WES and CNV analysis of NF1-associated plexiform neurofibromas
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PROVIDER: PRJNA393484 | ENA |
REPOSITORIES: ENA
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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
2011-09-29 | E-GEOD-24328 | biostudies-arrayexpress
Project description:WES and CNV analysis of NF1-associated plexiform neurofibromas
| PRJNA393485 | ENA
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.
2020-03-10 | GSE117781 | GEO
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.
2011-09-30 | GSE24328 | GEO
Project description:<p>Neurofibromatosis type 1 (NF1) is a common tumor-predisposition disorder due to germline mutations in the tumor suppressor gene <i>NF1</i>. A virtually pathognomonic finding of NF1 is the plexiform neurofibroma (PN), a benign, likely congenital tumor that arises from biallelic inactivation of <i>NF1</i>. PN can undergo transformation to a malignant peripheral nerve sheath tumor, an aggressive soft-tissue sarcoma. To better understand the non-<i>NF1</i> genetic contributions to PN pathogenesis, we performed whole-exome sequencing and genome-wide copy-number determination for 23 low-passage Schwann cell cultures established from surgical PN material with matching germline DNA. All resected tumors were derived from routine debulking surgeries. None of the tumors were considered at risk for malignant transformation at the time, <i>e.g.</i>, there was no pain or rapid growth. Deep (~500X) <i>NF1</i> exon sequencing was also conducted on tumor DNA. Non-<i>NF1</i> somatic mutation verification was performed using the Ampliseq/IonTorrent platform. We identified 100% of the germline <i>NF1</i> mutations and found somatic <i>NF1</i> inactivation in 74% of the PN. One individual with three PNs had different <i>NF1</i> somatic mutations in each tumor. The median number of somatic mutations per sample, including <i>NF1</i>, was one (range 0 - 8). <i>NF1</i> was the only gene that was recurrently somatically inactivated in multiple tumors. We found no recurrent non-<i>NF1</i> locus copy-number variation in PN. This is the first multi-sample whole-exome sequencing study of <i>NF1</i>-associated PN. Taken together with concurrent copy-number data, our comprehensive genetic analysis reveals the primacy of <i>NF1</i> loss as the driver of PN tumorigenesis.</p>
| phs001403 | dbGaP
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: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: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
Project description:Neurofibromatosis Type 1 (NF1) is a common cancer predisposition syndrome, caused by heterozygous loss of function mutations in the tumor suppressor gene NF1. Individuals with NF1 develop benign tumors of the peripheral nervous system (neurofibromas), originating from the Schwann cell linage after somatic loss of the wild type NF1 allele, some of which progress further to malignant peripheral nerve sheath tumors (MPNST). There is only one FDA approved targeted therapy for symptomatic plexiform neurofibromas and none approved for MPNST. The genetic basis of NF1 syndrome makes associated tumors ideal for using synthetic drug sensitivity approaches to uncover vulnerabilities. We developed a drug discovery pipeline to identify therapeutics for NF1-related tumors using isogeneic pairs of NF1 proficient and deficient immortalized human Schwann cells. We utilized these in a large-scale high throughput screen (HTS) for drugs that preferentially kill NF1 deficient cells, which identified 23 compounds capable of killing NF1 deficient Schwann cells with selectivity. Multiple hits from this screen clustered into classes defined by method of action. Four clinically interesting drugs from these classes were tested in vivo using both a genetically engineered mouse model of high-grade peripheral nerve sheath tumors and human MPNST xenografts. All trugs tested showed single agent efficacy in these models as well as significant synergy when used in combination with the MEK inhibitor selumetinib. This HTS platform has yielded novel therapeutically relevant compounds for the treatment of NF1-associated tumors and can serve as a tool to rapidly evaluate new compounds and combinations in the future.
2024-03-21 | GSE262030 | 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