BRAF Gene Duplication Constitutes a Mechanism of MAPK Pathway Activation in Low-grade Astrocytomas

Overview

Journal J Clin Invest

Specialty General Medicine

Date 2008 Apr 10

PMID 18398503

Citations 234

Authors

Stefan Pfister

Wibke G Janzarik

Marc Remke

Aurelie Ernst

Wiebke Werft

Natalia Becker

Grischa Toedt

Andrea Wittmann

Christian Kratz

Heike Olbrich

Rezvan Ahmadi

Barbara Thieme

Stefan Joos

Bernhard Radlwimmer

Andreas Kulozik

Torsten Pietsch

Christel Herold-Mende

Astrid Gnekow

Guido Reifenberger

Andrey Korshunov

Wolfram Scheurlen

Heymut Omran

Peter Lichter

Affiliations

Soon will be listed here.

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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References

Rodriguez-Viciana P, Tetsu O, Tidyman W, Estep A, Conger B, Santa Cruz M . Germline mutations in genes within the MAPK pathway cause cardio-facio-cutaneous syndrome. Science. 2006; 311(5765):1287-90. DOI: 10.1126/science.1124642. View

Zielinski B, Gratias S, Toedt G, Mendrzyk F, Stange D, Radlwimmer B . Detection of chromosomal imbalances in retinoblastoma by matrix-based comparative genomic hybridization. Genes Chromosomes Cancer. 2005; 43(3):294-301. DOI: 10.1002/gcc.20186. View

Zattara-Cannoni H, Gambarelli D, Lena G, Dufour H, Choux M, Grisoli F . Are juvenile pilocytic astrocytomas benign tumors? A cytogenetic study in 24 cases. Cancer Genet Cytogenet. 1998; 104(2):157-60. DOI: 10.1016/s0165-4608(97)00455-x. View

Sanoudou D, Tingby O, Ferguson-Smith M, Collins V, Coleman N . Analysis of pilocytic astrocytoma by comparative genomic hybridization. Br J Cancer. 2000; 82(6):1218-22. PMC: 2363345. DOI: 10.1054/bjoc.1999.1066. View

Bubendorf L, Kononen J, Koivisto P, Schraml P, Moch H, Gasser T . Survey of gene amplifications during prostate cancer progression by high-throughout fluorescence in situ hybridization on tissue microarrays. Cancer Res. 1999; 59(4):803-6. View

Orr L, Fleitz J, McGavran L, Wyatt-Ashmead J, Handler M, Foreman N . Cytogenetics in pediatric low-grade astrocytomas. Med Pediatr Oncol. 2002; 38(3):173-7. DOI: 10.1002/mpo.1305. View

Jenkins R, Kimmel D, Moertel C, Schultz C, Scheithauer B, Kelly P . A cytogenetic study of 53 human gliomas. Cancer Genet Cytogenet. 1989; 39(2):253-79. DOI: 10.1016/0165-4608(89)90192-1. View

Brose M, Volpe P, Feldman M, Kumar M, Rishi I, Gerrero R . BRAF and RAS mutations in human lung cancer and melanoma. Cancer Res. 2002; 62(23):6997-7000. View

Hirose Y, Aldape K, Chang S, Lamborn K, Berger M, Feuerstein B . Grade II astrocytomas are subgrouped by chromosome aberrations. Cancer Genet Cytogenet. 2003; 142(1):1-7. DOI: 10.1016/s0165-4608(02)00791-4. View

10.

Lichter P, Cremer T, Borden J, Manuelidis L, Ward D . Delineation of individual human chromosomes in metaphase and interphase cells by in situ suppression hybridization using recombinant DNA libraries. Hum Genet. 1988; 80(3):224-34. DOI: 10.1007/BF01790090. View

11.

Wessels P, Twijnstra A, Kessels A, Theunissen P, Ummelen M, Ramaekers F . Gain of chromosome 7, as detected by in situ hybridization, strongly correlates with shorter survival in astrocytoma grade 2. Genes Chromosomes Cancer. 2002; 33(3):279-84. DOI: 10.1002/gcc.10029. View

12.

Bos J, Fearon E, Hamilton S, Verlaan-de Vries M, VAN Boom J, Van Der Eb A . Prevalence of ras gene mutations in human colorectal cancers. Nature. 1987; 327(6120):293-7. DOI: 10.1038/327293a0. View

13.

Bigner S, McLendon R, Fuchs H, McKeever P, Friedman H . Chromosomal characteristics of childhood brain tumors. Cancer Genet Cytogenet. 1997; 97(2):125-34. DOI: 10.1016/s0165-4608(96)00404-9. View

14.

Pandit B, Sarkozy A, Pennacchio L, Carta C, Oishi K, Martinelli S . Gain-of-function RAF1 mutations cause Noonan and LEOPARD syndromes with hypertrophic cardiomyopathy. Nat Genet. 2007; 39(8):1007-12. DOI: 10.1038/ng2073. View

15.

Bentires-Alj M, Kontaridis M, Neel B . Stops along the RAS pathway in human genetic disease. Nat Med. 2006; 12(3):283-5. DOI: 10.1038/nm0306-283. View

16.

Lampel S, Stilgenbauer S, Nickolenko J, Benner A, Dohner H, Cremer T . Matrix-based comparative genomic hybridization: biochips to screen for genomic imbalances. Genes Chromosomes Cancer. 1997; 20(4):399-407. View

17.

Niihori T, Aoki Y, Narumi Y, Neri G, Cave H, Verloes A . Germline KRAS and BRAF mutations in cardio-facio-cutaneous syndrome. Nat Genet. 2006; 38(3):294-6. DOI: 10.1038/ng1749. View

18.

Kratz C, Niemeyer C, Zenker M . An unexpected new role of mutant Ras: perturbation of human embryonic development. J Mol Med (Berl). 2007; 85(3):227-35. PMC: 1820751. DOI: 10.1007/s00109-006-0135-4. View

19.

Ohgaki H, Kleihues P . Population-based studies on incidence, survival rates, and genetic alterations in astrocytic and oligodendroglial gliomas. J Neuropathol Exp Neurol. 2005; 64(6):479-89. DOI: 10.1093/jnen/64.6.479. View

20.

Basto D, Trovisco V, Lopes J, Martins A, Pardal F, Soares P . Mutation analysis of B-RAF gene in human gliomas. Acta Neuropathol. 2005; 109(2):207-10. DOI: 10.1007/s00401-004-0936-x. View