title: BRAF gene duplication constitutes a mechanism of MAPK pathway activation in low-grade astrocytomas.
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.
authors.affiliation: Division Molecular Genetics, German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Pfister
authors.forename: Wibke G
authors.initials: WG
authors.lastname: Janzarik
authors.forename: Marc
authors.initials: M
authors.lastname: Remke
authors.forename: Aurélie
authors.initials: A
authors.lastname: Ernst
authors.forename: Wiebke
authors.initials: W
authors.lastname: Werft
authors.forename: Natalia
authors.initials: N
authors.lastname: Becker
authors.forename: Grischa
authors.initials: G
authors.lastname: Toedt
authors.forename: Andrea
authors.initials: A
authors.lastname: Wittmann
authors.forename: Christian
authors.initials: C
authors.lastname: Kratz
authors.forename: Heike
authors.initials: H
authors.lastname: Olbrich
authors.forename: Rezvan
authors.initials: R
authors.lastname: Ahmadi
authors.forename: Barbara
authors.initials: B
authors.lastname: Thieme
authors.forename: Stefan
authors.initials: S
authors.lastname: Joos
authors.forename: Bernhard
authors.initials: B
authors.lastname: Radlwimmer
authors.forename: Andreas
authors.initials: A
authors.lastname: Kulozik
authors.forename: Torsten
authors.initials: T
authors.lastname: Pietsch
authors.forename: Christel
authors.initials: C
authors.lastname: Herold-Mende
authors.forename: Astrid
authors.initials: A
authors.lastname: Gnekow
authors.forename: Guido
authors.initials: G
authors.lastname: Reifenberger
authors.forename: Andrey
authors.initials: A
authors.lastname: Korshunov
authors.forename: Wolfram
authors.initials: W
authors.lastname: Scheurlen
authors.forename: Heymut
authors.initials: H
authors.lastname: Omran
authors.forename: Peter
authors.initials: P
authors.lastname: Lichter
mesh_terms: D001254:Astrocytoma / Q000201:enzymology* / Q000235:genetics* / Q000473:pathology; D001932:Brain Neoplasms / Q000201:enzymology* / Q000235:genetics* / Q000473:pathology; D002453:Cell Cycle / Q000502:physiology; D002648:Child; D002869:Chromosome Aberrations; D056741:Cyclin D; D016213:Cyclins / Q000235:genetics / Q000378:metabolism; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000378:metabolism; D005260:Female; D020440:Gene Duplication; D006801:Humans; D020935:MAP Kinase Signaling System / Q000502:physiology*; D008297:Male; D046228:Microarray Analysis; D020928:Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism*; D009154:Mutation; D009693:Nucleic Acid Hybridization / Q000379:methods; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics / Q000378:metabolism*
chemical_list: D056741:Cyclin D; D016213:Cyclins; D004791:Enzyme Inhibitors; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D020928:Mitogen-Activated Protein Kinases