title: Frequency of BRAF V600E mutations in 969 central nervous system neoplasms.
abstract: BACKGROUND
  Treatment options for oncological diseases have been enhanced by the advent of targeted therapies. The point mutation of the BRAF gene at codon 600 (BRAF V600E) is found in several tumor entities and can be approached with selective inhibitory antibodies. The BRAF inhibitor vemurafenib has demonstrated clinical efficacy in patients with BRAF V600E-mutant melanoma brain metastases and in other cancer diseases. Therefore the BRAF V600E mutation is a highly interesting oncological target in brain tumors.
  
  
  METHODS
  This study assesses the BRAF V600E mutation status in 969 intracranial neoplasms using a tissue microarray method and immunohistochemical staining with the mutation-specific VE-1 antibody, followed by sequencing of positively stained cases.
  
  
  RESULTS
  Out of 784 primary brain tumors seven cases with a BRAF V600E mutation were detected (7/784, 1 %). Six of these cases were neuroepithelial tumors (6/667, 1 %) encompassing 2 astrocytomas WHO grade II (2/42, 5 %), 1 gliosarcoma WHO grade IV (1/75, 1 %) and 3 glioblastomas WHO grade IV (3/312, 1 %). Interestingly, all three mutant glioblastomas showed epithelioid histopathological features. Patients with V600E mutated astrocytic tumors were significantly younger (mean age 15.3 years) than wildtype cases (58.2 years). Among three rhabdoid meningiomas, one case was mutated (1/3) while all other grade I-III meningiomas (1/116, 1 %) and all fifty vestibular schwannomas analyzed were of wildtype status. The vast majority of the BRAF V600E mutations were found in cerebral metastases of malignant melanomas and carcinomas (29/135, 22 %), with false-positive staining found in four breast cancer cases and two non-small-cell lung carcinoma (NSCLC) samples.
  
  
  CONCLUSIONS
  Our data suggest routine screening for BRAF V600E mutations for glioblastomas WHO grade IV below the age of 30, especially in glioblastomas with epithelioid features and in all rhabdoid meningiomas WHO grade III. For colorectal carcinoma, thyroid cancer, malignant melanoma and gliomas BRAF V600E immunostaining is sufficient for screening purposes. We also recommend routine immunohistochemical staining followed by sequencing validation in rare CNS metastases or metastases of unknown primary. Immunohistochemical analysis using mutation-specific antibodies on tissue microarrays is a feasible, time- and cost-efficient approach to high-throughput screening for specific mutations in large tumor series but sequencing validation is necessary in unexpected cases.
authors.affiliation: Department of Neurosurgery, Eberhard-Karls University, Hoppe-Seyler Street 3, 72076, Tübingen, Germany. felix.behling@med.uni-tuebingen.de.
authors.forename: Felix
authors.identifier: http://orcid.org/0000-0002-1083-1276
authors.initials: F
authors.lastname: Behling
authors.affiliation: Department of Neuropathology, Georg-August University, Robert-Koch-Street 40, 37075, Göttingen, Germany.
authors.forename: Alonso
authors.initials: A
authors.lastname: Barrantes-Freer
authors.affiliation: Department of Neurosurgery, Eberhard-Karls University, Hoppe-Seyler Street 3, 72076, Tübingen, Germany.
authors.forename: Marco
authors.initials: M
authors.lastname: Skardelly
authors.affiliation: Department of Pathology, Eberhard-Karls University, Liebermeisterstr. 8, 72076, Tübingen, Germany.
authors.forename: Maike
authors.initials: M
authors.lastname: Nieser
authors.affiliation: Department of Neuropathology, Hannover Medical School, Carl-Neuberg Street 1, 30625, Hannover, Germany.
authors.forename: Arne
authors.initials: A
authors.lastname: Christians
authors.affiliation: Department of Neurosurgery, Städtisches Klinikum Dresden-Friedrichstadt, Friedrichstr. 41, 01067, Dresden, Germany.
authors.forename: Florian
authors.initials: F
authors.lastname: Stockhammer
authors.affiliation: Department of Neurosurgery, Georg-August University, Robert-Koch-Street 40, 37075, Göttingen, Germany.
authors.forename: Veit
authors.initials: V
authors.lastname: Rohde
authors.affiliation: Department of Neurosurgery, Eberhard-Karls University, Hoppe-Seyler Street 3, 72076, Tübingen, Germany.
authors.forename: Marcos
authors.initials: M
authors.lastname: Tatagiba
authors.affiliation: Department of Neuropathology, Hannover Medical School, Carl-Neuberg Street 1, 30625, Hannover, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Hartmann
authors.affiliation: Department of Neuropathology, Georg-August University, Robert-Koch-Street 40, 37075, Göttingen, Germany.
authors.forename: Christine
authors.initials: C
authors.lastname: Stadelmann
authors.affiliation: Department of Neuropathology, Eberhard-Karls University, Calwer Str. 3, 72076, Tübingen, Germany.
authors.forename: Jens
authors.initials: J
authors.lastname: Schittenhelm
mesh_terms: D000293:Adolescent; D000328:Adult; D000367:Age Factors; D000368:Aged; D001254:Astrocytoma / Q000235:genetics; D014408:Biomarkers, Tumor / Q000235:genetics*; D002277:Carcinoma / Q000235:genetics* / Q000556:secondary; D016543:Central Nervous System Neoplasms / Q000235:genetics* / Q000556:secondary; D002648:Child; D015179:Colorectal Neoplasms / Q000235:genetics; D005909:Glioblastoma / Q000235:genetics; D006801:Humans; D008545:Melanoma / Q000235:genetics; D008875:Middle Aged; D017354:Point Mutation; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics*; D012878:Skin Neoplasms; D013964:Thyroid Neoplasms / Q000235:genetics; D055815:Young Adult; D000096142:Cutaneous Malignant Melanoma
chemical_list: D014408:Biomarkers, Tumor; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf
keywords: BRAF V600E mutation; Brain tumor; Cerebral metastases; Epithelioid glioblastoma; Glioblastoma; Gliosarcoma; Rhabdoid meningioma; Tissue microarray