RESUMEN
Neurofibromatosis Type 1 (NF1) is caused by loss of function variants in the NF1 gene. Most patients with NF1 develop skin lesions called cutaneous neurofibromas (cNFs). Currently the only approved therapeutic for NF1 is selumetinib, a mitogen -activated protein kinase (MEK) inhibitor. The purpose of this study was to analyze the transcriptome of cNF tumors before and on selumetinib treatment to understand both tumor composition and response. We obtained biopsy sets of tumors both pre- and on- selumetinib treatment from the same individuals and were able to collect sets from four separate individuals. We sequenced mRNA from 5844 nuclei and identified 30,442 genes in the untreated group and sequenced 5701 nuclei and identified 30,127 genes in the selumetinib treated group. We identified and quantified distinct populations of cells (Schwann cells, fibroblasts, pericytes, myeloid cells, melanocytes, keratinocytes, and two populations of endothelial cells). While we anticipated that cell proportions might change with treatment, we did not identify any one cell population that changed significantly, likely due to an inherent level of variability between tumors. We also evaluated differential gene expression based on drug treatment in each cell type. Ingenuity pathway analysis (IPA) was also used to identify pathways that differ on treatment. As anticipated, we identified a significant decrease in ERK/MAPK signaling in cells including Schwann cells but most specifically in myeloid cells. Interestingly, there is a significant decrease in opioid signaling in myeloid and endothelial cells; this downward trend is also observed in Schwann cells and fibroblasts. Cell communication was assessed by RNA velocity, Scriabin, and CellChat analyses which indicated that Schwann cells and fibroblasts have dramatically altered cell states defined by specific gene expression signatures following treatment (RNA velocity). There are dramatic changes in receptor-ligand pairs following treatment (Scriabin), and robust intercellular signaling between virtually all cell types associated with extracellular matrix (ECM) pathways (Collagen, Laminin, Fibronectin, and Nectin) is downregulated after treatment. These response specific gene signatures and interaction pathways could provide clues for understanding treatment outcomes or inform future therapies.
Asunto(s)
Bencimidazoles , Matriz Extracelular , Células de Schwann , Transducción de Señal , Neoplasias Cutáneas , Humanos , Células de Schwann/efectos de los fármacos , Células de Schwann/metabolismo , Células de Schwann/patología , Neoplasias Cutáneas/genética , Neoplasias Cutáneas/tratamiento farmacológico , Neoplasias Cutáneas/patología , Bencimidazoles/farmacología , Matriz Extracelular/metabolismo , Matriz Extracelular/efectos de los fármacos , Matriz Extracelular/genética , Transducción de Señal/efectos de los fármacos , Neurofibroma/genética , Neurofibroma/tratamiento farmacológico , Neurofibroma/metabolismo , Neurofibroma/patología , Femenino , Masculino , RNA-Seq , Persona de Mediana Edad , Adulto , Neurofibromatosis 1/genética , Neurofibromatosis 1/tratamiento farmacológico , Neurofibromatosis 1/patología , Inhibidores de Proteínas Quinasas/farmacología , Transcriptoma/efectos de los fármacosRESUMEN
In Neurofibromatosis type 1 (NF1), peripheral nerve sheaths tumors are common, with cutaneous neurofibromas resulting in significant aesthetic, painful and functional problems requiring surgical removal. To date, determination of adequate surgical resection margins-complete tumor removal while attempting to preserve viable tissue-remains largely subjective. Thus, residual tumor extension beyond surgical margins or recurrence of the disease may frequently be observed. Here, we introduce Shifted-Excitation Raman Spectroscopy in combination with deep neural networks for the future perspective of objective, real-time diagnosis, and guided surgical ablation. The obtained results are validated through established histological methods. In this study, we evaluated the discrimination between cutaneous neurofibroma (n = 9) and adjacent physiological tissues (n = 25) in 34 surgical pathological specimens ex vivo at a total of 82 distinct measurement loci. Based on a convolutional neural network (U-Net), the mean raw Raman spectra (n = 8,200) were processed and refined, and afterwards the spectral peaks were assigned to their respective molecular origin. Principal component and linear discriminant analysis was used to discriminate cutaneous neurofibromas from physiological tissues with a sensitivity of 100%, specificity of 97.3%, and overall classification accuracy of 97.6%. The results enable the presented optical, non-invasive technique in combination with artificial intelligence as a promising candidate to ameliorate both, diagnosis and treatment of patients affected by cutaneous neurofibroma and NF1.
