MAPK pathway activation in pilocytic astrocytoma

Abstract

Pilocytic astrocytoma (PA) is the most common tumor of the pediatric central nervous system (CNS). A body of research over recent years has demonstrated a key role for mitogen-activated protein kinase (MAPK) pathway signaling in the development and behavior of PAs. Several mechanisms lead to activation of this pathway in PA, mostly in a mutually exclusive manner, with constitutive BRAF kinase activation subsequent to gene fusion being the most frequent. The high specificity of this fusion to PA when compared with other CNS tumors has diagnostic utility. In addition, the frequency of alteration of this key pathway provides an opportunity for molecularly targeted therapy in this tumor. Here, we review the current knowledge on mechanisms of MAPK activation in PA and some of the downstream consequences of this activation, which are now starting to be elucidated both in vitro and in vivo, as well as clinical considerations and possible future directions.

Molecular neuro-oncology in clinical practice: a new horizon

“…41,42 These fusions are only very rarely found in other tumours. KIAA1549:BRAF gene fusions are therefore considered a very important diagnostic aid to distinguish pilocytic astrocytoma from higher grade astrocytic tumours, a distinction that can be both challenging and therapeutically highly relevant given the fact that pilocytic astrocytomas and glioblastomas share the morphological feature of microvascular proliferation.…”

“…45 The glioma-associated BRAF alterations all exert their oncogenic activity by activating the mitogen-activated protein kinase (MAPK) pathway. 42 More recent studies employing large scale sequencing identified an oncogenic hit in the MAPK pathway in (almost) all pilocytic astrocytomas (Pfister, unpublished) while they did not reveal any significantly mutated gene outside of this pathway, indicating that this tumour may indeed be a single-pathway disease. The availability of small-molecule BRAF kinase inhibitors such as vemurafenib (PLX4032), which specifically targets BRAF V600E -mutant tumours, provides a new therapeutic approach to these subgroups of gliomas and preliminary clinical evidence (Pfister, unpublished) suggests that the presence of a BRAF V600E mutation may indeed serve as a potent predictive marker for this subset of patients across gliomas of various grades.…”

Heterogeneity of histopathological presentation of pilocytic astrocytoma – diagnostic pitfalls. A review

“…However, their prognostic significance is unclear. KIAA1549-BRAF fusion causes a deletion of the amino-terminal domain of BRAF and constitutive activation of its kinase activity [44]. A proteomic study confirmed the predominance of the MAPK pathway for childhood PA and introduced novel findings regarding ERK-2 expression [6].…”

Expression of Methylthioadenosine Phosphorylase (MTAP) in Pilocytic Astrocytomas

“…Nf1-PAs are usually less aggressive and located at extracerebellar sites [8] . The overall prognosis for PAs is good, but in some cases they are aggressive, leading to death [9][10][11] . Extension of resection and high mitotic activity are key factors related to a poor prognosis in PAs [10,11] .…”