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

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 BRAFV600E 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 BRAFV600E 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 G. Schindler and D. Capper contributed equally to this work. D. Capper  C. Hartmann  A. von Deimling (&) Department of Neuropathology, Institute of Pathology, Ruprecht-Karls-University Heidelberg, Im Neuenheimer Feld 220/221, 69120 Heidelberg, Germany e-mail: andreas.vondeimling@med.uni-heidelberg.de D. Capper  J. Meyer  A. Korshunov  C. Hartmann  A. von Deimling Clinical Cooperation Unit Neuropathology G380, German Cancer Research Center, Heidelberg, Germany G. Schindler  K. Schmieder Department of Neurosurgery, Medical Faculty of the Ruprecht-Karls-University Heidelberg, Mannheim, Germany C. Herold-Mende Division of Neurosurgical Research, Department of Neurosurgery, Ruprecht-Karls-University Heidelberg, Heidelberg, Germany P. Wesseling Department of Pathology, Nijmegen Center for Molecular Life Sciences (NCMLS), Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands C. Mawrin Department of Neuropathology, Otto-von-Guericke-University Magdeburg, Magdeburg, Germany M. Hasselblatt  W. Paulus Institute of Neuropathology, University Hospital Mu¨nster, Mu¨nster, Germany D. N. Louis Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA S. Pfister Division Molecular Genetics, German Cancer Research Center, Heidelberg, Germany S. Pfister Pediatric Hematology and Oncology, Heidelberg University Hospital, Heidelberg, Germany G. Reifenberger Department of Neuropathology, Heinrich Heine University, Du¨sseldorf, Germany 123 Acta Neuropathol (2011) 121:397–405 DOI 10.1007/s00401-011-0802-6 absence of mutations. No mutations were detected in nonglial 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 BRAFV600E mutation as a valuable diagnostic marker for these rare tumor entities. Future clinical trials should address whether BRAFV600E mutant brain tumor patients will benefit from BRAFV600E-directed targeted therapies.