BRAF V600EMutation Is Associated withmTORSignaling Activation in Glioneuronal Tumors

Abstract

BRAF V600E mutations have been recently reported in glioneuronal tumors (GNTs). To evaluate the expression of the BRAF V600E mutated protein and its association with activation of the mammalian target of rapamycin (mTOR) pathway, immunophenotype and clinical characteristics in GNTs, we investigated a cohort of 174 GNTs. The presence of BRAF V600E mutations was detected by direct DNA sequencing and BRAF V600E immunohistochemical detection. Expression of BRAF-mutated protein was detected in 38/93 (40.8%) gangliogliomas (GGs), 2/4 (50%) desmoplastic infantile gangliogliomas (DIGs) and 23/77 (29.8%) dysembryoplastic neuroepithelial tumors (DNTs) by immunohistochemistry. In both GGs and DNTs, the presence of BRAF V600E mutation was significantly associated with the expression of CD34, phosphorylated ribosomal S6 protein (pS6; marker of mTOR pathway activation) in dysplastic neurons and synaptophysin (P < 0.05). In GGs, the presence of lymphocytic cuffs was more frequent in BRAF-mutated cases (31 vs. 15.8%; P=0.001). The expression of both BRAF V600E and pS6 was associated with a worse postoperative seizure outcome in GNT (P < 0.001). Immunohistochemical detection of BRAF V600E-mutated protein may be valuable in the diagnostic evaluation of these glioneuronal lesions and the observed association with mTOR activation may aid in the development of targeted treatment involving specific pathogenic pathways.

Epilepsy Related to Developmental Tumors and Malformations of Cortical Development

“…Enhanced mTOR signaling pathway activation has been detected in both GG and DNT (Fig. 1c) [28,31]. These findings support the inclusion of GNT within the group of MCD (such as FCD and TSC), characterized by cortical dysgenesis with abnormal cell proliferation ( [5]; Table 2).…”

“…The presence of the BRAF V600E mutation in DNTs strongly supports a relationship between DNTs and GGs, pointing to the pathogenic role of BRAF in different entities within the large spectrum of GNT, including other low-grade tumors arising in young age groups, such as pilocytic astrocytomas and pleomorphic xanthoastrocytoma [36,40]. Interestingly, the BRAF V600E mutation has been shown to be associated with the expression of phosphorylated ribosomal S6 protein (pS6; marker of mTOR pathway activation) in GNT [31]. Accordingly, the BRAF V600E mutation has been linked to enhanced mTOR signaling via regulation of the protein kinase B (Akt) pathway [41].…”

“…1d), desmoplastic infantile GGs [38], and DNTs [31,39]. The presence of the BRAF V600E mutation in DNTs strongly supports a relationship between DNTs and GGs, pointing to the pathogenic role of BRAF in different entities within the large spectrum of GNT, including other low-grade tumors arising in young age groups, such as pilocytic astrocytomas and pleomorphic xanthoastrocytoma [36,40].…”

“…P=phosphorylation; IGF-1=insulin-like growth factor-1; PI3K=PI3kinase; PDK1=phosphoinositide-dependent kinase-1; LKB1=tumor suppressor liver kinase B1; AMPK=AMP-activated protein kinase; HPV = human papilloma virus; S6K1 = p70S6kinase; 4E-BP1=elongation binding protein 1; pS6=phosphory-lated ribosomal S6 protein; Erk=extracellular signal regulated kinase; IRS=insulin receptor substrate; PTEN=Phosphatase and tensin homologue; Akt=protein kinase B; Rheb=ras homolog enriched in brain; mTORC=mammalian target of rapamycin complex; REDD1=regulated in DNA damage and development 1; DEPTOR=DEP domain containing MTOR-interacting protein through uncoupling of the LKB1-adenosine monophosphateactivated protein kinase-mTOR signaling. Interestingly, GGs have been reported in Peutz-Jeghers patients with a mutation of the LKB1 gene [45,46] and pLKB1 expression has been reported in GNT with the BRAF mutation [31]. These observations indicate that detection of BRAF V600E-mutated protein together with pS6 may be valuable in the diagnostic evaluation of GNT and may aid development of targeted treatment involving specific pathogenic pathways.…”

“…In GNT, particularly in GG, the prominent inflammatory changes are associated with evidence of alterations in bloodbrain barrier (BBB) dysfunction, with albumin extravasation and uptake in tumor astrocytes [31,76,78], which could play an additional role in the tumor epileptogenicity [79]. Interestingly, in GGs,a positive correlation between pS6 expression and the presence of perivascular cuffs of lymphocytes, as well as with MHC-I and MHC-II expression and albumin extravasation/glial uptake within the tumor, has been detected [31].…”