Abstract
Neurofibromatosis 1 is a hereditary syndrome characterized by the development of numerous benign neurofibromas, a small subset of which progress to malignant peripheral nerve sheath tumors (MPNSTs). To better understand the genetic basis for MPNSTs, we performed genome-wide or targeted sequencing on 50 cases. Sixteen MPNSTs but none of the neurofibromas tested were found to have somatic mutations in SUZ12, implicating it as having a central role in malignant transformation.
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Acknowledgements
We thank our patients for their courage and generosity. We also thank J. Ptak, N. Silliman, L. Dobbyn, J. Schaeffer and M. Papoli for expert technical assistance. The work was supported by the Virginia and D.K. Ludwig Fund for Cancer Research, a Burroughs Wellcome Career Award for Medical Scientists, a Johns Hopkins Clinical Scientist Award and grant 2014107 from the Doris Duke Charitable Foundation.
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K.W.K., N.P., B.V. and C.B. designed and supervised the project and analyzed the data. M.Z., Y.W., S.J., M.S., K.M. and Q.W. performed the sequencing studies and bioinformatics analysis. A.J.B., K.C., G.L.G., Z.L.G., G.J.R., J.-P.W. and C.B. contributed clinical samples and information. R.S., L.D.W., E.A.M. and R.H.H. performed pathological review and the immunohistochemistry experiments. M.Z., Y.W., S.J., M.S., A.J.B., K.C., G.L.G., Z.L.G., G.J.R., J.-P.W., L.D.W., E.A.M., R.H.H., K.W.K., N.P., B.V. and C.B. wrote and edited the manuscript.
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Under agreements between Johns Hopkins University, Genzyme, Sysmex-Inostics, Qiagen, Invitrogen and Personal Genome Diagnostics, N.P., B.V. and K.W.K. are entitled to a share of the royalties received by Johns Hopkins University on sales of products related to genes and technologies described in this manuscript. N.P., B.V. and K.W.K. are co-founders of Inostics and Personal Genome Diagnostics, are members of their Scientific Advisory Boards and own Personal Genome Diagnostics stock, which is subject to certain restrictions under Johns Hopkins University policy. The terms of these arrangements are managed by Johns Hopkins University in accordance with its conflict-of-interest policies.
Integrated supplementary information
Supplementary Figure 1 Circos plots.
Circos plots representing structural alterations in MPNST tumors that were analyzed via whole-genome sequencing.
Supplementary Figure 2 SUZ12 and H3K27me3 Immunohistochemistry.
Representative H&E, SUZ12 and H3K27me3 immunohistochemistry results from MPNTs with and without SUZ12 alterations. Each image is at 40× magnification and from a representative area of the tumor but not from identical locations given the scarcity of tissue.
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Supplementary Figures 1 and 2. (PDF 566 kb)
Supplementary Tables 1–5
Supplementary Tables 1–5. (XLSX 441 kb)
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Zhang, M., Wang, Y., Jones, S. et al. Somatic mutations of SUZ12 in malignant peripheral nerve sheath tumors. Nat Genet 46, 1170–1172 (2014). https://doi.org/10.1038/ng.3116
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DOI: https://doi.org/10.1038/ng.3116
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