title: Forward genetic screen for malignant peripheral nerve sheath tumor formation identifies new genes and pathways driving tumorigenesis.
abstract: 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.
authors.affiliation: Masonic Cancer Center, University of Minnesota, Minneapolis, MN, USA. rahr0003@umn.edu
authors.forename: Eric P
authors.initials: EP
authors.lastname: Rahrmann
authors.forename: Adrienne L
authors.initials: AL
authors.lastname: Watson
authors.forename: Vincent W
authors.initials: VW
authors.lastname: Keng
authors.forename: Kwangmin
authors.initials: K
authors.lastname: Choi
authors.forename: Branden S
authors.initials: BS
authors.lastname: Moriarity
authors.forename: Dominic A
authors.initials: DA
authors.lastname: Beckmann
authors.forename: Natalie K
authors.initials: NK
authors.lastname: Wolf
authors.forename: Aaron
authors.initials: A
authors.lastname: Sarver
authors.forename: Margaret H
authors.initials: MH
authors.lastname: Collins
authors.forename: Christopher L
authors.initials: CL
authors.lastname: Moertel
authors.forename: Margaret R
authors.initials: MR
authors.lastname: Wallace
authors.forename: Bernat
authors.initials: B
authors.lastname: Gel
authors.forename: Eduard
authors.initials: E
authors.lastname: Serra
authors.forename: Nancy
authors.initials: N
authors.lastname: Ratner
authors.forename: David A
authors.initials: DA
authors.lastname: Largaespada
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D004252:DNA Mutational Analysis; D004251:DNA Transposable Elements / Q000235:genetics; D052138:Genes, Neoplasm / Q000502:physiology; D056726:Genetic Association Studies; D005820:Genetic Testing / Q000379:methods*; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation / Q000502:physiology; D018317:Nerve Sheath Neoplasms / Q000235:genetics*; D009455:Neurofibroma / Q000235:genetics; D000090063:Proto-Oncogene Mas; D015398:Signal Transduction / Q000235:genetics
chemical_list: D004251:DNA Transposable Elements; C000715470:MAS1 protein, human; D000090063:Proto-Oncogene Mas