Identification of recurrent NAB2-STAT6 gene fusions in solitary fibrous tumor by integrative sequencing.
Abstact
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
- Antonescu CR
- Cao X
- Chen CL
- Chinnaiyan AM
- Iyer MK
- Kalyana-Sundaram S
- Kunju LP
- Lonigro RJ
- Mosquera JM
- Pienta KJ
- Robinson DR
- Roychowdhury S
- Schuetze SM
- Siddiqui J
- Singer S
- Su F
- Sung YS
- Talpaz M
- Wang R
- Wu YM
- Zhang L