title: Identification of recurrent NAB2-STAT6 gene fusions in solitary fibrous tumor by integrative sequencing.
abstract: A 44-year old woman with recurrent solitary fibrous tumor (SFT)/hemangiopericytoma was enrolled in a clinical sequencing program including whole-exome and transcriptome sequencing. A gene fusion of the transcriptional repressor NAB2 with the transcriptional activator STAT6 was detected. Transcriptome sequencing of 27 additional SFTs identified the presence of a NAB2-STAT6 gene fusion in all tumors. Using RT-PCR and sequencing, we detected this fusion in all 51 SFTs, indicating high levels of recurrence. Expression of NAB2-STAT6 fusion proteins was confirmed in SFT, and the predicted fusion products harbor the early growth response (EGR)-binding domain of NAB2 fused to the activation domain of STAT6. Overexpression of the NAB2-STAT6 gene fusion induced proliferation in cultured cells and activated the expression of EGR-responsive genes. These studies establish NAB2-STAT6 as the defining driver mutation of SFT and provide an example of how neoplasia can be initiated by converting a transcriptional repressor of mitogenic pathways into a transcriptional activator.
authors: Michigan Center for Translational Pathology, University of Michigan Medical School, Ann Arbor, Michigan, USA.
authors: Dan R
authors: DR
authors: Robinson
authors: Yi-Mi
authors: YM
authors: Wu
authors: Shanker
authors: S
authors: Kalyana-Sundaram
authors: Xuhong
authors: X
authors: Cao
authors: Robert J
authors: RJ
authors: Lonigro
authors: Yun-Shao
authors: YS
authors: Sung
authors: Chun-Liang
authors: CL
authors: Chen
authors: Lei
authors: L
authors: Zhang
authors: Rui
authors: R
authors: Wang
authors: Fengyun
authors: F
authors: Su
authors: Matthew K
authors: MK
authors: Iyer
authors: Sameek
authors: S
authors: Roychowdhury
authors: Javed
authors: J
authors: Siddiqui
authors: Kenneth J
authors: KJ
authors: Pienta
authors: Lakshmi P
authors: LP
authors: Kunju
authors: Moshe
authors: M
authors: Talpaz
authors: Juan Miguel
authors: JM
authors: Mosquera
authors: Samuel
authors: S
authors: Singer
authors: Scott M
authors: SM
authors: Schuetze
authors: Cristina R
authors: CR
authors: Antonescu
authors: Arul M
authors: AM
authors: Chinnaiyan
mesh_terms: D000328:Adult; D001483:Base Sequence; D049109:Cell Proliferation; D002478:Cells, Cultured; D047369:Chromatin Immunoprecipitation; D004252:DNA Mutational Analysis; D059472:Exome / Q000235:genetics; D005260:Female; D005455:Fluorescent Antibody Technique; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics*; D050939:Gene Fusion / Q000235:genetics*; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D015151:Immunoblotting; D008156:Luciferases; D008957:Models, Genetic; D008969:Molecular Sequence Data; D060888:Real-Time Polymerase Chain Reaction; D050436:Regulatory Elements, Transcriptional / Q000235:genetics*; D012097:Repressor Proteins / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050800:STAT6 Transcription Factor / Q000235:genetics*; D054364:Solitary Fibrous Tumors / Q000235:genetics*; D059467:Transcriptome / Q000235:genetics
chemical_list: C491000:NAB2 protein, human; D012097:Repressor Proteins; D050800:STAT6 Transcription Factor; C494101:STAT6 protein, human; D008156:Luciferases