Malignant peripheral nerve sheath tumors (MPNSTs) are sarcomas of Schwann cell lineage origin that occur sporadically or in association with the inherited syndrome neurofibromatosis type 1. To identify genetic drivers of MPNST development, we used the Sleeping Beauty (SB) transposon-based somatic mutagenesis system in mice with somatic loss of transformation-related protein p53 (Trp53) function and/or overexpression of human epidermal growth factor receptor (EGFR). Common insertion site (CIS) analysis of 269 neurofibromas and 106 MPNSTs identified 695 and 87 sites with a statistically significant number of recurrent transposon insertions, respectively. Comparison to human data sets identified new and known driver genes for MPNST formation at these sites. Pairwise co-occurrence analysis of CIS-associated genes identified many cooperating mutations that are enriched in Wnt/β-catenin, PI3K-AKT-mTOR and growth factor receptor signaling pathways. Lastly, we identified several new proto-oncogenes, including Foxr2 (encoding forkhead box R2), which we functionally validated as a proto-oncogene involved in MPNST maintenance.
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We would like to thank the Biomedical Genomics Center at the University of Minnesota for performing Illumina deep sequencing. We would like to thank the Biological Materials Procurement Network (BioNet), specifically S. Schmechel, A. Rizzardi, C. Forster and S. Bowell, for the construction, immunohistochemical staining and scanning of the TMA. We also acknowledge the following shared resources of the Masonic Cancer Center at the University of Minnesota: The Mouse Genetics Laboratory, Biostatistics and Bioinformatics, Comparative Pathology and the Tissue Procurement Facility. We thank the Minnesota Supercomputing Institute for computational resources. We thank the Research Animal Resources at the University of Minnesota and specifically A. Aliye for his technical support in mouse maintenance. This work received funding from the US National Institutes of Health (NIH) National Institute of Neurological Disorders and Stroke (NINDS) through grant P50 N5057531, the Margaret Harvey Schering Trust, The Zachary Neurofibromatosis Research Fund and The Jacqueline Dunlap Neurofibromatosis Research Fund. Work performed by A.L.W. was supported by Children’s Tumor Foundation Young Investigators Award 2011-01-018.