title: Comprehensive genetic analysis identifies a pathognomonic NAB2/STAT6 fusion gene, nonrandom secondary genomic imbalances, and a characteristic gene expression profile in solitary fibrous tumor.
abstract: Solitary fibrous tumor (SFT) is a mesenchymal neoplasm displaying variable morphologic and clinical features. To identify pathogenetically important genetic rearrangements, 44 SFTs were analyzed using a variety of techniques. Chromosome banding and fluorescence in situ hybridization (FISH) showed recurrent breakpoints in 12q13, clustering near the NAB2 and STAT6 genes, and single nucleotide polymorphism array analysis disclosed frequent deletions affecting STAT6. Quantitative real-time PCR revealed high expression levels of the 5'-end of NAB2 and the 3'-end of STAT6, which at deep sequencing of enriched DNA corresponded to NAB2/STAT6 fusions. Subsequent reverse-transcriptase PCR (RT-PCR) analysis identified a NAB2/STAT6 fusion in 37/41 cases, confirming that this fusion gene underlies the pathogenesis of SFT. The hypothesis that the NAB2/STAT6 fusions will result in altered properties of the transcriptional co-repressor NAB2--a key regulator of the early growth response 1 (EGR1) transcription factor - was corroborated by global gene expression analysis; SFTs showed deregulated expression of EGR1 target genes, as well as of other, developmentally important genes. We also identified several nonrandom secondary changes, notably loss of material from 13q and 14q. As neither chromosome banding nor FISH analysis identify more than a minor fraction of the fusion-positive cases, and because multiple primer combinations are required to identify all possible fusion transcripts by RT-PCR, alternative diagnostic markers might instead be found among deregulated genes identified at global gene expression analysis. Indeed, using immunohistochemistry on tissue microarrays, the top up-regulated gene, GRIA2, was found to be differentially expressed also at the protein level.
authors.affiliation: Department of Clinical Genetics, University and Regional Laboratories, Lund University, Lund, Sweden.
authors.forename: Arezoo
authors.initials: A
authors.lastname: Mohajeri
authors.forename: Johnbosco
authors.initials: J
authors.lastname: Tayebwa
authors.forename: Anna
authors.initials: A
authors.lastname: Collin
authors.forename: Jenny
authors.initials: J
authors.lastname: Nilsson
authors.forename: Linda
authors.initials: L
authors.lastname: Magnusson
authors.forename: Fredrik Vult
authors.initials: FV
authors.lastname: von Steyern
authors.forename: Otte
authors.initials: O
authors.lastname: Brosjö
authors.forename: Henryk A
authors.initials: HA
authors.lastname: Domanski
authors.forename: Olle
authors.initials: O
authors.lastname: Larsson
authors.forename: Raf
authors.initials: R
authors.lastname: Sciot
authors.forename: Maria
authors.initials: M
authors.lastname: Debiec-Rychter
authors.forename: Jason L
authors.initials: JL
authors.lastname: Hornick
authors.forename: Nils
authors.initials: N
authors.lastname: Mandahl
authors.forename: Karolin H
authors.initials: KH
authors.lastname: Nord
authors.forename: Fredrik
authors.initials: F
authors.lastname: Mertens
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D005260:Female; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D007150:Immunohistochemistry; D017404:In Situ Hybridization, Fluorescence; D008297:Male; D008875:Middle Aged; D015514:Oncogene Proteins, Fusion / Q000235:genetics*; D016133:Polymerase Chain Reaction; D020641:Polymorphism, Single Nucleotide; D012097:Repressor Proteins / Q000235:genetics*; D050800:STAT6 Transcription Factor / Q000235:genetics*; D054364:Solitary Fibrous Tumors / Q000235:genetics*; D059467:Transcriptome; D055815:Young Adult
chemical_list: C491000:NAB2 protein, human; D015514:Oncogene Proteins, Fusion; D012097:Repressor Proteins; D050800:STAT6 Transcription Factor; C494101:STAT6 protein, human
keywords: The Swedish Cancer Foundation; and the Medical Faculty of Lund University; the Gunnar Nilsson Cancer Foundation; the IngaBritt and Arne Lundberg Foundation; the National Research Council of Sweden; the Swedish Childhood Cancer Foundation