Asunto(s)
Neurofibroma , Neurofibromatosis 1 , Neuroma , Neoplasias Cutáneas , Humanos , Espectrometría Raman/métodos , Inteligencia Artificial , Neurofibroma/diagnóstico , Neurofibroma/genética , Neurofibroma/patología , Neurofibromatosis 1/diagnóstico , Neurofibromatosis 1/genética , Neurofibromatosis 1/patología , Neoplasias Cutáneas/diagnóstico , Neoplasias Cutáneas/genética , Neoplasias Cutáneas/patología , Redes Neurales de la ComputaciónRESUMEN
BACKGROUND: Neurofibromatosis type 1 (NF1) is characterized by the highly variable and unpredictable development of benign peripheral nerve sheath tumours: cutaneous (cNFs), subcutaneous (scNFs) and plexiform (pNFs) neurofibromas. OBJECTIVES: To identify neurofibroma modifier genes, in order to develop a database of patients with NF1. METHODS: All patients were phenotypically evaluated by a medical practitioner using a standardized questionnaire and the causal NF1 variant identified. We enrolled 1333 patients with NF1 who were genotyped for > 7 million common variants. RESULTS: A genome-wide association case-only study identified a significant association with 9q21.33 in the pNF phenotype in the discovery cohort. Twelve, three and four regions suggestive of association at the P ≤ 1 × 10-6 threshold were identified for pNFs, cNFs and scNFs, respectively. Evidence of replication was observed for 4, 2 and 6 loci, including 168 candidate modifier protein-coding genes. Among the candidate modifier genes, some were implicated in the RAS-mitogen-activated protein kinase pathway, cell-cycle control and myelination. Using an original CRISPR/Cas9-based functional assay, we confirmed GAS1 and SPRED2 as pNF and scNF candidate modifiers, as their inactivation specifically affected NF1-mutant Schwann cell growth. CONCLUSIONS: Our study may shed new light on the pathogenesis of NF1-associated neurofibromas and will, hopefully, contribute to the development of personalized care for patients with this deleterious and life-threatening condition.
Asunto(s)
Neurofibroma Plexiforme , Neurofibroma , Neurofibromatosis 1 , Humanos , Neurofibromatosis 1/genética , Neurofibroma Plexiforme/complicaciones , Neurofibroma Plexiforme/genética , Estudio de Asociación del Genoma Completo , Neurofibroma/complicaciones , Neurofibroma/genética , Genotipo , Proteínas Represoras/genéticaRESUMEN
Neurofibromatosis 1 is a prevalent hereditary neurocutaneous disorder. Among the clinical phenotypes of neurofibromatosis 1, cutaneous neurofibroma (cNF) and plexiform neurofibroma (pNF) have distinct clinical manifestations, and pNF should be closely monitored owing to its malignant potential. However, the detailed distinct features of neurofibromatosis 1 phenotypes remain unknown. To determine whether the transcriptional features and microenvironment of cNF and pNF differ, single-cell RNA sequencing was performed on isolated cNF and pNF cells from the same patient. Six cNF and five pNF specimens from different subjects were also immunohistochemically analyzed. Our findings revealed that cNF and pNF had distinct transcriptional profiles even within the same subject. pNF is enriched in Schwann cells with characteristics similar to those of their malignant counterpart, fibroblasts, with a cancer-associated fibroblast-like phenotype, angiogenic endothelial cells, and M2-like macrophages, whereas cNF is enriched in CD8 T cells with tissue residency markers. The results of immunohistochemical analyses performed on different subjects agreed with those of single-cell RNA sequencing. This study found that cNF and pNF, the different neurofibromatosis phenotypes in neurofibromatosis 1, from the same subject are transcriptionally distinct in terms of the cell types involved, including T cells.
