BRAF gene duplication constitutes a mechanism of MAPK pathway activation in low-grade astrocytomas.
J Clin Invest
; 118(5): 1739-49, 2008 May.
Article
em En
| MEDLINE
| ID: mdl-18398503
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.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Astrocitoma
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Neoplasias Encefálicas
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Duplicação Gênica
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Proteínas Quinases Ativadas por Mitógeno
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Sistema de Sinalização das MAP Quinases
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Proteínas Proto-Oncogênicas B-raf
Limite:
Child
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Female
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Humans
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Male
Idioma:
En
Revista:
J Clin Invest
Ano de publicação:
2008
Tipo de documento:
Article
País de afiliação:
Alemanha