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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.

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Figure 1: Integrative sequencing and mutational analysis of MO_1005 (SFT index case).
Figure 2: Validation and recurrence of NAB2-STAT6 gene fusions in SFT.
Figure 3: Characterization and functional analysis of the NAB2-STAT6 fusion protein.
Figure 4: A proposed model for the function of the NAB2-STAT6 gene fusion in SFT.

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Acknowledgements

The authors thank T. Barrette for hardware and database management, S. Birkeland, M. Pierce-Burlingame and K. Giles for assistance with sample and manuscript preparation and X. Jing for carrying out microarray experiments. We also thank the larger MI-ONCOSEQ team, including cancer geneticists S. Gruber and J. Innis; bioethicists J.S. Roberts and S.Y. Kim; genetic counselors J. Everett, J. Long and V. Raymond; and radiologists E. Higgins, E. Caoili and R. Dunnick. M. Quist performed initial SNV analysis. L. Sam, A. Balbin and P. Vats assisted with bioinformatics analysis. This project was supported in part by the National Cancer Institute (NCI) Early Detection Research Network (U01 CA111275), the National Functional Genomics Center (W81XWH-11-1-0520) and the US Department of Defense (A.M.C.). Additional infrastructure support was generously provided by the Prostate Cancer Foundation. The work was also supported in part by the US National Institutes of Health through the University of Michigan's Cancer Center Support Grant (5 P30 CA46592) and grants PO1 CA047179-15A2 (C.R.A. and S.S.) and P50 CA 140146-01 (C.R.A. and S.S.); the Linn Fund and Cycle for Survival (C.R.A.); the Alan Rosenthal Research Fund for research in sarcoma (C.R.A.); and the Weinstein Solitary Fibrous Tumor Research Fund (C.R.A.). A.M.C. is supported by the Doris Duke Charitable Foundation Clinical Scientist Award and a Burroughs Wellcome Foundation Award in Clinical Translational Research. A.M.C. is an American Cancer Society Research Professor and an A. Alfred Taubman Scholar.

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D.R.R., C.R.A. and A.M.C. conceived the experiments. D.R.R., Y.-M.W. and X.C. performed exome and transcriptome sequencing. S.K.-S. and M.K.I. carried out bioinformatics analysis of high-throughput sequencing data and nomination of gene fusions. R.J.L. carried out bioinformatics analysis of high-throughput sequencing data for gene expression, copy-number and tumor-content determination. Y.-S.S., C.-L.C., D.R.R., Y.-M.W. and F.S. isolated nucleic acids and performed PCR and Sanger sequencing experiments. Y.-M.W. and F.S. carried out gene fusion validations and gene fusion cloning. Y.-M.W., R.W., F.S. and D.R.R. carried out cell-based in vitro experiments and qPCR assays. L.Z. and C.-L.C. performed immunoblot and immunofluorescence experiments on tissue samples. J.S. collected and prepared tissue samples for next-generation sequencing. L.P.K., J.M.M. and C.R.A. provided pathology review. S.M.S. and S.S. provided the case samples and clinical data. S.R., K.J.P., M.T., S.K.-S., R.J.L., J.S., D.R.R., Y.-M.W., X.C. and A.M.C. developed the integrated clinical sequencing protocol. D.R.R., Y.-M.W., C.R.A. and A.M.C. prepared the manuscript, which was reviewed by all authors.

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Correspondence to Cristina R Antonescu or Arul M Chinnaiyan.

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This manuscript was disclosed to the University of Michigan Office of Technology Transfer, which has filed a patent on the findings.

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Supplementary Figures 1–10 and Supplementary Tables 1–8 (PDF 30883 kb)

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Robinson, D., Wu, YM., Kalyana-Sundaram, S. et al. Identification of recurrent NAB2-STAT6 gene fusions in solitary fibrous tumor by integrative sequencing. Nat Genet 45, 180–185 (2013). https://doi.org/10.1038/ng.2509

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