Asunto(s)
Neurofibroma Plexiforme , Neurofibroma , Neurofibromatosis 1 , Neoplasias Cutáneas , Humanos , Células Endoteliales/metabolismo , Neurofibroma/genética , Neurofibroma/complicaciones , Neurofibroma/metabolismo , Neurofibroma Plexiforme/genética , Neurofibromatosis 1/genética , Neoplasias Cutáneas/metabolismo , Microambiente TumoralRESUMEN
PURPOSE: Plexiform neurofibromas (PNF) are benign peripheral nerve sheath tumors (PNST) associated with neurofibromatosis type 1 (NF1). Despite similar histologic appearance, these neoplasms exhibit diverse evolutionary trajectories, with a subset progressing to 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 histopathologic features and CDKN2A copy-number loss. Although genomic studies have uncovered key driver events promoting tumor progression, the transcriptional changes preceding malignant transformation remain poorly defined. EXPERIMENTAL DESIGN: Here we resolve gene-expression profiles in PNST across the neurofibroma-to-MPNST continuum in NF1 patients and mouse models, revealing early molecular features associated with neurofibroma evolution and transformation. RESULTS: Our findings demonstrate that ANF exhibit enhanced signatures of antigen presentation and immune response, which are suppressed as malignant transformation ensues. MPNST further displayed deregulated survival and mitotic fidelity pathways, and targeting key mediators of these pathways, CENPF and BIRC5, disrupted the growth and viability of human MPNST cell lines and primary murine Nf1-Cdkn2a-mutant Schwann cell precursors. Finally, neurofibromas contiguous with MPNST manifested distinct alterations in core oncogenic and immune surveillance programs, suggesting that early molecular events driving disease progression may precede histopathologic evidence of malignancy. CONCLUSIONS: If validated prospectively in future studies, these signatures may serve as molecular diagnostic tools to augment conventional histopathologic diagnosis by identifying neurofibromas at high risk of undergoing malignant transformation, facilitating risk-adapted care.
Asunto(s)
Neoplasias de la Vaina del Nervio , Neurofibroma , Neurofibromatosis 1 , Neurofibrosarcoma , Animales , Humanos , Ratones , Perfilación de la Expresión Génica , Neoplasias de la Vaina del Nervio/genética , Neurofibroma/genética , Neurofibromatosis 1/genética , Neurofibrosarcoma/genéticaRESUMEN
Cutaneous neurofibromas (cNFs) are tumors that develop in more than 99% of individuals with neurofibromatosis type 1 (NF1). They develop in the dermis and can number in the thousands. cNFs can be itchy and painful and negatively impact self-esteem. There is no US Food and Drug Administration (FDA)-approved drug for their treatment. Here, we screen a library of FDA-approved drugs using a cNF cell model derived from human induced pluripotent stem cells (hiPSCs) generated from an NF1 patient. We engineer an NF1 mutation in the second allele to mimic loss of heterozygosity, differentiate the NF1+/- and NF1-/- hiPSCs into Schwann cell precursors (SCPs), and use them to screen a drug library to assess for inhibition of NF1-/- but not NF1+/- cell proliferation. We identify econazole nitrate as being effective against NF1-/- hiPSC-SCPs. Econazole cream selectively induces apoptosis in Nf1-/- murine nerve root neurosphere cells and human cNF xenografts. This study supports further testing of econazole for cNF treatment.
