BRAF alterations in brain tumours: molecular pathology and therapeutic opportunities

To summarize the current knowledge on v-RAF murine sarcoma viral oncogene homologue B1 (BRAF) aberrations in tumours of the central nervous system.

BRAF alterations are found in variable frequencies across a wide spectrum of diverse central nervous system neoplasms. BRAF V600 point mutations (most commonly of the V600E type) are most common in pleomorphic xanthoastrocytoma (approximately 60% of cases), gangliogliomas (50%), dysembryoplastic neuroepithelial tumours (30%), Langerhans cell histiocytosis (50%), melanoma brain metastases (50%) and papillary craniopharyngiomas (96%) and are also detectable in a fraction of glioblastomas (overall mutation rate of 2-12%, with a higher rate of approximately 50% in epithelioid glioblastomas). BRAF fusions (most commonly KIAA1549: BRAF) are typical for pilocytic astrocytomas and are almost absent from other tumour types. Clinical trials have established tyrosine-kinase inhibitors of BRAF as feasible treatment option in selected patients with mutation-bearing brain metastases of melanoma. Preclinical studies, some case reports and small patient series have documented tumour responses of primary brain tumours with BRAF aberrations to BRAF inhibition.

Molecular testing for BRAF alterations in brain tumours may be of clinical relevance for differential diagnostic considerations in some situations or to guide selection of patients for targeted therapy with specific inhibitors. Prospective clinical trials evaluating the efficacy of BRAF inhibitors in central nervous system tumours are strongly supported by the available evidence.