scholarly journals Distinctive epigenomic alterations in NF1-deficient cutaneous and plexiform neurofibromas drive differential MKK/P38 signaling

2019 ◽  
Author(s):  
Jamie L. Grit ◽  
Benjamin K. Johnson ◽  
Patrick S. Dischinger ◽  
Curt J. Essenburg ◽  
Stacy Campbell ◽  
...  
Keyword(s):  
Conformational Changes ◽  
Trp Channels ◽  
Transcriptome Profiling ◽  
Neurofibromatosis Type ◽  
Mapk Signaling ◽  
Ras Signaling ◽  
Clinical Behavior ◽  
Plexiform Neurofibromas ◽  
Cellular Processes ◽  
Peripheral Nerve Sheath Tumors

ABSTRACTBenign peripheral nerve sheath tumors are the clinical hallmark of Neurofibromatosis Type 1. They account for substantial morbidity in NF1 and are difficult to manage. Cutaneous (CNF) and plexiform neurofibromas (PNF) share identical histology, but maintain different growth rates and risk of malignant conversion. The reasons for their disparate clinical behavior are not well explained on the basis of recent genome or transcriptome profiling studies. We hypothesized that CNFs and PNFs are epigenetically distinct tumor types that exhibit differential signaling due to genome-wide and site-specific methylation events. We interrogated the methylation profiles of 45 CNFs and 17 PNFs (Illumina EPIC 850K) using normal tissue controls from NF1 subjects. Based on these profiles, we confirm that CNFs and PNFs are epigenetically distinct tumors with broad differences in higher order chromatin states, and specific methylation events altering genes involved in key biological and cellular processes such as inflammatory mediator regulation of TRP channels, RAS/MAPK signaling, actin cytoskeleton rearrangement, and oxytocin signaling. Based our identification of 2 separate DMRs associated with alternative leading exons in MAP2K3, we demonstrate differential RAS/MKK3/P38 signaling between CNFs and PNFs. Epigenetic reinforcement of RAS/MKK/P38 was a defining characteristic of CNFs leading to pro-inflammatory signaling and chromatin conformational changes, whereas PNFs signaled predominantly through RAS/ERK. Tumor size also correlated with specific CpG methylation events. Taken together, these findings confirm that epigenetic regulation of RAS signaling fates accounts for observed differences in CNF and PNF clinical behavior. CNFs may also respond differently than PNFs to RAS-targeted therapeutics raising the possibility of targeting P38-mediated inflammation for CNF treatment.

scholarly journals Distinctive epigenomic alterations in NF1-deficient cutaneous and plexiform neurofibromas drive differential MKK/p38 signaling

2021 ◽  
Vol 14 (1) ◽  
Author(s):  
Jamie L. Grit ◽  
Benjamin K. Johnson ◽  
Patrick S. Dischinger ◽  
Curt J. Essenburg ◽  
Marie Adams ◽  
...  
Keyword(s):  
Conformational Changes ◽  
Transcriptome Profiling ◽  
Neurofibromatosis Type ◽  
Mapk Signaling ◽  
Ras Signaling ◽  
Methylation Array ◽  
Clinical Behavior ◽  
Plexiform Neurofibromas ◽  
Cellular Processes ◽  
Peripheral Nerve Sheath Tumors

AbstractBenign peripheral nerve sheath tumors are the clinical hallmark of Neurofibromatosis Type 1. They account for substantial morbidity and mortality in NF1. Cutaneous (CNF) and plexiform neurofibromas (PNF) share nearly identical histology, but maintain different growth rates and risk of malignant conversion. The reasons for this disparate clinical behavior are not well explained by recent genome or transcriptome profiling studies. We hypothesized that CNFs and PNFs are epigenetically distinct tumor types that exhibit differential signaling due to genome-wide and site-specific methylation events. We interrogated the methylation profiles of 45 CNFs and 17 PNFs from NF1 subjects with the Illumina EPIC 850K methylation array. Based on these profiles, we confirm that CNFs and PNFs are epigenetically distinct tumors with broad differences in higher-order chromatin states and specific methylation events altering genes involved in key biological and cellular processes, such as inflammation, RAS/MAPK signaling, actin cytoskeleton rearrangement, and oxytocin signaling. Based on our identification of two separate DMRs associated with alternative leading exons in MAP2K3, we demonstrate differential RAS/MKK3/p38 signaling between CNFs and PNFs. Epigenetic reinforcement of RAS/MKK/p38 was a defining characteristic of CNFs leading to pro-inflammatory signaling and chromatin conformational changes, whereas PNFs signaled predominantly through RAS/MEK. Tumor size also correlated with specific CpG methylation events. Taken together, these findings confirm that NF1 deficiency influences the epigenetic regulation of RAS signaling fates, accounting for observed differences in CNF and PNF clinical behavior. The extension of these findings is that CNFs may respond differently than PNFs to RAS-targeted therapeutics raising the possibility of targeting p38-mediated inflammation for CNF treatment.

