Page 93 - Molecular features of low-grade developmental brain tumours

THE CODING AND NON-CODING TRANSCRIPTIONAL LANDSCAPE OF SEGA
Introduction
Tuberous sclerosis complex (TSC) is a multisystem genetic disorder affecting approximately 1 million people worldwide. It is caused by mutations in either TSC1 or TSC2 and is characterized by the development of benign tumours in multiple organs, including the brain 1-3. In the central nervous system, TSC is associated with subcortical/cortical tubers, subependymal nodules (SENs) and subependymal giant cell astrocytomas (SEGAs) 4-6.
SEGAs are benign slow growing tumours classified as WHO grade I representing 1-2% of all pediatric brain tumours and occur almost exclusively in patients with TSC 7,8. The prevalence of SEGAs in patients with TSC ranges from 5% to 25% and they usually arise during the first two decades of life 9-13. SEGAs arise around the ventricle zone, mostly at the height of the foramen of Monro and are thought to develop from SENs 14-16. Despite their slow growing nature, extended growth of the tumour can cause obstruction of the cerebral fluid tract leading to (acute) hydrocephalus and in rare cases even sudden death 17,18.
Hamartin (TSC1), tuberin (TSC2) and TBC1 Domain Family Member 7 (TBC1D7) can form a complex containing a GTPase-activating protein (GAP) for the small GTPase Ras homolog enriched in brain 1 (RHEB1), a direct positive regulator of the mechanistic target of rapamycin complex 1 (mTORC1) located on the late endosome/lysosome surface 19-21. Loss of function mutations in TSC1 or TSC2 result in constitutive activation of the mTORC1 pathway 22. In TSC, germline mutations in TSC1 or TSC2 can be familial inherited in a autosomal dominant fashion, but more often are sporadic in nature. Furthermore, loss of heterozygosity (LOH) of TSC1 or TSC2 has been reported in approximately 80% of SEGAs 22-24. However, “second-hit” mutations in TSC1 and TSC2 are not always observed in brain lesions including SEGA, suggesting that additional genetic events are involved in the growth and progression of SEGAs. Several studies have reported an activation of the mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) pathway in SEGA 25-27 and it has been shown that inhibiting ERK can effect the proliferation of SEGA cells 28, indicating that the MAPK/ERK pathway could play an important role in SEGA development. Furthermore, it has been shown that both the mTORC1 and MAPK/ERK pathway can be activated by the lysosomal Ragulator complex consisting of late endosomal/lysosomal adaptor, MAPK and mTOR activator 1-5 (LAMTOR1/p18, LAMTOR2/p14, LAMTOR3/MP1, LAMTOR4/C7orf59 and LAMTOR5/HBXIP) 29-32. Therefore, the role of the Ragulator complex in the development of SEGAs warrants further investigation.
Current treatment options for growing SEGAs include surgical resection or use of mTORC1 inhibitors, such as everolimus and rapamycin 33-39. Although, mTORC1 inhibitors have shown to be effective in patients with TSC, the response to mTORC1 inhibitors can be variable and cessation of treatment may result in tumour regrowth. 34,38-43.
Previous gene expression studies on SEGA focus on the expression of protein- coding genes using either a microarray 28 or RNA sequencing (RNA-seq) 23. In the present study, we aimed to map both the protein-coding and non-coding RNA, including small RNAs, of SEGA compared to periventricular control tissue in order to identify signaling pathways deregulated in SEGA and explore the possibility of novel therapeutic targets.
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