Project description:22 plexiform neurofibromas from 18 unrelated neurofibromatosis-type 1 patients were screened with a high resolution array-CGH. Each PNF DNA (somatic tumor DNA) was individually hybridized on Agilent whole human genome 244K microarrays (Platform GPL4091) using the matched genomic constitutional DNA (lymphocytes DNA) from the corresponding patient as reference, in order to detect tumor-specific aberrations. NF1-associated plexiform neurofibromas DNA vs. constitutional DNA
Project description:Patients carrying an inactive NF1 allele develop tumours of Schwann cell origin called neurofibromas (NFs). Genetically engineered mouse models have significantly enriched our understanding of plexiform forms of NFs (pNFs). However, this has not been the case for cutaneous neurofibromas (cNFs), observed in all NF1 patients, as no previous model recapitulates their development. Here, we show that conditional Nf1 inactivation in Prss56-positive boundary cap cells leads to bona fide pNFs and cNFs. This work identifies subepidermal glia as a likely candidate for the cellular origin of cNFs, and provides insights on disease mechanisms, revealing a long, multistep pathological process in which inflammation play pivotal role. This new mouse model is an important asset for future clinical and therapeutic investigations of NF1-associated neurofibromas.
Project description: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 would facilitate the identification of somatic mutations driving this process. We have previously reported that transgenic mice overexpressing the growth factor neuregulin-1 in Schwann cells (P0-GGFβ3 mice) develop MPNSTs. To determine whether P0-GGFβ3 mice accurately model neurofibroma-MPNST progression, cohorts of these animals were followed to death and necropsied. 94% of the mice 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, P0-GGFβ3 MPNSTs, like human NF1-associated MPNSTs, demonstrated Ras hyperactivation. P0-GGFβ3 MPNSTs also showed abnormalities in the p16INK4A-cyclin D/CDK4-Rb and p19ARF-Mdm-p53 pathways analogous to their human counterparts. Array comparative genomic hybridization (CGH) demonstrated reproducible chromosomal alterations in P0-GGFβ3 MPNST cells (including universal chromosome 11 gains) and focal gains and losses affecting 39 genes previously implicated in neoplasia (e.g., Pten, Tpd52, Myc , Gli1, Xiap, Bbc3/PUMA). Array CGH also identified recurrent focal copy number variations affecting genes not previously linked to neurofibroma or MPNST pathogenesis. We conclude that P0-GGFβ3 mice represent a robust model of neurofibroma-MPNST progression that can be used to identify novel genes driving neurofibroma and MPNST pathogenesis.
Project description: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 would facilitate the identification of somatic mutations driving this process. We have previously reported that transgenic mice overexpressing the growth factor neuregulin-1 in Schwann cells (P0-GGF?3 mice) develop MPNSTs. To determine whether P0-GGF?3 mice accurately model neurofibroma-MPNST progression, cohorts of these animals were followed to death and necropsied. 94% of the mice 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, P0-GGF?3 MPNSTs, like human NF1-associated MPNSTs, demonstrated Ras hyperactivation. P0-GGF?3 MPNSTs also showed abnormalities in the p16INK4A-cyclin D/CDK4-Rb and p19ARF-Mdm-p53 pathways analogous to their human counterparts. Array comparative genomic hybridization (CGH) demonstrated reproducible chromosomal alterations in P0-GGF?3 MPNST cells (including universal chromosome 11 gains) and focal gains and losses affecting 39 genes previously implicated in neoplasia (e.g., Pten, Tpd52, Myc , Gli1, Xiap, Bbc3/PUMA). Array CGH also identified recurrent focal copy number variations affecting genes not previously linked to neurofibroma or MPNST pathogenesis. We conclude that P0-GGF?3 mice represent a robust model of neurofibroma-MPNST progression that can be used to identify novel genes driving neurofibroma and MPNST pathogenesis. Array CGH comparison of malignant peripheral nerve sheath tumor (MPNST) cells vs non-neoplastic Schwann cells
Project description:Comparison of copy number changes in MPNST samples against benign neurofibromas in NF1 patients 24 MPNSTs and 3 NF samples were hybridised to the human 32K BAC tiling path array
Project description:Plexiform neurofibromas (PN) are benign nerve sheath Schwann cell tumors, common in patients with neurofibromatosis type 1 (NF1), that are characterized by biallelic mutations in the NF1 tumor suppressor gene. Atypical neurofibromas (ANF) show additional frequent loss of CDKN2A/Ink4a/Arf and may be precursor lesions of aggressive malignant peripheral nerve sheath tumors (MPNST). We combined loss of Nf1 in developing
