BRAF Alteration in Central and Peripheral Nervous System Tumors

Abstract

BRAF (alternately referred to as v-raf murine sarcoma viral oncogene homolog B1) is a proto-oncogene involved in the mitogen-activated protein kinase (MAPK) pathway. BRAF alterations are most commonly missense mutations or aberrant fusions. These mutations are observed in numerous primary central nervous system tumors as well as metastases. This review discusses the prevalence of BRAF alteration within select notable CNS tumors, and their prognostic associations. Included are some novel entities such as diffuse leptomeningeal glioneuronal tumor (DLGNT), polymorphous low grade neuroepithelial tumor of the young (PLNTY), and multinodular and vacuolating neuronal tumor (MVNT). Knowledge of this gene's integrity in CNS and PNS tumors can have profound diagnostic and therapeutic implications. Also reviewed are the current state of targeted therapy against aberrant BRAF as it pertains mostly to the CNS and to a lesser extent in PNS, and certain diagnostic aspects.

Glioneuronal Tumors: Insights into a Rare Tumor Entity

“…About 42.9% of patients display two or more types of seizures with more patients presenting with complex partial seizures (dialeptic seizure, with vegetative or affective aura, psycho-sensorial aura and automatisms) or partial seizures evolving to secondarily generalized seizures (8). Temporal location is common, and the seizure presentation can be associated with focal cortical dysplasia (6). Although previous publications indicated a possible predilection for male (8) or female gender (1,14,30), more recent data suggests a 1:1 distribution (5,22).…”

“…Some gliomas and glioneuronal tumors are characterized by a fusion between the BRAF gene and the locus KIAA1549 (45) (Table 1). The fusion causes a constitutional activation of the tyrosine kinase domain of BRAF and a permanent activation of the MAP kinase (MAPK) pathway (6,66). The detection of a BRAF rearrangement can help distinguish cancers with favorable prognosis such as glioneuronal tumors from those with poorer prognosis, such as diffuse gliomas, including diffuse astrocytomas and oligodendrogliomas.…”

“…Glioneuronal tumors are rare tumors comprised of both neural and glial components present in heterogenous proportions displaying indolent WHO grade I behavior (1)(2)(3). More recently, molecular characterization has allowed for more robust classification (4)(5)(6)(7)(8)(9). The subtypes falling under the umbrella of glioneuronal tumors are actively evolving but currently include: central, extraventricular and lipo-neurocytoma; desmoplastic infantile astrocytoma and ganglioglioma (DIA/DIG), diffuse leptomeningeal glioneuronal tumor, dysembryoplastic neuroepithelial tumor (DNET), papillary glioneuronal tumor (PGNT), rosette-forming glioneuronal tumor of the fourth ventricle (RGNT), rosetted glioneuronal tumor with neuropil-like islands (GNTNI), gangliocytoma (GC), ganglioglioma (GG) and anaplastic ganglioglioma and paraganglioma (1,2).…”

Targeted Therapies in Rare Brain Tumours

“…The activation of MAPK pathway fosters several intracellular signals which promote cell growth and survival. The pathological activation of such system (due to either BRAF gain of function or loss of function of regulatory proteins) is implicated in tumourigenesis [ 24 ]. In particular, gain of function of BRAF plays a critical role in a heterogeneous group of gliomas, as well as in the majority of metastatic melanoma and other cancers (including papillary thyroid cancer, colon carcinomas, hairy cell leukaemia) [ 25 ].…”

“…BRAF alterations are frequently seen in glioneuronal tumours: KIAA1549: BRAF fusion and BRAF V600E mutation are seen in 25% and 13–56% of gangliogliomas and gangliocytomas, respectively. BRAF single nucleotide mutations are found in 11%, 51%, 43% and 65% of desmoplastic infantile astrocytoma/ganglioglioma, dysembryoplastic neuroepithelial tumour, subependymal giant cell astrocytoma, and diffuse leptomeningeal glioneuronal tumour [ 24 ]. Growing attention has been devoted to design tailored therapies with MAPK-inhibitors in brain tumours with BRAF activation, with particular regard to paediatric low-grade gliomas (PLGGs) [ 26 , 31 ].…”