BRAF mutations constitute a major genetic alteration in this histologic group of pediatric brain tumors and may serve as a molecular target for biologically based inhibitors.
Recently, aberrant methylation of MLH1, MGMT and MSI were shown to be associated with mutations in genes such as BRAF, RAS and IDH1 in colon and brain tumours.
Sorafenib, the first agent developed to target BRAF mutant melanoma, is a multi-kinase inhibitor that was approved by the FDA for therapy of kidney and subsequently liver cancer, and is currently in clinical trials for thyroid, lung and brain cancer.
PKM2-regulated MLC2 phosphorylation, which is greatly enhanced by EGF stimulation or EGFRvIII, K-Ras G12V and B-RafV600E mutant expression, plays a pivotal role in cytokinesis, cell proliferation and brain tumour development.
The BRAFV600E mutation occurs frequently in certain brain tumors such as pleomorphic xanthoastrocytoma, ganglioglioma, and pilocytic astrocytoma, and less frequently in epithelioid and giant cell glioblastoma.
Glioneuronal tumors (GNTs) are the most common histological type of brain tumors in patients who received epilepsy surgery, and part of them presented with BRAFV600E mutation.
Molecular markers such as MGMT, EGFR, IDH, 1p19q, ATRX, TERT, FGFR-TACC, and BRAF are now being used to classify brain tumors as well as influence management decisions.
Our method successfully detected KIAA1549-v-raf murine sarcoma viral oncogene homolog B1 (BRAF) fusion in 14 out of 19 patients suffering from five types of paediatric brain tumours providing information on fusion breakpoints within 2 h.
Accordingly, this study provides direct evidence of a BRAF somatic mutation contributing to the intrinsic epileptogenicity in pediatric brain tumors and suggests that BRAF and REST could be treatment targets for intractable epilepsy.