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

Authors:
  • WJWibke G. Janzarik
    Wibke G. Janzarik
  • AEAurélie Ernst
    Aurélie Ernst
  • WWWiebke Werft
    Wiebke Werft
  • NBNatalia Becker
    Natalia Becker
  • GTGrischa Toedt
    Grischa Toedt
  • AWAndrea Wittmann
    Andrea Wittmann
  • CKChristian Kratz
    Christian Kratz
  • HOHeike Olbrich
    Heike Olbrich
  • RARezvan Ahmadi
    Rezvan Ahmadi
  • BTBarbara Thieme
    Barbara Thieme
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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.

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