title: 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.
authors.affiliation: Department of Neurosurgery, Medical Faculty of the Ruprecht-Karls-University Heidelberg, Mannheim, Germany.
authors.forename: Genevieve
authors.initials: G
authors.lastname: Schindler
authors.forename: David
authors.initials: D
authors.lastname: Capper
authors.forename: Jochen
authors.initials: J
authors.lastname: Meyer
authors.forename: Wibke
authors.initials: W
authors.lastname: Janzarik
authors.forename: Heymut
authors.initials: H
authors.lastname: Omran
authors.forename: Christel
authors.initials: C
authors.lastname: Herold-Mende
authors.forename: Kirsten
authors.initials: K
authors.lastname: Schmieder
authors.forename: Pieter
authors.initials: P
authors.lastname: Wesseling
authors.forename: Christian
authors.initials: C
authors.lastname: Mawrin
authors.forename: Martin
authors.initials: M
authors.lastname: Hasselblatt
authors.forename: David N
authors.initials: DN
authors.lastname: Louis
authors.forename: Andrey
authors.initials: A
authors.lastname: Korshunov
authors.forename: Stefan
authors.initials: S
authors.lastname: Pfister
authors.forename: Christian
authors.initials: C
authors.lastname: Hartmann
authors.forename: Werner
authors.initials: W
authors.lastname: Paulus
authors.forename: Guido
authors.initials: G
authors.lastname: Reifenberger
authors.forename: Andreas
authors.initials: A
authors.lastname: von Deimling
mesh_terms: D000293:Adolescent; D000328:Adult; D001254:Astrocytoma / Q000235:genetics* / Q000473:pathology; D001932:Brain Neoplasms / Q000235:genetics / Q000473:pathology; D002648:Child; D002675:Child, Preschool; D005091:Exons / Q000235:genetics; D018303:Ganglioglioma / Q000235:genetics* / Q000473:pathology; D005787:Gene Frequency / Q000235:genetics*; D006801:Humans; D020125:Mutation, Missense / Q000235:genetics*; D009423:Nervous System Neoplasms / Q000235:genetics* / Q000473:pathology; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics*; D012189:Retrospective Studies; D015398:Signal Transduction; D014944:World Health Organization; D055815:Young Adult
chemical_list: C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf