Artikel
Analysis of BRAF V600E mutation in nervous system tumors reveals high mutation frequencies in pleomorphic xanthoastrocytoma, ganglioglioma and extra-cerebellar pilocytic astrocytoma
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Autoren
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G. Schindler
- Klinik für Neurochirurgie der Medizinischen Fakultät Mannheim der Ruprecht-Karls-Universität Heidelberg, Deutschland
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D. Capper
- Abteilung für Neuropathologie, Institut für Pathologie, Ruprecht-Karls-Universität Heidelberg, Deutschland; Klinischen Kooperationseinheit G380 Neuropathologie des Deutschen Krebsforschungszentrums Heidelberg, Deutschland
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K. Schmieder
- Klinik für Neurochirurgie der Medizinischen Fakultät Mannheim der Ruprecht-Karls-Universität Heidelberg, Deutschland
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D.N. Louis
- Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, United States
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S. Pfister
- Abteilung für Molekulare Genetik des Deutschen Krebsforschungszentrum, Heidelberg, Deutschland
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A.V. Deimling
- Abteilung für Neuropathologie, Institut für Pathologie, Ruprecht-Karls-Universität Heidelberg, Deutschland; Klinischen Kooperationseinheit G380 Neuropathologie des Deutschen Krebsforschungszentrums Heidelberg, Deutschland
| Veröffentlicht: | 4. Juni 2012 |
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Gliederung
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Objective: The V600E missense mutations constitutes the vast majority of tumor-associated somatic alterations in the v-RAF murine sarcoma viral oncogene homolog B1 (BRAF) gene. High mutation frequencies have been reported in melanoma, colon and papillary thyroid carcinoma. Of late alterations have also been observed in primary nervous system tumors although at a low frequency. Our investigation aimed at examining the exon 15 of BRAF, spanning the V600 locus in adult and pediatric tumors of the nervous system.
Methods: The DNA-Product of 1,320 brain tumors including various types of glial, embryonal, neuronal and glioneuronal, meningeal, adenohypophyseal/sellar, and peripheral nervous system tumors was amplified by means of RT-PCR and then analysed via direct sequencing.
Results: 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.
Conclusions: 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 especially those with inoperable tumors will benefit from BRAF (V600E)-directed targeted therapies.