Asunto(s)
Células Madre Pluripotentes Inducidas , Neurofibroma , Neurofibromatosis 1 , Neoplasias Cutáneas , Estados Unidos , Humanos , Animales , Ratones , Neurofibromatosis 1/tratamiento farmacológico , Neurofibromatosis 1/genética , Neurofibromatosis 1/metabolismo , Econazol , Células Madre Pluripotentes Inducidas/metabolismo , Neurofibroma/genética , Neurofibroma/metabolismo , Neurofibroma/patología , Neoplasias Cutáneas/tratamiento farmacológico , Neoplasias Cutáneas/genética , Neoplasias Cutáneas/metabolismo , Apoptosis/genéticaRESUMEN
BACKGROUND: Malignant peripheral nerve sheath tumour (MPNST) is an aggressive orphan disease commonly affecting adolescents or young adults. Current knowledge of molecular tumour biology has been insufficient for development of rational treatment strategies. We aimed to discover molecular subtypes of potential clinical relevance. METHODS: Fresh frozen samples of MPNSTs (n = 94) and benign neurofibromas (n = 28) from 115 patients in a European multicentre study were analysed by DNA copy number and/or transcriptomic profiling. Unsupervised transcriptomic subtyping was performed and the subtypes characterized for genomic aberrations, clinicopathological associations and patient survival. FINDINGS: MPNSTs were classified into two transcriptomic subtypes defined primarily by immune signatures and proliferative processes. "Immune active" MPNSTs (44%) had sustained immune signals relative to neurofibromas, were more frequently low-grade (P = 0.01) and had favourable prognostic associations in a multivariable model of disease-specific survival with clinicopathological factors (hazard ratio 0.25, P = 0.003). "Immune deficient" MPNSTs were more aggressive and characterized by proliferative signatures, high genomic complexity, aberrant TP53 and PRC2 loss, as well as high relative expression of several potential actionable targets (EGFR, ERBB2, EZH2, KIF11, PLK1, RRM2). Integrated gene-wise analyses suggested a DNA copy number-basis for proliferative transcriptomic signatures in particular, and the tumour copy number burden further stratified the transcriptomic subtypes according to patient prognosis (P < 0.01). INTERPRETATION: Approximately half of MPNSTs belong to an "immune deficient" transcriptomic subtype associated with an aggressive disease course, PRC2 loss and expression of several potential therapeutic targets, providing a rationale for molecularly-guided intervention trials. FUNDING: Research grants from non-profit organizations, as stated in the Acknowledgements.
Asunto(s)
Neoplasias de la Vaina del Nervio , Neurofibroma , Neurofibrosarcoma , Adolescente , Adulto Joven , Humanos , Neoplasias de la Vaina del Nervio/diagnóstico , Neoplasias de la Vaina del Nervio/genética , Neoplasias de la Vaina del Nervio/metabolismo , Transcriptoma , Neurofibroma/genética , Neurofibroma/patología , Genómica , ADNRESUMEN
Cutaneous neurofibromas (cNFs) are a hallmark of patients with the neurofibromatosis type 1 (NF1) genetic disorder. These benign nerve sheath tumors, which can amount to thousands, develop from puberty onward, often cause pain and are considered by patients to be the primary burden of the disease. Mutations of NF1, encoding a negative regulator of the RAS signaling pathway, in the Schwann cell (SCs) lineage are considered to be at the origin of cNFs. The mechanisms governing cNFs development are poorly understood, and therapeutics to reduce cNFs are missing, mainly due to the lack of appropriate animal models. To address this, we designed the Nf1-KO mouse model that develops cNFs. Using this model, we found that cNFs development is a singular event and goes through 3 successive stages: initiation, progression, and stabilization characterized by changes in the proliferative and MAPK activities of tumor SCs. We found that skin trauma accelerated the development of cNFs and further used this model to explore the efficacy of the MEK inhibitor binimetinib to cure these tumors. We showed that while topically delivered binimetinib has a selective and minor effect on mature cNFs, the same drug prevents their development over long periods.
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Neurofibroma , Neurofibromatosis 1 , Neoplasias Cutáneas , Humanos , Ratones , Animales , Neurofibromatosis 1/tratamiento farmacológico , Neurofibromatosis 1/genética , Neurofibromatosis 1/metabolismo , Neurofibroma/tratamiento farmacológico , Neurofibroma/genética , Bencimidazoles , Neoplasias Cutáneas/tratamiento farmacológico , Neoplasias Cutáneas/genética , Neoplasias Cutáneas/prevención & control , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Quinasas Activadas por MitógenosRESUMEN
Neurofibromatosis type 1 is one of the most common genetic disorders of the nervous system and predisposes patients to develop benign and malignant tumors. Cutaneous neurofibromas (cNFs) are NF1-associated benign tumors that affect nearly 100% of patients with NF1. cNFs dramatically reduce patients' QOL owing to their unaesthetic appearance, physical discomfort, and corresponding psychological burden. There is currently no effective drug therapy option, and treatment is restricted to surgical removal. One of the greatest hurdles for cNF management is the variability of clinical expressivity in NF1, resulting in intrapatient and interpatient cNF tumor burden heterogeneity, that is, the variability in the presentation and evolution of these tumors. There is growing evidence that a wide array of factors are involved in the regulation of cNF heterogeneity. Understanding the mechanisms underlying this heterogeneity of cNF at the molecular, cellular, and environmental levels can facilitate the development of innovative and personalized treatment regimens.
