Page 155 - Molecular features of low-grade developmental brain tumours

MIR-519D & MIR-4758 CAN IDENTIFY GG FROM DNT AND ASTROCYTOMAS
Introduction
Low-grade epilepsy-associated brain tumours (LEATs), including glioneuronal tumours (GNTs) such as gangliogliomas (GGs) and dysembryoplastic neuroepithelial tumours (DNTs), represent the most frequent tumour entity in young patients who undergo surgery for chronic intractable focal epilepsy 1-4. Patients with LEATs often have a history of 2 or more years of drug-resistant epilepsy 5. GGs and DNTs are low grade, stationary or very slow growing, cortical based tumours with a very low risk for tumour recurrence and malignant progression 3,5. These tumours often present with early seizure onset at a mean age of 16.5 years 1,2. In the majority of cases surgical resection shows favourable prognosis, both in terms of tumour management and seizure outcome. However in a small proportion of cases, seizures may persist 2,3,6.
The histopathological features of GNTs include a mixture of neuronal (dysplastic neurons) and glial elements in GGs, while a specific glioneuronal element is evident in DNTs 3,7. Immature neural elements combined with expression of stem cell markers and the coexistence with cortical dysplasia suggest a developmental pathogenesis for GGs and DNTs. This is supported by studies indicating that these tumours are associated with molecular alterations of key developmental signalling pathways, including the enhanced activation of the mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK) and the phosphoinositide 3-kinase/Protein Kinase B/mechanistic target of rapamycin (PI3K/AKT/ mTOR) pathway 1,8-11. The BRAF c.1799T>A (p.V600E; BRAFV600E) mutation was found to be a common genetic driver in GGs (18-56%). However, the frequency of this mutation varies considerably between studies 8,12-15. In other LEATs, the BRAF mutation has been observed in 30-51% of DNTs 13,15,16 and in 3/10 of the recently described polymorphous low-grade neuroepithelial tumours of the young (PLNTY) 17, but not in multinodular and vacuolating neuronal tumours (MVNT) 18 and angiocentric gliomas 19. In other low grade gliomas such as pleomorphic xanthoastrocytoma (PXA) and pilocytic astrocytomas (PA) the BRAFV600E mutation has also been observed 8,20,21. Therefore, the presence of the BRAFV600E mutation cannot be regarded as specific for any tumour entity. In contrast to the BRAFV600E mutation, tyrosine kinase activating FGFR1 gene mutations were found more frequently in DNTs (58- 82%) 9,19, suggesting this mutation could be a good marker for DNTs. However, besides the FGFR1 mutations, BRAF mutations and copy number abnormalities also occur in DNTs, making it difficult to distinguish between GGs and DNTs based on the presence of BRAF and FGFR1 mutations only 13,15,16,22.
The 2016 revised WHO classification for LEATs is based on histological criteria, but does not involve an integration of molecular and pathological analysis techniques 1. Although, several histological classification systems have been proposed 1-3, the broad spectrum of LEATs renders classification using these systems very difficult. Recently, a molecular classification was suggested for glioneuronal tumours, highlighting the importance of integrating molecular diagnostics in classifying these tumours 23,24.
The aim of the present study was to find molecular markers that can be used to identify specific LEATs. The focus was on microRNAs (miRNAs), since they are important
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