Abstract

Schwannomas are common peripheral nerve sheath tumors that can cause debilitating morbidities. We performed an integrative analysis to determine genomic aberrations common to sporadic schwannomas. Exome sequence analysis with validation by targeted DNA sequencing of 125 samples uncovered, in addition to expected NF2 disruption, recurrent mutations in ARID1A, ARID1B and DDR1. RNA sequencing identified a recurrent in-frame SH3PXD2A-HTRA1 fusion in 12/125 (10%) cases, and genomic analysis demonstrated the mechanism as resulting from a balanced 19-Mb chromosomal inversion on chromosome 10q. The fusion was associated with male gender predominance, occurring in one out of every six men with schwannoma. Methylation profiling identified distinct molecular subgroups of schwannomas that were associated with anatomical location. Expression of the SH3PXD2A-HTRA1 fusion resulted in elevated phosphorylated ERK, increased proliferation, increased invasion and in vivo tumorigenesis. Targeting of the MEK-ERK pathway was effective in fusion-positive Schwann cells, suggesting a possible therapeutic approach for this subset of tumors.

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Acknowledgements

This work was supported by the Canadian Institute of Health Research (CIHR) post-doctoral fellowship (S.A.). The contributions of T.J.P., K.D.A. and G.Z. to this project were supported by the Princess Margaret Cancer Foundation. We thank the staff of the Princess Margaret Genomics Centre (N. Winegarden, J. Tsao and N. Khuu) and Bioinformatics Services (C. Virtanen and Z. Lu) for their expertise in generating the sequencing data used in this study. G.Z. is supported by the Wilkins Family Chair in Brain Tumor Research, CIHR grants, and The Terry Fox Research Institute. K.D.A. is supported by funding from the MacFeeters-Hamilton Neuro-Oncology Research Program. The human immortalized Schwann cells were a gift from A. Hoke (The Johns Hopkins School of Medicine, Baltimore, Maryland, USA).

Author information

Author notes

    • Kenneth D Aldape
    •  & Gelareh Zadeh

    These authors jointly directed this work.

Affiliations

  1. MacFeeters Hamilton Centre for Neuro-Oncology Research, Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada.

    • Sameer Agnihotri
    • , Shahrzad Jalali
    • , Mark R Wilson
    • , Mira Li
    • , George Klironomos
    • , Alireza Mansouri
    • , Osaama Khan
    • , Yasin Mamatjan
    • , Natalie Landon-Brace
    • , Takyee Tung
    • , Kelly E Burrell
    • , Peter D Tonge
    • , Amir Alamsahebpour
    • , Kenneth D Aldape
    •  & Gelareh Zadeh
  2. Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada.

    • Arnavaz Danesh
    • , Mark Dowar
    • , Tiantian Li
    • , Jeffrey P Bruce
    • , Trevor J Pugh
    • , Kenneth D Aldape
    •  & Gelareh Zadeh
  3. SPARC Biocentre, The Hospital for Sick Children, Toronto, Ontario, Canada.

    • Jonathan R Krieger
  4. Department of Neurosurgery, University Hospital of Cologne, Cologne Germany.

    • Boris Krischek
  5. Harvard Medical School, Boston, Massachusetts, USA.

    • Pankaj Kumar Agarwalla
    • , Wenya Linda Bi
    • , Ian F Dunn
    •  & Rameen Beroukhim
  6. Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.

    • Pankaj Kumar Agarwalla
    • , Wenya Linda Bi
    •  & Rameen Beroukhim
  7. Department of Neurosurgery, Massachusetts General Hospital, Boston, Massachusetts, USA.

    • Pankaj Kumar Agarwalla
  8. Dana-Farber Cancer Institute, Boston, Massachusetts, USA.

    • Pankaj Kumar Agarwalla
    • , Wenya Linda Bi
    •  & Rameen Beroukhim
  9. Department of Neurosurgery, Brigham and Women's Hospital, Boston, Massachusetts, USA.

    • Wenya Linda Bi
    • , Ian F Dunn
    •  & Rameen Beroukhim
  10. Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.

    • Rameen Beroukhim
  11. Department of Neurosurgery, University Health Network, Toronto, Ontario, Canada.

    • Michael G Fehlings
    •  & Gelareh Zadeh
  12. Department of Medicine (Neurology), and the Elizabeth Raab Neurofibromatosis Program, University of Toronto, Toronto, Ontario, Canada.

    • Vera Bril
  13. Department of Science and Technology, Università degli Studi del Sannio, Benevento, Italy.

    • Stefano M Pagnotta
  14. Department of Pathology and Cell Biology and Neurology, Columbia University, New York, New York, USA.

    • Stefano M Pagnotta
    •  & Antonio Iavarone
  15. Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada.

    • Trevor J Pugh
    •  & Kenneth D Aldape
  16. Department of Pathology, Maryland Anderson Cancer Center, Houston, Texas, USA.

    • Kenneth D Aldape
  17. Department of Laboratory Medicine and Pathology, University of Toronto, Toronto, Ontario, Canada.

    • Kenneth D Aldape

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Contributions

S.A., K.D.A. and G.Z. conceived the entire project, designed, performed and analyzed the majority of the experiments in this study, prepared figures and wrote the manuscript. M.R.W. and M.L. performed in vitro experiments and in vivo studies. S.J., M.D. and T.L. performed QC and targeted sequencing library preparations. T.T., G.K., A.M., O.K. and B.K. clinically annotated schwannomas samples. J.R.K., Y.M., N.L.-B., A.A., M.D., T.L., T.J.P., S.M.P., K.E.B. and P.D.T. provided technical assistance and data interpretation. A.D. and T.J.P. analyzed and interpreted fusion breakpoint, point mutations and indels from targeted re-sequencing. K.D.A. and G.Z. funded the study. J.P.B., P.K.A., W.L.B., I.F.D. and R.B. provided technical assistance and data interpretation. A.I. and S.M.P. provided computation expertise and data interpretation. M.G.F. and V.B. provided clinical expertise.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to Kenneth D Aldape or Gelareh Zadeh.

Integrated supplementary information

Supplementary information

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  1. 1.

    Supplementary Text and Figures

    Supplementary Figures 1–15 and Supplementary Tables 1–3, 5, 6 and 10

Excel files

  1. 1.

    Supplementary Table 4

    Mutations identified in schwannoma patients

  2. 2.

    Supplementary Table 7

    RNA-seq fusion detection results

  3. 3.

    Supplementary Table 8

    SH3PXD2A-HTRA1 fusion peptides identified in patient samples

  4. 4.

    Supplementary Table 9

    Capture probes for targeted sequencing and fusion breakpoint identification

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DOI

https://doi.org/10.1038/ng.3688

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