Asunto(s)
Neurofibroma , Neurofibromatosis 1 , Neoplasias Cutáneas , Humanos , Neurofibromatosis 1/genética , Neurofibromatosis 1/terapia , Calidad de Vida , Carga Tumoral , Neurofibroma/genética , Neoplasias Cutáneas/genéticaRESUMEN
Neurofibromatosis type 1 (NF1) is caused by a nonfunctional copy of the NF1 tumor suppressor gene that predisposes patients to the development of cutaneous neurofibromas (cNFs), the skin tumor that is the hallmark of this condition. Innumerable benign cNFs, each appearing by an independent somatic inactivation of the remaining functional NF1 allele, form in nearly all patients with NF1. One of the limitations in developing a treatment for cNFs is an incomplete understanding of the underlying pathophysiology and limitations in experimental modeling. Recent advances in preclinical in vitro and in vivo modeling have substantially enhanced our understanding of cNF biology and created unprecedented opportunities for therapeutic discovery. We discuss the current state of cNF preclinical in vitro and in vivo model systems, including two- and three-dimensional cell cultures, organoids, genetically engineered mice, patient-derived xenografts, and porcine models. We highlight the models' relationship to human cNFs and how they can be used to gain insight into cNF development and therapeutic discovery.
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Neurofibroma , Neurofibromatosis 1 , Neoplasias Cutáneas , Ratones , Humanos , Animales , Porcinos , Neurofibromatosis 1/genética , Neurofibromatosis 1/terapia , Mutación , Neurofibroma/genética , Neoplasias Cutáneas/genética , Neoplasias Cutáneas/patología , AlelosRESUMEN
Neurofibromatosis type I (NF1) microdeletion syndrome, accounting for 5-11% of NF1 patients, is caused by the heterozygous deletion of NF1 and a variable number of flanking genes in the 17q11.2 region. This syndrome is characterized by more severe symptoms than those shown by patients with intragenic NF1 mutation and by variable expressivity, which is not fully explained by the haploinsufficiency of the genes included in the deletions. We here reevaluate an 8-year-old NF1 patient, who carries an atypical deletion generating the RNF135-SUZ12 chimeric gene, previously described when he was 3 years old. As the patient has developed multiple cutaneous/subcutaneous neurofibromas over the past 5 years, we hypothesized a role of RNF135-SUZ12 chimeric gene in the onset of the patient's tumor phenotype. Interestingly, SUZ12 is generally lost or disrupted in NF1 microdeletion syndrome and frequently associated to cancer as RNF135. Expression analysis confirmed the presence of the chimeric gene transcript and revealed hypo-expression of five out of the seven analyzed target genes of the polycomb repressive complex 2 (PRC2), to which SUZ12 belongs, in the patient's peripheral blood, indicating a higher transcriptional repression activity mediated by PRC2. Furthermore, decreased expression of tumor suppressor gene TP53, which is targeted by RNF135, was detected. These results suggest that RNF135-SUZ12 chimera may acquire a gain of function, compared with SUZ12 wild type in the PRC2 complex, and a loss of function relative to RNF135 wild type. Both events may have a role in the early onset of the patient's neurofibromas.
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Neurofibroma , Neurofibromatosis 1 , Masculino , Humanos , Neurofibromatosis 1/genética , Complejo Represivo Polycomb 2/genética , Neurofibroma/genética , Fenotipo , Mutación , Ubiquitina-Proteína Ligasas/genéticaRESUMEN
Neurofibromatosis type 1 (NF1) is one of the most common tumor-predisposing genetic disorders. Neurofibromas are NF1-associated benign tumors. A hallmark feature of neurofibromas is an abundant collagen-rich extracellular matrix (ECM) that constitutes more than 50% of the tumor dry weight. However, little is known about the mechanism underlying ECM deposition during neurofibroma development and treatment response. We performed a systematic investigation of ECM enrichment during plexiform neurofibroma (pNF) development and identified basement membrane (BM) proteins, rather than major collagen isoforms, as the most upregulated ECM component. Following MEK inhibitor treatment, the ECM profile displayed an overall downregulation signature, suggesting ECM reduction as a therapeutic benefit of MEK inhibition. Through these proteomic studies, TGF-ß1 signaling was identified as playing a role in ECM dynamics. Indeed, TGF-ß1 overexpression promoted pNF progression in vivo. Furthermore, by integrating single-cell RNA sequencing, we found that immune cells including macrophages and T cells produce TGF-ß1 to induce Schwann cells to produce and deposit BM proteins for ECM remodeling. Following Nf1 loss, neoplastic Schwann cells further increased BM protein deposition in response to TGF-ß1. Our data delineate the regulation governing ECM dynamics in pNF and suggest that BM proteins could serve as biomarkers for disease diagnosis and treatment response.
