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- Title
BRAF gene duplication constitutes a mechanism of MAPK pathway activation in low-grade astrocytomas.
- Authors
Pfister, Stefan; Janzarik, Wibke G.; Remke, Marc; Ernst, Aurélie; Werft, Wiebke; Becker, Natalia; Toedt, Grischa; Wittmann, Andrea; Kratz, Christian; Olbrich, Heike; Ahmadi, Rezvan; Thieme, Barbara; Joos, Stefan; Radlwimmer, Bernhard; Kulozik, Andreas; Pietsch, Torsten; Herold-Mende, Christel; Gnekow, Astrid; Reifenberger, Guido; Korshunov, Andrey
- Abstract
The molecular pathogenesis of pediatric astrocytomas is still poorly understood. To further understand the genetic abnormalities associated with these tumors, we performed a genome-wide analysis of DNA copy number aberrations in pediatric low-grade astrocytomas by using array-based comparative genomic hybridization. Duplication of the BRAF protooncogene was the most frequent genomic aberration, and tumors with BRAF duplication showed significantly increased mRNA levels of BRAF and a downstream target, CCND1, as compared with tumors without duplication. Furthermore, denaturing HPLC showed that activating BRAF mutations were detected in some of the tumors without BRAF duplication. Similarly, a marked proportion of low-grade astrocytomas from adult patients also had BRAF duplication. Both the stable silencing of BRAF through shRNA lentiviral transduction and pharmacological inhibition of MEK1/2, the immediate downstream phosphorylation target of BRAF, blocked the proliferation and arrested the growth of cultured tumor cells derived from low-grade gliomas. Our findings implicate aberrant activation of the MAPK pathway due to gene duplication or mutation of BRAF as a molecular mechanism of pathogenesis in low-grade astrocytomas and suggest inhibition of the MAPK pathway as a potential treatment.
- Subjects
GENE expression; MITOGEN-activated protein kinases; ASTROCYTOMAS; GENETIC disorders; CANCER cells; DNA
- Publication
Journal of Clinical Investigation, 2008, Vol 118, Issue 5, p1739
- ISSN
0021-9738
- Publication type
journal article
- DOI
10.1172/JCI33656