Analysis of BRAF V600E mutation in 1,320 nervous system tumors reveals high mutation frequencies in pleomorphic xanthoastrocytoma, ganglioglioma and extra-cerebellar pilocytic astrocytoma

Abstract

Missense mutations of the V600E type constitute the vast majority of tumor-associated somatic alterations in the v-RAF murine sarcoma viral oncogene homolog B1 (BRAF) gene. Initially described in melanoma, colon and papillary thyroid carcinoma, these alterations have also been observed in primary nervous system tumors albeit at a low frequency. We analyzed exon 15 of BRAF spanning the V600 locus by direct sequencing in 1,320 adult and pediatric tumors of the nervous system including various types of glial, embryonal, neuronal and glioneuronal, meningeal, adenohypophyseal/sellar, and peripheral nervous system tumors. A total of 96 BRAF mutations were detected; 93 of the V600E type and 3 cases with a three base pair insertion between codons 599 and 600. The highest frequencies of BRAF (V600E) mutations were found in WHO grade II pleomorphic xanthoastrocytomas (42/64; 66%) and pleomorphic xanthoastrocytomas with anaplasia (15/23; 65%), as well as WHO grade I gangliogliomas (14/77; 18%), WHO grade III anaplastic gangliogliomas (3/6) and pilocytic astrocytomas (9/97; 9%). In pilocytic astrocytomas BRAF (V600E) mutation was strongly associated with extra-cerebellar location (p = 0.009) and was most frequent in diencephalic tumors (4/12; 33%). Glioblastomas and other gliomas were characterized by a low frequency or absence of mutations. No mutations were detected in non-glial tumors, including embryonal tumors, meningiomas, nerve sheath tumors and pituitary adenomas. The high mutation frequencies in pleomorphic xanthoastrocytomas, gangliogliomas and extra-cerebellar pilocytic astrocytomas implicate BRAF (V600E) mutation as a valuable diagnostic marker for these rare tumor entities. Future clinical trials should address whether BRAF (V600E) mutant brain tumor patients will benefit from BRAF (V600E)-directed targeted therapies.

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

“…We studied few cases of PXA (nine cases) and DNT (seven cases); this may explain why the frequencies of BRAF‐V600E mutation were lower than those reported in the literature (44.5% vs 66% for PXA/APXA and 0% vs 25% for DNT) (Chappé et al., 2013; Dougherty et al., 2010; Schindler et al., 2011). …”

“…As expected, the percentage of BRAF‐V600E mutant PA in our series was low (6.6%), which is comparable to the results obtained in other studies (Chappé et al., 2013; Schindler et al., 2011). It is interesting to note that the four mutant PA in our cohort were all of supratentorial location (basal ganglia, third ventricle, and optic pathways).…”

“…BRAF is an oncogene mutated in about half of melanomas (BRAF‐V600E mutation in most cases) and in other tumor entities as well (thyroid papillary carcinoma, colorectal carcinoma, hairy cell leukemia, Langerhans cell histiocytosis) (Andrulis, Penzel, Weichert, von Deimling, & Capper, 2012; Garnett & Marais, 2004; Ida et al., 2013; Long et al., 2013; Michaloglou, Vredeveld, Mooi, & Peeper, 2008; Rahman, Salajegheh, Smith, & Lam, 2013; Ritterhouse & Barletta, 2015; Sahm et al., 2012; Schindler et al., 2011). 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).…”

BRAF V600E-specific immunohistochemistry reveals low mutation rates in biliary tract cancer and restriction to intrahepatic cholangiocarcinoma

“…3 In addition, we tested BRAF V600E-mutated cases for KRAS hotspot mutations by sequencing (complete exon 1) using standard primers. Microdissection was performed if tumor content was o60%.…”

“…Mutation of the BRAF gene is one mechanism of constitutive activation and occurs in many human cancers including cutaneous melanoma, papillary thyroid carcinoma, borderline ovarian carcinoma, pleomorphic xanthoastrocytoma, colorectal carcinoma, non-small cell lung carcinoma, and hairy cell leukemia, among others. [3][4][5][6] The most common BRAF mutation results in a single aminoacid substitution of valine for glutamic acid at residue 600 (V600E). Early publications referred to codon 600 mutations as codon 599 mutations.…”