Abstract
Glioneuronal tumours, including gangliogliomas and dysembryoplastic neuroepithelial tumours, represent the most common low-grade epilepsy-associated brain tumours and are a well-recognized cause of intractable focal epilepsy in children and young adults. Classification is predominantly based on histological features, which is difficult due to the broad histological spectrum of these tumours. The aim of the present study was to find molecular markers that can be used to identify entities within the histopathology spectrum of glioneuronal tumours. The focus of this study was on microRNAs (miRNAs). miRNAs are important post-transcriptional regulators of gene expression and are involved in the pathogenesis of different neurological diseases and oncogenesis. Using a miRNA array, miR-519d and miR-4758 were found to be upregulated in gangliogliomas (n=26) compared to control cortex (n=17), peritumoural tissue (n=7), dysembryoplastic neuroepithelial tumours (n=9) and astrocytomas (grade I-IV; subependymal giant cell astrocytomas, n=10; pilocytic astrocytoma, n=15; diffuse astrocytoma grade II, n=10; grade III, n=14 and glioblastoma n=15). Furthermore, the PI3K/AKT3/P21 pathway, which is predicated to be targeted by miR-519d and miR-4758, was deregulated in gangliogliomas. Functionally, overexpression of miR-519d in an astrocytic cell line resulted in a downregulation of CDKN1A (P21) and an increase in cell proliferation, whereas co-transfection with miR-4758 counteracted this effect. These results suggest that miR-519d and miR-4758 might work in concert as regulators of the cell cycle in low grade gliomas. Furthermore, these miRNAs could be used to distinguish gangliogliomas from dysembryoplastic neuroepithelial tumours and other low and high grade gliomas and may lead to more targeted therapy.
Highlights
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 [1,2,3,4].Patients with LEATs often have a history of 2 or more years of drug-resistant epilepsy [5]
We evaluated the expression of both miRNAs in GG compared to other gliomas, including pilocytic astrocytomas (PA) (n=15), diffuse astrocytoma grade II (AII; n=10), diffuse astrocytoma grade III (AIII; n=14) and glioblastoma (GB; n=15; Figure 1A-1B). miR-519d was upregulated in GG compared to all other gliomas, whereas miR-4758 was upregulated compared to AII, AIII, GB but not PA
We showed that miR-519d and miR4758 are upregulated in GGs compared to control tissue, DNTs and other gliomas
Summary
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 [1,2,3,4].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 of 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. In a small proportion of cases, seizures may persist [2, 3, 6]
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