Comprehensive molecular characterisation of epilepsy-associated glioneuronal tumours

T J Stone ,John Apps,Martin Tisdall,Angus Keeley,William Harkness,Tim Forshew,Jonathan Ham,Darren Hargrave,J Helen Cross,Alex Virasami,Lisa Wilkhu,Tony Brooks,Jane Chalker,Maria Thom,William Mifsud,Alice Gutteridge,Mark Kristiansen,Michael Hubank ,Elisa Izquierdo ,Thomas S Jacques

doi:10.1007/s00401-017-1773-z

Abstract

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.

Highlights

Epilepsy is the most common serious chronic neurological condition of childhood, which has long-term effects on health and quality of life
Surgical cases were principally retrieved from the Great Ormond Street Hospital (GOSH) archives. 111 patients diagnosed with a ganglioglioma, dysembryoplastic neuroepithelial tumour (DNET), or glioneuronal tumour between 1991 and 2015 were identified and corresponding diagnostic formalin fixed paraffin embedded (FFPE) sections were retrieved
From a cohort of 111 archival cases retrieved from the GOSH archives, we identified 99 glioneuronal tumours upon histological review

Summary

Introduction

Epilepsy is the most common serious chronic neurological condition of childhood, which has long-term effects on health and quality of life. In the UK, the incidence of epilepsy in children between 0 and 7 years of age has been estimated at 71-116/100,000 persons-years-at-risk [12]. The cumulative incidence of epilepsy rose to 8.4/1000 by the age of 23 [9]. Structural abnormalities of the brain are frequently observed in patients with intractable childhood epilepsy [1]. Of these abnormalities, brain tumours represent the second most common cause of seizures [5]. Brain tumours represent the second most common cause of seizures [5] This is true for low-grade cortical glioneuronal tumours, the most prevalent of which are ganglioglioma (GG) and dysembryoplastic neuroepithelial tumour (DNET)

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Conclusion