title: Transgenic mice overexpressing neuregulin-1 model neurofibroma-malignant peripheral nerve sheath tumor progression and implicate specific chromosomal copy number variations in tumorigenesis.
abstract: Patients with neurofibromatosis type 1 (NF1) develop benign plexiform neurofibromas that frequently progress to become malignant peripheral nerve sheath tumors (MPNSTs). A genetically engineered mouse model that accurately models plexiform neurofibroma-MPNST progression in humans would facilitate identification of somatic mutations driving this process. We previously reported that transgenic mice overexpressing the growth factor neuregulin-1 in Schwann cells (P(0)-GGFβ3 mice) develop MPNSTs. To determine whether P(0)-GGFβ3 mice accurately model human neurofibroma-MPNST progression, cohorts of these animals were monitored through death and were necropsied; 94% developed multiple neurofibromas, with 70% carrying smaller numbers of MPNSTs. Nascent MPNSTs were identified within neurofibromas, suggesting that these sarcomas arise from neurofibromas. Although neurofibromin expression was maintained, P(0)-GGFβ3 MPNSTs exhibited Ras hyperactivation, as in human NF1-associated MPNSTs. P(0)-GGFβ3 MPNSTs also exhibited abnormalities in the p16(INK4A)-cyclin D/CDK4-Rb and p19(ARF)-Mdm-p53 pathways, analogous to their human counterparts. Array comparative genomic hybridization (CGH) demonstrated reproducible chromosomal alterations in P(0)-GGFβ3 MPNST cells (including universal chromosome 11 gains) and focal gains and losses affecting 39 neoplasia-associated genes (including Pten, Tpd52, Myc, Gli1, Xiap, and Bbc3/PUMA). Array comparative genomic hybridization also identified recurrent focal copy number variations affecting genes not previously linked to neurofibroma or MPNST pathogenesis. We conclude that P(0)-GGFβ3 mice represent a robust model of neurofibroma-MPNST progression useful for identifying novel genes driving neurofibroma and MPNST pathogenesis.
authors: Department of Pathology, The University of Alabama at Birmingham, Birmingham, Alabama 35294-0017, USA.
authors: Syed J
authors: SJ
authors: Kazmi
authors: Stephanie J
authors: SJ
authors: Byer
authors: Jenell M
authors: JM
authors: Eckert
authors: Amy N
authors: AN
authors: Turk
authors: Richard P H
authors: RP
authors: Huijbregts
authors: Nicole M
authors: NM
authors: Brossier
authors: William E
authors: WE
authors: Grizzle
authors: Fady M
authors: FM
authors: Mikhail
authors: Kevin A
authors: KA
authors: Roth
authors: Steven L
authors: SL
authors: Carroll
mesh_terms: D000818:Animals; D020029:Base Pairing / Q000235:genetics; D014408:Biomarkers, Tumor / Q000378:metabolism; D002453:Cell Cycle; D002471:Cell Transformation, Neoplastic / Q000235:genetics* / Q000473:pathology; D033481:Chromosomes, Mammalian / Q000235:genetics*; D055028:Comparative Genomic Hybridization; D056915:DNA Copy Number Variations / Q000235:genetics*; D004195:Disease Models, Animal; D018450:Disease Progression; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D018317:Nerve Sheath Neoplasms / Q000235:genetics / Q000473:pathology*; D020890:Neuregulin-1 / Q000378:metabolism*; D009455:Neurofibroma / Q000235:genetics / Q000473:pathology*; D025542:Neurofibromin 1 / Q000378:metabolism; D017933:Peripheral Nervous System / Q000378:metabolism / Q000473:pathology; D015398:Signal Transduction / Q000235:genetics; D018631:ras Proteins / Q000378:metabolism
chemical_list: D014408:Biomarkers, Tumor; D020890:Neuregulin-1; D025542:Neurofibromin 1; D018631:ras Proteins