BRAF V600E Mutations Are Common in Pleomorphic Xanthoastrocytoma: Diagnostic and Therapeutic Implications

Abstract

Pleomorphic xanthoastrocytoma (PXA) is low-grade glial neoplasm principally affecting children and young adults. Approximately 40% of PXA are reported to recur within 10 years of primary resection. Upon recurrence, patients receive radiation therapy and conventional chemotherapeutics designed for high-grade gliomas. Genetic changes that can be targeted by selective therapeutics have not been extensively evaluated in PXA and ancillary diagnostic tests to help discriminate PXA from other pleomorphic and often more aggressive astrocytic malignancies are limited. In this study, we apply the SNaPshot multiplexed targeted sequencing platform in the analysis of brain tumors to interrogate 60 genetic loci that are frequently mutated in 15 cancer genes. In our analysis we detect BRAF V600E mutations in 12 of 20 (60%) WHO grade II PXA, in 1 of 6 (17%) PXA with anaplasia and in 1 glioblastoma arising in a PXA. Phospho-ERK was detected in all tumors independent of the BRAF mutation status. BRAF duplication was not detected in any of the PXA cases. BRAF V600E mutations were identified in only 2 of 71 (2.8%) glioblastoma (GBM) analyzed, including 1 of 9 (11.1%) giant cell GBM (gcGBM). The finding that BRAF V600E mutations are common in the majority of PXA has important therapeutic implications and may help in differentiating less aggressive PXAs from lethal gcGBMs and GBMs.

Combined pleomorphic xanthoastrocytoma-ganglioglioma with BRAF V600E mutation: case report

“…Total or partial responses of PXAs to these therapies have been reported. 4 Two independent studies have reported a high frequency of BRAF mutation in PXA (60%-66%), 5,23 and Dougherty et al 6 also explored GG and pilocytic astrocytoma, finding 18% and 9% of these lesions, respectively, with BRAF mutations. Moreover, a common origin for these 3 tumors has been proposed.…”

Emerging insights into the molecular and cellular basis of glioblastoma

“…Together with other identified fusion events such as SRGAP3:RAF1 ), RAF fusion events occur in >80% of pilocytic astrocytomas (von Deimling et al 2011). Furthermore, BRAF V600E mutations have been found most commonly in WHO grade II pleomorphic xanthoastrocytomas (66%) (Dias-Santagata et al 2011;Schindler et al 2011) as well as WHO grade I gangliogliomas (18%) (MacConaill et al 2009;Schindler et al 2011). In addition, Wu et al (2012) used wholegenome sequencing to identify recurrent mutations in H3FA, which encodes the H3.3 protein, and the closely related HIST1H3B gene, which encodes the H3.1 protein isoform, in pediatric diffuse pontine gliomas.…”

BRAF‐V600E immunohistochemistry in a large series of glial and glial–neuronal tumors

“…BRAF rearrangements have also been identified in CNS tumors (Brastianos et al., 2014; Dias‐Santagata et al., 2011; Dougherty et al., 2010; Kleinschmidt‐DeMasters, Aisner, Birks, & Foreman, 2013; Koelsche et al., 2013, 2014). Very recently, the mutation V600E has been reported in 96% of papillary craniopharyngiomas (Brastianos et al., 2014).…”