Abstract
Neurofibromatosis type 1 (NF1) is an autosomal dominant disorder, associated with a variable clinical phenotype including café-au-lait spots, intertriginous freckling, Lisch nodules, neurofibromas, optic pathway gliomas and distinctive bony lesions. NF1 is caused by a mutation in the NF1 gene, which codes for neurofibromin, a large protein involved in the MAPK- and the mTOR-pathway through RAS-RAF signalling. NF1 is a known tumour predisposition syndrome, associated with different tumours of the nervous system including low grade gliomas (LGGs) in the paediatric population. The focus of this review is on grade I pilocytic astrocytomas (PAs), the most commonly observed histologic subtype of low grade gliomas in NF1. Clinically, these PAs have a better prognosis and show different localisation patterns than their sporadic counterparts, which are most commonly associated with a KIAA1549:BRAF fusion. In this review, possible mechanisms of tumourigenesis in LGGs with and without NF1 will be discussed, including the contribution of different signalling pathways and tumour microenvironment. Furthermore we will discuss how increased understanding of tumourigenesis may lead to new potential targets for treatment.
Highlights
Cerebellar neural stem cells transduced with the KIAA1549:BRAF fusion show increased cell growth. After injection of these cerebellar neural stem cells in mouse cerebella, these mice develop glioma-like lesions after 6 months. Because this effect is not seen in cortical neural stem cells nor in astrocytes, this is in concordance with a brain region- and cell-specific response to the KIAA1549:BRAF fusion, comparable with that seen in Neurofibromatosis type 1 (NF1) (Kaul et al, 2012, 2013)
These results may be biased by the selection of a group of NF1 associated optic pathway gliomas (OPGs) that were eligible for surgery (Bartels et al, 2006)
The exact mechanism behind this vasculopathy remains unclear, neurofibromin is widely expressed in blood vessels, suggesting a possible role for NF1 signalling in NF1 vasculopathy (Rodrigues et al, 2013)
Summary
Neurofibromatosis type 1 (NF1) or von Recklinghausen’s disease is an autosomal dominant disorder with a worldwide incidence of 1 per 2500–3000 individuals. It is characterized by the presence of café-au-lait spots, intertriginous freckling, Lisch nodules, neurofibromas, optic pathway gliomas and distinctive bony lesions. Loss of neurofibromin increases RAS activity and induces downstream activity of the MEK-ERK (MAPK, mitogen activated protein kinase) pathway as well as the PI3KAkt-mTOR (mammalian target of rapamycin) pathway (Sandsmark et al, 2007; Banerjee et al, 2011a; Johannessen et al, 2005) Through these signalling pathways, neurofibromin functions as a negative regulator of cell growth and proliferation (Fig. 1)
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