Abstract
Alterations of the v-raf murine sarcoma viral oncogene homolog B (BRAF) have been extensively studied in several tumor entities and are known to drive cell growth in several tumor entities. Effective targeted therapies with mutation-specific small molecule inhibitors have been developed and established for metastasized malignant melanoma. The BRAF V600E mutation and KIAA1549-BRAF fusion are alterations found in several brain tumors and show a distinct prognostic impact in some entities. Besides the diagnostic significance for the classification of central nervous system tumors, these alterations present possible therapy targets that may be exploitable for oncological treatments, as it has been established for malignant melanomas. In this review the different central nervous system tumors harboring BRAF alterations are presented and the diagnostic significance, prognostic role, and therapeutic potential are discussed.
Highlights
Like many other neoplasms, brain tumors, especially the ones originating from glia of white and grey matter, can harbor v-raf murine sarcoma viral oncogene homolog B1 (BRAF) gene alterations.Early animal models with Ras-1 induced glioma formation and experimental blocking of the BRAF hotspot mutation in brain tumor cell cultures suggest that tumor growth is regulated via mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK) as seen in non-CNS tumors [1,2]
In the open-label, nonrandomized, multicohort VE-BASKET study, three anaplastic gangliogliomas and two pilocytic astrocytomas with BRAF V600E mutations were treated with vemurafenib twice daily and a partial response was observed in one patient with a pilocytic astrocytoma and one with an anaplastic ganglioglioma [40]
Even though the clinical behavior of mutated gliomas seems to be similar to wildtype tumors, screening for the BRAF V600E mutation is recommended for younger patients diagnosed with glioblastoma and in tumors with predominantly temporal lobe location, because mutation specific targeted treatment options exist [67] and encouraging case reports have been published
Summary
Brain tumors, especially the ones originating from glia of white and grey matter, can harbor v-raf murine sarcoma viral oncogene homolog B1 (BRAF) gene alterations. BRAF activation in human neural stem and progenitor cells promotes tumor growth, and subsequently causes oncogene-induced senescence in some low-grade brain tumors [3] This may explain the relatively high frequency of BRAF mutant brain tumors associated with favorable outcome. By exploiting a nicely constructed Cre/lox animal model Robinson and colleagues were able to demonstrate that the combination of BRAF mutation with Akt activation or Ink4a/ARF loss is required to generate brain tumors with high-grade appearance [4]. This highlights the important role of BRAF alterations in oncogenic signaling in brain tumors.
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