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Neurofibroma , Neurofibromatosis 1 , Humanos , Neurofibromatosis 1/tratamiento farmacológico , Neurofibromatosis 1/genética , Neurofibromatosis 1/complicaciones , Factor de Crecimiento Transformador beta1/genética , Factor de Crecimiento Transformador beta1/metabolismo , Proteínas de la Membrana/metabolismo , Proteómica , Neurofibroma/tratamiento farmacológico , Neurofibroma/genética , Inhibidores de Proteínas Quinasas , Colágeno/metabolismo , Membrana Basal/metabolismo , Membrana Basal/patología , Matriz Extracelular/metabolismo , Quinasas de Proteína Quinasa Activadas por Mitógenos , Células de Schwann/patologíaRESUMEN
BACKGROUND: Plexiform 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. METHODS: We investigated 40 tumors histologically diagnosed as ANF and compared their global methylation profile to other peripheral nerve sheath tumors. RESULTS: Unsupervised 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. CONCLUSIONS: Our 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.
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Neoplasias de la Vaina del Nervio , Neurilemoma , Neurofibroma , Neurofibromatosis , Neurofibromatosis 1 , Neurofibrosarcoma , Humanos , Neurofibromatosis 1/patología , Neurofibrosarcoma/genética , Neurofibroma/genética , Neurofibroma/patología , Neoplasias de la Vaina del Nervio/genética , Neoplasias de la Vaina del Nervio/patología , Neurofibromatosis/genética , Neurilemoma/genética , Neurilemoma/patología , Epigénesis GenéticaRESUMEN
Neurofibromatosis type 1 (NF1) is a genetic condition commonly associated with a predisposition to tumor development. Affected individuals have an increased risk of benign and malignant tumors of the central and peripheral nervous system. Though pediatric patients with NF1 have an increased risk of tumors such as optic gliomas and neurofibromas during childhood, neuroblastic tumors are less often observed in this population. We report a rare case of a 5-year-old female with ganglioneuroblastoma intermixed and known history of NF1 and review the existing literature on the occurrence of ganglioneuroblastoma in pediatric patients with NF1.
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Ganglioneuroblastoma , Neurofibroma , Neurofibromatosis 1 , Glioma del Nervio Óptico , Femenino , Humanos , Niño , Preescolar , Neurofibromatosis 1/genética , Neurofibroma/complicaciones , Neurofibroma/genética , GenotipoRESUMEN
Neurofibromatosis type 1 (NF1) is a neurocutaneous condition with an autosomal dominant pattern of inheritance. This congenital disease is characterized by a wide spectrum of clinical manifestations and degree of severity. This case report describes a female patient in her early 20s who presented with a complaint of lumbosciatica-like pain evolving for several months. The condition initially escaped the attention of clinicians until a lumbar computed tomography scan and spinal magnetic resonance imaging were performed. The patient was then transferred to the general surgery department, where a clinical diagnosis of NF1 was established. The clinical manifestations were specific for this disease, including café-au-lait macules, plexiform neurofibroma, and a history of neurofibromatosis in her mother. The patient underwent surgical resection of the neurofibroma, which resulted in a favorable outcome. However, 2 years later, a new mass attached to the second lumbar spinal nerve was revealed by a follow-up computed tomography scan. Long-term and close follow-up of NF1 is required because of the high risk of malignancy and recurrence in NF1 patients.
