BRAF gene duplication constitutes a mechanism of MAPK pathway activation in low-grade astrocytomas.
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.
Pfister
Stefan
S
Division Molecular Genetics, German Cancer Research Center (DKFZ), Heidelberg, Germany.
Janzarik
Wibke G
WG
Remke
Marc
M
Ernst
Aurélie
A
Werft
Wiebke
W
Becker
Natalia
N
Toedt
Grischa
G
Wittmann
Andrea
A
Kratz
Christian
C
Olbrich
Heike
H
Ahmadi
Rezvan
R
Thieme
Barbara
B
Joos
Stefan
S
Radlwimmer
Bernhard
B
Kulozik
Andreas
A
Pietsch
Torsten
T
Herold-Mende
Christel
C
Gnekow
Astrid
A
Reifenberger
Guido
G
Korshunov
Andrey
A
Scheurlen
Wolfram
W
Omran
Heymut
H
Lichter
Peter
P
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*
D056741:Cyclin D; D016213:Cyclins; D004791:Enzyme Inhibitors; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D020928:Mitogen-Activated Protein Kinases