Page 41 - Molecular features of low-grade developmental brain tumours

SEGA IN TSC HAVE TSC1/TSC2 BIALLELIC INACTIVATION & NO BRAF MUTATIONS
Introduction
Subependymal giant cell astrocytomas (SEGAs) are rare, low-grade brain tumours that generally develop during the first two decades of life in 10-20% of patients with tuberous sclerosis complex (TSC) 1-3. TSC is an autosomal dominant neurocutaneous disorder caused by mutations in either TSC1 encoding hamartin, or TSC2 encoding tuberin. Together these two proteins form the TSC protein complex that regulates mechanistic target of rapamycin complex 1 (mTORC1) 4-6. In the central nervous system, TSC is characterized by the development of SEGAs, subependymal nodules (SEN), cortical tubers and cortical migration tracts 7. SEGAs represent 1%-2% of all pediatric brain tumours and usually arise near the foramen of Monro 8-10. They are a potential cause of major morbidity and mortality in TSC 11. Extended growth of the tumour can cause obstruction of cerebrospinal fluid tract resulting in hydrocephalus and increased intracranial pressure with subsequent death if neglected. SEGAs are treated with either surgical resection or mTORC1 inhibitors including everolimus. Histopathologically, SEGAs consist of spindle cells, gemistocytic-like cells and giant cells. According to the present world health organization (WHO) classification of brain tumours, SEGAs belong to the group of astrocytic neoplasms, even though they have both glial and neuronal expression patterns 12,13. SEGAs likely develop from SEN, but the molecular mechanisms underlying their progressive growth, in contrast to SEN, are unknown so far 14,15. There is evidence of second-hit inactivation of TSC1 or TSC2 in SEGAs, suggesting that one contributor to SEGA development is the complete loss of a functional tuberin-hamartin complex and the subsequent mTORC1 activation 16-18. However, it is likely that second-hit mutations in TSC1 and TSC2 also contribute to SEN formation, suggesting that additional genetic events may contribute to the progressive growth of SEGAs.
BRAF is a kinase that activates the mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK) pathway which regulates cell proliferation, survival and cell-cycle arrest 19. The BRAF c.1799T>A (p.V600E) mutation (BRAFV600E) results in constitutive activation of MAPK/ERK signaling and is well known in both pediatric and adult low-grade gliomas, including pilocytic astrocytoma (PA), pleomorphic xanthoastrocytoma (PXA), ganglioglioma (GG), desmoplastic infantile gangliogliomas (DIG), and dysembyoplastic neuroepithelial tumour (DNET) 20-26. Although the prevalence of BRAF mutations in low grade gliomas is relatively low 22, BRAFV600E mutations have been consistently reported as genetic driver in gangliogliomas (18-56%), and have been associated with mTORC1 activation 20,25. Both protein kinase B (AKT) and MAPK/ERK pathways have been reported to be activated in SEGAs 27-31. However, the genetic basis for MAPK/ERK and AKT activation in SEGAs is unknown. The BRAFV600E mutation was reported in a small set (6 of 14 cases) of SEGAs 23 suggesting that it could explain MAPK/ERK and AKT activation in SEGAs. However, subsequent studies have produced contradictory results, failing to confirm the presence of the BRAFV600E mutation in SEGAs 18,21,23,26,32.
In the present study, we examined the possibility that BRAF mutations occur in SEGA using a large international cohort of fifty-eight SEGAs from both pediatric and adult TSC patients.
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