Oncogenic FAM131B–BRAF fusion resulting from 7q34 deletion comprises an alternative mechanism of MAPK pathway activation in pilocytic astrocytoma

Autor: Wolfram Scheurlen, Axel Benner, Astrid Gnekow, Marc Remke, Claus Meyer, Tilman Brummer, Sebastian Bender, Ricarda Herr, Heymut Omran, Ton Nu Van Anh, Andrey Korshunov, V. Peter Collins, Arnulf Pekrun, Peter Lichter, Andreas E. Kulozik, Karine Jacob, David T.W. Jones, Sally R. Lambert, Huriye Cin, Rolf Marschalek, Heike Olbrich, Andreas von Deimling, Hendrik Witt, Olaf Witt, Nada Jabado, Fabian Falkenstein, Stefan M. Pfister, Wibke G. Janzarik
Rok vydání: 2011
Předmět:
Male
Proto-Oncogene Proteins B-raf
MAPK/ERK pathway
Neuroblastoma RAS viral oncogene homolog
Oncogene Proteins
Fusion
endocrine system diseases
MAP Kinase Signaling System
Astrocytoma
Biology
Transfection
medicine.disease_cause
Statistics
Nonparametric
Pathology and Forensic Medicine
Fusion gene
Mice
Cellular and Molecular Neuroscience
medicine
Animals
Humans
HRAS
Phosphorylation
neoplasms
Oligonucleotide Array Sequence Analysis
Sequence Deletion
Comparative Genomic Hybridization
Pilocytic astrocytoma
Brain Neoplasms
Kinase
Gene Expression Profiling
Infant
medicine.disease
Molecular biology
digestive system diseases
Gene Expression Regulation
Neoplastic
Gene expression profiling
Child
Preschool
Mutation
NIH 3T3 Cells
Female
Neurology (clinical)
KRAS
Chromosomes
Human
Pair 7
Follow-Up Studies
Zdroj: Acta Neuropathologica. 121:763-774
ISSN: 1432-0533
0001-6322
Popis: Activation of the MAPK signaling pathway has been shown to be a unifying molecular feature in pilocytic astrocytoma (PA). Genetically, tandem duplications at chromosome 7q34 resulting in KIAA1549-BRAF fusion genes constitute the most common mechanism identified to date. To elucidate alternative mechanisms of aberrant MAPK activation in PA, we screened 125 primary tumors for RAF fusion genes and mutations in KRAS, NRAS, HRAS, PTPN11, BRAF and RAF1. Using microarray-based comparative genomic hybridization (aCGH), we identified in three cases an interstitial deletion of ~2.5 Mb as a novel recurrent mechanism forming BRAF gene fusions with FAM131B, a currently uncharacterized gene on chromosome 7q34. This deletion removes the BRAF N-terminal inhibitory domains, giving a constitutively active BRAF kinase. Functional characterization of the novel FAM131B-BRAF fusion demonstrated constitutive MEK phosphorylation potential and transforming activity in vitro. In addition, our study confirmed previously reported BRAF and RAF1 fusion variants in 72% (90/125) of PA. Mutations in BRAF (8/125), KRAS (2/125) and NF1 (4/125) and the rare RAF1 gene fusions (2/125) were mutually exclusive with BRAF rearrangements, with the exception of two cases in our series that concomitantly harbored more than one hit in the MAPK pathway. In summary, our findings further underline the fundamental role of RAF kinase fusion products as a tumor-specific marker and an ideally suited drug target for PA.
Databáze: OpenAIRE
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