Molecular Heterogeneity in BRAF-Mutant Gliomas: Diagnostic, Prognostic, and Therapeutic Implications

Abstract

Over the last few decades, deciphering the alteration of molecular pathways in brain tumors has led to impressive changes in diagnostic refinement. Among the molecular abnormalities triggering and/or driving gliomas, alterations in the MAPK pathway reign supreme in the pediatric population, as it is encountered in almost all low-grade pediatric gliomas. Activating abnormalities in the MAPK pathway are also present in both pediatric and adult high-grade gliomas. Across those alterations, BRAF p.V600E mutations seem to define homogeneous groups of tumors in terms of prognosis. The recent development of small molecules inhibiting this pathway retains the attention of neurooncologists on BRAF-altered tumors, as conventional therapies showed no significant effect, nor prolonged efficiency on the high-grade or low-grade unresectable forms. Nevertheless, tumoral heterogeneity and especially molecular alteration(s) associated with MAPK-pathway abnormalities are not fully understood with respect to how they might lead to the specific dismal prognosis of those gliomas and/or affect their response to targeted therapies. This review is an attempt to provide comprehensive information regarding molecular alterations related to the aggressiveness modulation in BRAF-mutated gliomas and the current knowledge on how to use those targeted therapies in such situations.

Keywords: BRAF inhibitor; BRAF p.V600E mutation; CDKN2A; MAPK-induced gliomas; MEK inhibitor; driver; oncogene-induced senescence; passenger molecular alterations.

Figure 1

Summary of the molecular abnormalities in the MAPK pathway driving low- and high-grade gliomas. The low-grade entities are listed in green with their more frequent paired molecular aberrations, whereas the high-grade gliomas (HGGs) are described in red and LGG in greed. The alterations are listed in black color. DNET, dysembryoplastic neuroepithelial; PA, pilocytic astrocytoma; HGAP, high-grade astrocytoma with piloïd features; PLNTY, polymorphous low-grade neuroepithelial tumor of the young; GBM, glioblastoma; HGG, high-grade glioma; GGL, ganglioglioma; aGGL, anaplastic GGL; PXA, pleomorphic xanthoastrocytomas; aPXA, anaplastic PXA; MVNT, multinodular and vacuolating neuronal tumors.