we show that there are two molecular groups within glioneuronal tumours. The first of these displays astrocytic differentiation and is driven by BRAF mutations, while the second displays oligodendroglial differentiation and is driven by FGFR1 mutations.