Page 11 - Molecular features of low-grade developmental brain tumours

GENERAL INTRODUCTION & OUTLINE OF THE THESIS
Low-grade gliomas
Clinically brain tumours can present with various symptoms, of which seizures are the most prominent 1. Several factors are associated with the epileptogenicity of brain tumours, such as the type of tumour, grade, anatomical location, size, time interval before resection and the age of the patient. Particularly, slow-growing, low-grade glial and glioneuronal tumours are found to be highly epileptogenic. Most likely the slow growth rate gives enough time for reorganization of the adjacent cortex or other brain areas such as the hippocampus, leading to increased hypersensitivity and ultimately increasing the chance of epileptogenesis 2. Low grade gliomas (LGGs) are considered grades I/II according to the WHO 3. Low-grade astrocytic and oligodendroglial tumours include diffuse astrocytoma and oligodendrogliomas, whereas low-grade glioneuronal tumours include a large spectrum of entities such as desmoplastic infantile astrocytoma/ganglioglioma (DIA/DIG), papillary glioneuronal tumour, rosette- forming glioneuronal tumour, pilomyxoid astrocytoma, pleomorphic xanthoastrocytoma (PXA), pilocytic astrocytomas (PA), subependymal giant cell astrocytoma (SEGA), ganglioglioma (GG) and dysembryoplastic neuroepithelial tumour (DNT). According to the 2016 WHO classification, diagnosis of these tumours is based predominately on histological criteria, however interobserver variations are present and the histological characteristics overlap between entities, making classification based on their morphology alone challenging 4-6. Therefore, the use of molecular markers based on genetic alterations and epigenetics is suggested 7.
While adult low-grade gliomas are capable of developing into higher-grade lesions, pLGGs seldomly transform into a malignant state, which most likely is a consequence of the molecular and genetic differences 8,9. In adult patients with LGGs, a genetically based classification exists, where low-grade astrocytomas are defined by Isocitrate dehydrogenase (IDH) mutations, usually combined with ATRX chromatin remodeler (ATRX) and tumour protein 53 (TP53) mutations, while oligodendrogliomas have whole arm 1p/19q co-deletion combined with IDH mutations 10,11. Moreover, the presence of IDH1/2 mutations can exclude the diagnosis of GG, DNT and gangliocytoma 3. In paediatric LGGs (pLGGs) these genetic alterations are more rare. Genetic events involving the extracellular signal–regulated kinase (ERK)/mitogen-activated protein kinase (MAPK) pathway are most common in pLGGs, such as the B-Raf proto-oncogene, serine/threonine kinase (BRAF) c.1799T>A (p.V600E; BRAFV600E) mutation or the KIAA1549-BRAF fusion gene, which both result in constitutive activation of BRAF 12-19. Other genetic alterations in fibroblast growth factor receptor (FGFR) 1/2/3, Raf-1 proto-oncogene, serine/threonine kinase (RAF1), ALK receptor tyrosine kinase (ALK), neurotrophic receptor tyrosine kinase 2 (NTRK2), MET proto-oncogene, receptor tyrosine kinase (MET), ROS proto- oncogene 1, receptor tyrosine kinase (ROS1), MYB Proto-Oncogene, Transcription Factor (MYB), MYB proto-oncogene like 1 (MYBL1), IDH1/2, and H3.3 histone A (H3F3A) are less common 20-22. Additionally, in contrast to most adult gliomas, pLGGs can also have a hereditary component. For example, SEGAs are low grade brain tumours that account for ~2% of pLGGs and occur almost exclusively in patients with tuberous sclerosis complex (TSC), a neurocutaneous disease caused by a germline mutation in either the TSC1 or TSC2 gene, which results in
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