Atypical neurofibromas in neurofibromatosis type 1 are premalignant tumors
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
DISEASE(S): NF1 atypical neurofibroma
SUBMITTER: Eline Beert
PROVIDER: E-MEXP-3052 | biostudies-arrayexpress |
REPOSITORIES: biostudies-arrayexpress
Publications
Comparative oncogenomic analysis of copy number alterations in human and zebrafish tumors enables cancer driver discovery.
Zhang GuangJun G Hoersch Sebastian S Amsterdam Adam A Whittaker Charles A CA Beert Eline E Catchen Julian M JM Farrington Sarah S Postlethwait John H JH Legius Eric E Hopkins Nancy N Lees Jacqueline A JA
PLoS genetics 20130829 8
The identification of cancer drivers is a major goal of current cancer research. Finding driver genes within large chromosomal events is especially challenging because such alterations encompass many genes. Previously, we demonstrated that zebrafish malignant peripheral nerve sheath tumors (MPNSTs) are highly aneuploid, much like human tumors. In this study, we examined 147 zebrafish MPNSTs by massively parallel sequencing and identified both large and focal copy number alterations (CNAs). Given ...[more]
Similar Datasets
Project description:Malignant peripheral nerve sheath tumors (MPNST) are aggressive cancers that occur spontaneously (sporadic MPNST) or from pre-existing, benign plexiform neurofibromas in neurofibromatosis type 1 (NF1) patients. MPNSTs metastasize easily, are resistant to therapeutic intervention and are frequently fatal. The molecular changes underlying the transition to malignancy in the NF1 setting are incompletely understood. Here we investigate the involvement of microRNAs in this process. Using an RT-PCR platform microRNA expression profiles were determined from a unique series of archival paired samples of plexiform neurofibroma and MPNST. At least 90 differentially expressed microRNAs (p<0.025; FDR<10%) were identified between the paired samples. Most microRNAs (91%) were found downregulated and 9% of the microRNAs were upregulated in MPNST. Based on the fold changes and statistical significance three downregulated microRNAs (let-7b-5p, miR-143-3p, miR-145-5p) and two upregulated microRNAs (miR135b-5p and miR-889-3p) were selected for further functional characterization. Their expression levels were validated in a relevant cell line panel and a series of unpaired fresh frozen tumor samples containing plexiform neurofibromas, atypical neurofibromas and MPNSTs. As part of the validation process we also determined and analyzed microRNA expression profiles of sporadic MPNSTs observing that microRNA expression discriminates NF1-associated and sporadic MPNSTs emphasizing their different etiologies. The involvement of microRNAs in tumorigenesis and cancer progression was examined in NF1-derived MPNST cell lines through modulating microRNA levels by transient transfection of microRNA mimics or inhibitors. The effects of microRNAs on cellular proliferation, migration, invasion and Wnt/ẞ-catenin signaling were determined. Our findings indicate that, some of the selected microRNAs affect migratory and invasive capabilities and Wnt signaling activity. It was observed that the functional effects upon microRNA modulation are distinct in different cell lines. From our study we conclude that miRNAs play essential regulatory roles in MPNST facilitating tumor progression.
2019-11-26 | GSE140913 | GEO
Project description:Neurofibromatosis Type 1 (NF1) patients develop benign neurofibromas and malignant peripheral nerve sheath tumors (MPNST). These incurable peripheral nerve tumors result from loss of NF1 tumor suppressor gene function, causing hyperactive Ras signaling. Activated Ras controls numerous downstream effectors, but specific pathways mediating effects of hyperactive Ras in NF1 tumors are unknown. Cross-species transcriptome analyses of mouse and human neurofibromas and MPNSTs identified global negative feedback of genes that regulate Ras-Raf- MEK- extracellular signal-regulated protein kinase (ERK) signaling in both species. Nonetheless, activation of ERK was sustained in mouse and human neurofibromas and MPNST. PD0325901, a highly selective pharmacological inhibitor of MEK, was used to test whether sustained Ras-Raf-MEK-ERK signaling contributes to neurofibroma growth in the Nf1fl/fl;Dhh-cre mouse model or in NF1 patient MPNST cell xenografts. PD0325901 treatment reduced aberrantly proliferating cells in neurofibroma and MPNST, prolonged survival of mice implanted with human MPNST cells, and shrank neurofibromas in >80% of mice tested. PD0325901 also caused effects on tumor vasculature. Our data demonstrate that deregulated Ras/ERK signaling is critical for the growth of NF1 peripheral nerve tumors and provide strong rationale for testing MEK inhibitors in NF1 clinical trials.
2012-12-28 | GSE41747 | GEO
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
2020-12-23 | GSE148249 | GEO
Project description:Neurofibromatosis Type 1 (NF1) patients develop benign neurofibromas and malignant peripheral nerve sheath tumors (MPNST). These incurable peripheral nerve tumors result from loss of NF1 tumor suppressor gene function, causing hyperactive Ras signaling. Activated Ras controls numerous downstream effectors, but specific pathways mediating effects of hyperactive Ras in NF1 tumors are unknown. Cross-species transcriptome analyses of mouse and human neurofibromas and MPNSTs identified global negative feedback of genes that regulate Ras-Raf- MEK- extracellular signal-regulated protein kinase (ERK) signaling in both species. Nonetheless, activation of ERK was sustained in mouse and human neurofibromas and MPNST. PD0325901, a highly selective pharmacological inhibitor of MEK, was used to test whether sustained Ras-Raf-MEK-ERK signaling contributes to neurofibroma growth in the Nf1fl/fl;Dhh-cre mouse model or in NF1 patient MPNST cell xenografts. PD0325901 treatment reduced aberrantly proliferating cells in neurofibroma and MPNST, prolonged survival of mice implanted with human MPNST cells, and shrank neurofibromas in >80% of mice tested. PD0325901 also caused effects on tumor vasculature. Our data demonstrate that deregulated Ras/ERK signaling is critical for the growth of NF1 peripheral nerve tumors and provide strong rationale for testing MEK inhibitors in NF1 clinical trials. 83 microarrays: Mouse control (15), Mouse neurofibroma (15), Mouse MPNST (18); Human nerve (3), Human neurofibroma (26), Human MPNST (6) We used the same human tumor samples as in series GSE14038 (dNF, pNF and MPNST). However, instead of referencing gene expression changes to the normal human Schwann cell samples (NHSC) as we did in series GSE14038, we generated three (new) normal nerve samples (samples jan-N1-3) and referenced gene expression changes to those samples. Moreover, the analysis of series GSE14038 evaluated changes in expression between NHSC, benign tumor subtypes (dNF and pNF), and malignant tumors (MPNST), while our present submission evaluated changes between normal nerve, benign tumors (combined dNF and pNF),and malignant tumors (MPNST). The Series supplementary 'merged_data.txt' file contains the data for 9,891 transcripts that were statistically different in at least one of the two species and present in both mouse and human data sets.
2012-12-28 | E-GEOD-41747 | biostudies-arrayexpress
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
2012-12-31 | E-GEOD-40212 | biostudies-arrayexpress
Project description:Neurofibromatosis 1 (NF1) is a genetic, neurocutaneous syndrome caused by a mutation in the gene encoding neurofibromin. Individuals with NF1 develop growths that define the NF1 phenotype, including Lisch nodules, cafe-au-lait spots, and neurofibromas. However, more than 50% of individuals with NF1 have cognitive deficits, such as learning disorders and attention deficit/hyperactive disorder that are neuroanatomically unrelated to the neurofibromas. The purpose of this study is to determine the molecular basis of the neurodevelopmental changes that result from the primary gene mutation using a mouse model of NF. These mice are heterozygous for the Nf1 gene (NF+/-), and develop learning and memory difficulties that mimic humans, but do not develop tumors. By applying the technique of gene expression profiling to both NF+/- and control mice, we expect get a "genetic fingerprint" of 12,000 RNA molecules expressed in different parts of the brain during development. Comparison of the "genetic fingerprints" in these mice during development may help us identify key molecular changes that eventually result in cognitive deficits. Such an understanding of the molecular changes triggered by the primary gene mutation may eventually lead to treatments that prevent the cognitive deficits in NF1. Keywords: other
2004-06-17 | GSE1482 | GEO
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
2010-05-18 | E-GEOD-16041 | biostudies-arrayexpress
Project description:Malignant peripheral nerve sheath tumors (MPNST) are aggressive cancers that occur spontaneously (sporadic MPNST) or from pre-existing, benign plexiform neurofibromas in neurofibromatosis type 1 (NF1) patients. MPNSTs metastasize easily, are resistant to therapeutic intervention and are frequently fatal. The molecular changes underlying the transition to malignancy in the NF1 setting are incompletely understood. Here we investigate the involvement of microRNAs in this process. Using an RT-PCR platform microRNA expression profiles were determined from a unique series of archival paired samples of plexiform neurofibroma and MPNST. At least 90 differentially expressed microRNAs (p<0.025; FDR<10%) were identified between the paired samples. Most microRNAs (91%) were found downregulated and 9% of the microRNAs were upregulated in MPNST. Based on the fold changes and statistical significance three downregulated microRNAs (let-7b-5p, miR-143-3p, miR-145-5p) and two upregulated microRNAs (miR135b-5p and miR-889-3p) were selected for further functional characterization. Their expression levels were validated in a relevant cell line panel and a series of unpaired fresh frozen tumor samples containing plexiform neurofibromas, atypical neurofibromas and MPNSTs. As part of the validation process we also determined and analyzed microRNA expression profiles of sporadic MPNSTs observing that microRNA expression discriminates NF1-associated and sporadic MPNSTs emphasizing their different etiologies. The involvement of microRNAs in tumorigenesis and cancer progression was examined in NF1-derived MPNST cell lines through modulating microRNA levels by transient transfection of microRNA mimics or inhibitors. The effects of microRNAs on cellular proliferation, migration, invasion and Wnt/ẞ-catenin signaling were determined. Our findings indicate that, some of the selected microRNAs affect migratory and invasive capabilities and Wnt signaling activity. It was observed that the functional effects upon microRNA modulation are distinct in different cell lines. From our study we conclude that miRNAs play essential regulatory roles in MPNST facilitating tumor progression.
2019-11-26 | GSE140986 | GEO
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.
2012-12-31 | GSE40212 | GEO
Project description:Malignant peripheral nerve sheath tumors (MPNSTs) are the leading cause of premature death for patients with Neurofibromatosis type 1 and no approved targeted therapies are available. Transformation from Nf1-null benign plexiform neurofibromas is driven by the loss of the Cdkn2a (Arf) locus. Here, genetically engineered mouse models with combined Nf1 flox/flox and Arf flox/flox alleles were used (crossed with Postn-Cre+ mice). Tissue from MPNSTs that form in the Nf1-/-;Arf-/- setting were used for mRNA sequencing and compared to benign plexiform neurofibroma tissue (Nf1-/- from Nf1 flox/flox; Postn-Cre+ mice, GSE213789) to identify transcriptome signatures from MPNST and compare them to benign plexiform neurofibroma.
2023-12-12 | GSE232707 | GEO