[HTML][HTML] BRAF gene duplication constitutes a mechanism of MAPK pathway activation in low-grade astrocytomas

S Pfister, WG Janzarik, M Remke… - The Journal of …, 2008 - Am Soc Clin Investig
S Pfister, WG Janzarik, M Remke, A Ernst, W Werft, N Becker, G Toedt, A Wittmann, C Kratz
The Journal of clinical investigation, 2008Am Soc Clin Investig
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 …
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.
The Journal of Clinical Investigation