title: Oncogenic FAM131B-BRAF fusion resulting from 7q34 deletion comprises an alternative mechanism of MAPK pathway activation in pilocytic astrocytoma.
abstract: 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.
authors.affiliation: Division of Molecular Genetics, German Cancer Research Center, Heidelberg, Germany.
authors.forename: Huriye
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authors.lastname: Meyer
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authors.initials: WG
authors.lastname: Janzarik
authors.forename: Sally
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authors.forename: Ton Nu
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authors.forename: Heike
authors.initials: H
authors.lastname: Olbrich
authors.forename: Andreas
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authors.lastname: von Deimling
authors.forename: Arnulf
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authors.lastname: Pekrun
authors.forename: Andreas E
authors.initials: AE
authors.lastname: Kulozik
authors.forename: Astrid
authors.initials: A
authors.lastname: Gnekow
authors.forename: Wolfram
authors.initials: W
authors.lastname: Scheurlen
authors.forename: Olaf
authors.initials: O
authors.lastname: Witt
authors.forename: Heymut
authors.initials: H
authors.lastname: Omran
authors.forename: Nada
authors.initials: N
authors.lastname: Jabado
authors.forename: V Peter
authors.initials: VP
authors.lastname: Collins
authors.forename: Tilman
authors.initials: T
authors.lastname: Brummer
authors.forename: Rolf
authors.initials: R
authors.lastname: Marschalek
authors.forename: Peter
authors.initials: P
authors.lastname: Lichter
authors.forename: Andrey
authors.initials: A
authors.lastname: Korshunov
authors.forename: Stefan M
authors.initials: SM
authors.lastname: Pfister
mesh_terms: D000818:Animals; D001254:Astrocytoma / Q000235:genetics*; D001932:Brain Neoplasms / Q000235:genetics*; D002675:Child, Preschool; D002897:Chromosomes, Human, Pair 7 / Q000235:genetics; D055028:Comparative Genomic Hybridization; D005260:Female; D005500:Follow-Up Studies; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics; D006801:Humans; D007223:Infant; D020935:MAP Kinase Signaling System / Q000235:genetics*; D008297:Male; D051379:Mice; D009154:Mutation / Q000235:genetics*; D041681:NIH 3T3 Cells; D020411:Oligonucleotide Array Sequence Analysis; D015514:Oncogene Proteins, Fusion / Q000235:genetics*; D010766:Phosphorylation / Q000235:genetics; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics*; D017384:Sequence Deletion; D018709:Statistics, Nonparametric; D014162:Transfection / Q000379:methods
chemical_list: D015514:Oncogene Proteins, Fusion; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf