Atypical Neurofibromas reveal distinct epigenetic features with proximity to benign peripheral nerve sheath tumor entities
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PROVIDER: PRJNA892883 | ENA |
REPOSITORIES: ENA
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Project description:Unsupervised hierarchical clustering and t-SNE analysis indicated that 36/40 ANF cluster separately from MPNST and instead close to the benign tumor entities. Of these 36 tumors, 23 ANF formed a molecularly distinct cluster in proximity to schwannomas. Tumors from this cluster had frequent heterozygous or homozygous loss of CDKN2A/B and significantly more lymphocyte infiltration than MPNST, schwannomas, and NF. Few ANF clustered closely with neurofibromas, schwannomas, or MPNST, raising the question, whether diagnosis based on histological features alone might pose a risk to both over- and underestimate the aggressiveness of these lesions.
2023-03-01 | GSE216262 | GEO
Project description:BackgroundPlexiform neurofibromas can transform into atypical neurofibromas (ANF) and then further progress to aggressive malignant peripheral nerve sheath tumors (MPNST). ANF have been described to harbor distinct histological features and frequent loss of CDKN2A/B. However, histological evaluation may be rater-dependent, and detailed knowledge about the molecular mechanisms of malignant transformation is scarce. In general, malignant transformation can be accompanied by significant epigenetic changes, and global DNA methylation profiling is able to differentiate relevant tumor subgroups. Therefore, epigenetic profiling might provide a valuable tool to distinguish and characterize ANF with differing extent of histopathological atypia from neurofibromas and MPNST.MethodsWe investigated 40 tumors histologically diagnosed as ANF and compared their global methylation profile to other peripheral nerve sheath tumors.ResultsUnsupervised class discovery and t-SNE analysis indicated that 36/40 ANF cluster with benign peripheral nerve sheath tumors with clear separation from MPNST. 21 ANF formed a molecularly distinct cluster in proximity to schwannomas. Tumors in this cluster had a frequent heterozygous or homozygous loss of CDKN2A/B and significantly more lymphocyte infiltration than MPNST, schwannomas, and NF. Few ANF clustered closely with neurofibromas, schwannomas, or MPNST, raising the question, whether diagnosis based on histological features alone might pose a risk to both over- and underestimate the aggressiveness of these lesions.ConclusionsOur data suggest that ANF with varying histological morphology show distinct epigenetic similarities and cluster in proximity to benign peripheral nerve sheath tumor entities. Future investigations should pay special respect to correlating this methylation pattern to clinical outcomes.
| S-EPMC10479771 | biostudies-literature
Project description:No consensus treatment regime exists beyond surgery for malignant peripheral nerve sheath tumours (MPNST), and the purpose of the present study was to find new approaches to stratify patients with good and poor prognosis and to better guide therapeutic intervention for this aggressive soft tissue cancer. Genome-wide RNA expression was analysed for 30 MPNSTs and eight neurofibromas from Scandinavian patients, and the overall gene expression in these two groups were compared in order to identify prognostic markers.
2015-03-11 | E-GEOD-66743 | biostudies-arrayexpress
Project description:Aberrant DNA methylation (DNAm) was first linked to cancer over 25 years ago. Since then, many studies have associated hypermethylation of tumour suppressor genes and hypomethylation of oncogenes to the tumourigenic process. However, most of these studies have been limited to the analysis of promoters and CpG islands (CGIs). Recently, new technologies for whole-genome DNAm (methylome) analysis have been developed, enabling unbiased analysis of cancer methylomes. Using MeDIP-seq, we report a sequencing-based comparative methylome analysis of malignant peripheral nerve sheath tumours (MPNST), benign Neurofibromas and normal Schwann cells. Analysis of these methylomes revealed a complex landscape of DNAm alterations. Contrary to the current dogma, significant global hypomethylation was not observed in the MPNST methylome. However, a highly significant (P<10-100) directional difference in DNAm was found in satellite repeats, suggesting these repeats to be the main target for hypomethylation in MPNST. Comparative analysis of the MPNST and Schwann cell methylomes identified 101,466 cancer-associated differentially methylated regions (cDMRs). Analysis showed these cDMRs to be significantly enriched for two satellite repeat types (SATR1 and ARLM-NM-1) and suggests an association between aberrant DNAm of these sequences and transition from healthy cells to malignant disease. Significant enrichment of hypermethylated cDMRs in CGI shores (P<10-60), non-CGI-associated promoters (P<10-4) and hypomethylated cDMRs in SINE repeats (P<10-100) was also identified. Integration of DNAm and gene expression data showed that the expression pattern of genes associated with CGI shore cDMRs was able to discriminate between disease phenotypes. This study establishes MeDIP-seq as an effective method to analyse cancer methylomes. Examination of methylation profiles in malignant, benign and normal tissue
2011-01-01 | E-GEOD-21714 | 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 | GSE140913 | 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
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: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:Comparison of copy number changes in MPNST samples against benign neurofibromas in NF1 patients
2009-05-20 | GSE16041 | GEO
Project description:Plexiform neurofibromas (PNF) are benign peripheral nerve sheath tumors (PNST) that arise in persons with neurofibromatosis type 1 (NF1). Despite similar histological appearance, these neoplasms proceed along diverse evolutionary trajectories, with a subset progressing to a devastating form of sarcoma called malignant peripheral nerve sheath tumor (MPNST), the leading cause of premature death in individuals with NF1. Malignant transformation of PNF often occurs through the development of atypical neurofibroma (ANF) precursor lesions characterized by distinct histopathological features and CDKN2A copy number loss. While genomic studies have improved our understanding of key driver events promoting tumor progression, the transcriptional alterations that precede malignant transformation remain poorly understood. Here we resolve gene expression profiles in PNSTs across the neurofibroma-to-MPNST continuum in NF1 patients and genetically engineered mouse models, providing insight into nascent molecular features associated with neurofibroma evolution and transformation. These findings highlight the need for molecular diagnostic tools that augment conventional histopathological criteria to identify neurofibromas at high risk of undergoing malignant transformation, facilitating risk-adapted care.
2023-12-14 | GSE239561 | GEO