Abstract
The RAS/RAF/MEK/ERK kinase pathway is pivotal in the transduction of mitogenic stimuli from activated growth factor receptors, which regulates cell proliferation, survival, and differentiation. Up-regulation of this pathway due to RAS mutations is found in approximately 30% of human tumors. Recently, activating mutations of B-RAF were identified in a large proportion of human cancers. Gliomas are the most frequent primary central nervous system tumors and the molecular mechanisms that underlie the development and progression of these tumors are far from being completely understood. The purpose of this study was to clarify the incidence of B-RAF mutations and their possible relation with tumor progression in a series of 82 human gliomas, including 49 astrocytic and 33 oligodendroglial tumors. The analysis of B-RAF hotspot regions, exons 11 and 15, showed presence of B-RAF mutations in only 2 out of 34 (6%) glioblastomas, and absence in the remaining histological types. Both mutations were located in the hotspot residue 600 (V600E) at exon 15, which leads to constitutive B-RAF kinase activity. These data suggest that activating mutations of B-RAF are not a frequent event in gliomas; nevertheless, when present they are associated with high-grade malignant lesions.
Similar content being viewed by others
References
Bollag G, Freeman S, Lyons JF, Post LE (2003) Raf pathway inhibitors in oncology. Curr Opin Investig Drugs 4:1436–1441
Bos JL (1989) ras oncogenes in human cancer: a review. Cancer Res 49:4682–4689
Davies H, Bignell GR, Cox C, Stephens P, Edkins S, Clegg S, Teague J, Woffendin H, Garnett MJ, Bottomley W, et al (2002) Mutations of the BRAF gene in human cancer. Nature 417:949–954
Ding H, Roncari L, Shannon P, Wu X, Lau N, Karaskova J, Gutmann DH, Squire JA, Nagy A, Guha A (2001) Astrocyte-specific expression of activated p21-ras results in malignant astrocytoma formation in a transgenic mouse model of human gliomas. Cancer Res 61:3826–3836
Downward J (2003) Targeting RAS signaling pathways in cancer therapy. Nat Rev Cancer 3:11–22
Forsyth PA, Cairncross JG (1995) Treatment of malignant glioma in adults. Curr Opin Neurol 8:414–418
Guha A, Feldkamp MM, Lau N, Boss G, Pawson A (1997) Proliferation of human malignant astrocytomas is dependent on Ras activation. Oncogene 15:2755–2765
Gurney JG, Kadan-Lottick N (2001) Brain and other central nervous system tumors: rates, trends, and epidemiology. Curr Opin Oncol 13:160–166
Holland EC, Celestino J, Dai C, Schaefer L, Sawaya RE, Fuller GN (2000) Combined activation of Ras and Akt in neural progenitors induces glioblastoma formation in mice. Nat Genet 25:55–57
Kleihues P, Cavenee WK (2000) Pathology and genetics of tumours of the nervous system, 2nd edn. IARC Press, Lyon
Kolch W (2000) Meaningful relationships: the regulation of the Ras/Raf/MEK/ERK pathway by protein interactions. Biochem J 351:289–305
Kumar R, Angelini S, Czene K, Sauroja I, Hahka-Kemppinen M, Pyhonen S, Hemminki K (2003) BRAF mutations in metastatic melanomas: a possible association with clinical outcome. Clin Cancer Res 9:3362–3368
Pollock PM, Harper UL, Hansen KS, Yudt LM, Stark M, Robbins CM, Moses TY, Hostetter G, Wagner U, Kakareka J, et al (2003) High frequency of BRAF mutations in nevi. Nat Genet 33:19–20
Rajagopalan H, Bardelli A, Lengauer C, Kinzler KW, Vogelstein B, Velculescu VE (2002) Tumorigenesis: RAF/RAS oncogenes and mismatch-repair status. Nature 418:934
Rapp UR, Goldsborough MD, Mark GE, Bonner TI, Groffen J, Reynolds FH Jr, Stephenson JR (1983) Structure and biological activity of v-raf, a unique oncogene transduced by a retrovirus. Proc Natl Acad Sci USA 80:4218–4222
Reis RM, Konu-Lebleblicioglu D, Lopes JM, Kleihues P, Ohgaki H (2000) Genetic profile of gliosarcomas. Am J Pathol 156:425–432
Robinson MJ, Cobb MH (1997) Mitogen-activated protein kinase pathways. Curr Opin Cell Biol 9:180–186
Soares P, Trovisco V, Rocha AS, Lima J, Castro P, Preto A, Maximo V, Botelho T, Seruca R, Sobrinho-Simoes M (2003) BRAF mutations and RET/PTC rearrangements are alternative events in the etiopathogenesis of PTC. Oncogene 22:4578–4580
Sonoda Y, Ozawa T, Hirose Y, Aldape KD, McMahon M, Berger MS, Pieper RO (2001) Formation of intracranial tumors by genetically modified human astrocytes defines four pathways critical in the development of human anaplastic astrocytoma. Cancer Res 61:4956–4960
Surawicz TS, Davis F, Freels S, Laws ER, Menck HR (1998) Brain tumor survival: results from the National Cancer Data Base. J Neurooncol 40:151–160
Wan PT, Garnett MJ, Roe SM, Lee S, Niculescu-Duvaz D, Good VM, Jones CM, Marshall CJ, Springer CJ, Barford D, Marais R (2004) Mechanism of activation of the RAF-ERK signaling pathway by oncogenic mutations of B-RAF. Cell 116:855–867
Zhu Y, Parada LF (2002) The molecular and genetic basis of neurological tumours. Nat Rev Cancer 2:616–626
Author information
Authors and Affiliations
Corresponding author
Additional information
The first two authors contributed equally to the present study
Rights and permissions
About this article
Cite this article
Basto, D., Trovisco, V., Lopes, J.M. et al. Mutation analysis of B-RAF gene in human gliomas. Acta Neuropathol 109, 207–210 (2005). https://doi.org/10.1007/s00401-004-0936-x
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00401-004-0936-x