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

SIMPLE SUMMARY: Drugs targeting activating BRAF mutations have transformed the prognosis and treatment of MAPK-pathway-induced cancers. In neuro-oncology, the better knowledge of the MAPK pathway’s involvement in gliomagenesis offers hope in a subset of brain cancers where conventional therapies have produced disappointing results. The temptation to use BRAF inhibitors alone or in combination in cerebral mutant tumors is high and is providing survival benefit in trials. Nonetheless, it is currently not clear what kind of gliomas can be treated and when the patient will benefit from these therapies in terms of permanent curability. This review will summarize the up-to-date literature regarding BRAF-altered gliomas, their molecular diagnosis, their prognosis, their associated molecular alterations, and how potentially treat those tumors. 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.