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Neurofibroma , Neurofibromatosis , Neurofibromatosis 1 , Humanos , Femenino , Neurofibromatosis 1/complicaciones , Neurofibromatosis 1/diagnóstico por imagen , Neurofibromatosis 1/genética , Manchas Café con Leche/diagnóstico , Manchas Café con Leche/patología , Neurofibroma/diagnóstico por imagen , Neurofibroma/genética , Neurofibroma/cirugía , Imagen por Resonancia MagnéticaRESUMEN
ABSTRACT: Neurofibroma is a benign tumor originating from Schwann cells. It is diagnosed as a symptom of neurofibromatosis type 1 (NF1) or solitary neurofibroma. Neurofibromatosis type 1 belongs to a class of hereditary diseases, whereas solitary neurofibroma is not. Presence of germline NF1 gene mutations can be used to distinguish the 2 conditions. However, due to false negative results in gene tests, NF1 may be misdiagnosed as solitary neurofibroma. This calls for development of more accurate diagnostic methods. The authors report 2 patients with neurofibroma who required surgery and fertility consulting. using primary cell culture and next-generation sequencing experiments, the authors found NF1 mutation in neurofibroma Schwann cells. But this mutation was not exit in peripheral blood, hence demonstrate this NF1 mutation was somatic rather than germline. These results confirmed the diagnosis of solitary neurofibroma rather than NF1. The presented method is, therefore, suitable for fertility consultation and diagnosis of solitary neurofibroma patient.
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Neurofibroma , Neurofibromatosis 1 , Mutación de Línea Germinal , Humanos , Mutación , Neurofibroma/diagnóstico , Neurofibroma/genética , Neurofibroma/cirugía , Neurofibromatosis 1/diagnóstico , Células de Schwann/patologíaRESUMEN
ABSTRACT: We present an extraordinary case of metastatic cutaneous melanoma to a pre-existing neurofibroma in a 75-year-old man with a history of primary invasive melanoma in an anatomically close vicinity. Histological examination of the metastatic melanoma showed a well-circumscribed intradermal nodule of frankly malignant epithelioid melanocytes without an intraepidermal component, surrounded and sharply demarcated from a diffuse spindle cell proliferation with morphological features of a neurofibroma. The spindle cell component showed bland cytologic features, with no mitotic activity or lymphocytic inflammation and no features of malignancy. By immunohistochemistry, both components expressed S100, while HMB45 positivity and complete loss of p16 were only observed in the epithelioid cells. The morphologically distinct areas were analyzed by fluorescent in situ hybridization, which demonstrated an abnormal profile (gain of RREB1 and homozygous loss of CDKN2A) in the epithelioid nodule; however, no abnormalities were detected in the spindle cell component. Next-generation sequencing showed somatic NRAS and PTEN mutations in the melanoma cells only. The overall molecular findings supported the immunomorphological diagnosis of metastatic melanoma within a neurofibroma over the potential differential diagnosis of melanoma with a neurofibroma-like spindle/desmoplastic component.
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Melanoma , Neoplasias Primarias Secundarias , Neurofibroma , Neoplasias Cutáneas , Anciano , Humanos , Hibridación Fluorescente in Situ , Masculino , Melanoma/patología , Neurofibroma/genética , Neoplasias Cutáneas/patología , Melanoma Cutáneo MalignoRESUMEN
Neurofibromatosis type 1 (NF1) is characterized by nerve tumors called neurofibromas, in which Schwann cells (SCs) show deregulated RAS signaling. NF1 is also implicated in regulation of cAMP. We identified the G-protein-coupled receptor (GPCR) P2ry14 in human neurofibromas, neurofibroma-derived SC precursors (SCPs), mature SCs, and mouse SCPs. Mouse Nf1-/- SCP self-renewal was reduced by genetic or pharmacological inhibition of P2ry14. In a mouse model of NF1, genetic deletion of P2ry14 rescued low cAMP signaling, increased mouse survival, delayed neurofibroma initiation, and improved SC Remak bundles. P2ry14 signals via Gi to increase intracellular cAMP, implicating P2ry14 as a key upstream regulator of cAMP. We found that elevation of cAMP by either blocking the degradation of cAMP or by using a P2ry14 inhibitor diminished NF1-/- SCP self-renewal in vitro and neurofibroma SC proliferation in in vivo. These studies identify P2ry14 as a critical regulator of SCP self-renewal, SC proliferation, and neurofibroma initiation.