scholarly journals Distinctive Epigenomic Alterations in NF1-deficient Cutaneous and Plexiform Neurofibromas Drive Differential MKK/p38 Signaling

2020 ◽  
Author(s):  
Jamie L. Grit ◽  
Benjamin K. Johnson ◽  
Patrick S. Dischinger ◽  
Curt J. Essenburg ◽  
Marie Adams ◽  
...  
Keyword(s):  
Conformational Changes ◽  
Transcriptome Profiling ◽  
Neurofibromatosis Type ◽  
Mapk Signaling ◽  
Ras Signaling ◽  
Methylation Array ◽  
Clinical Behavior ◽  
Plexiform Neurofibromas ◽  
Cellular Processes ◽  
Peripheral Nerve Sheath Tumors

Abstract Benign peripheral nerve sheath tumors are the clinical hallmark of Neurofibromatosis Type 1. They account for substantial morbidity and mortality in NF1. Cutaneous (CNF) and plexiform neurofibromas (PNF) share nearly identical histology but maintain different growth rates and risk of malignant conversion. The reasons for this disparate clinical behavior are not well explained by recent genome or transcriptome profiling studies. We hypothesized that CNFs and PNFs are epigenetically distinct tumor types that exhibit differential signaling due to genome-wide and site-specific methylation events. We interrogated the methylation profiles of 45 CNFs and 17 PNFs from NF1 subjects with the Illumina EPIC 850K methylation array. Based on these profiles, we confirm that CNFs and PNFs are epigenetically distinct tumors with broad differences in higher order chromatin states and specific methylation events altering genes involved in key biological and cellular processes, such as inflammation, RAS/MAPK signaling, actin cytoskeleton rearrangement, and oxytocin signaling. Based on our identification of two separate DMRs associated with alternative leading exons in MAP2K3, we demonstrate differential RAS/MKK3/p38 signaling between CNFs and PNFs. Epigenetic reinforcement of RAS/MKK/p38 was a defining characteristic of CNFs leading to pro-inflammatory signaling and chromatin conformational changes, whereas PNFs signaled predominantly through RAS/MEK. Tumor size also correlated with specific CpG methylation events. Taken together, these findings confirm that NF1 deficiency influences the epigenetic regulation of RAS signaling fates, accounting for observed differences in CNF and PNF clinical behavior. The extension of these findings is that CNFs may respond differently than PNFs to RAS-targeted therapeutics raising the possibility of targeting p38-mediated inflammation for CNF treatment.

Trametinib Induces Neurofibroma Shrinkage and Enables Surgery

2019 ◽  
Vol 50 (05) ◽  
pp. 300-303 ◽  
Author(s):  
Pia Vaassen ◽  
Nikola Dürr ◽  
Andreas Röhrig ◽  
Rainer Willing ◽  
Thorsten Rosenbaum
Keyword(s):  
Vertebral Column ◽  
Plexiform Neurofibroma ◽  
Neurofibromatosis Type ◽  
Mek Inhibitor ◽  
Suppressor Gene ◽  
Complete Disappearance ◽  
Therapeutic Success ◽  
Mek Inhibitors ◽  
Plexiform Neurofibromas ◽  
Peripheral Nerve Sheath Tumors

AbstractPlexiform neurofibromas are congenital peripheral nerve sheath tumors characteristic of neurofibromatosis type 1 (NF1)—a frequent neurocutaneous disorder caused by mutations of the NF1 tumor suppressor gene. Since plexiform neurofibromas are a major cause of the burden of disease and may also progress to malignancy, many efforts have been undertaken to find a cure for these tumors. However, neither surgery nor medication has so far produced a breakthrough therapeutic success. Recently, a clinical phase I study reported significant shrinkage of plexiform neurofibromas following treatment with the MEK inhibitor selumetinib. Here, we report an 11-year-old NF1 patient with a large plexiform neurofibroma of the neck that had led to a sharp-angled kinking of the cervical spine and subsequent myelopathy. Although surgical stabilization of the cervical vertebral column was urgently recommended, the vertebral column was inaccessible due to extensive tumor growth. In this situation, treatment with the MEK inhibitor trametinib was initiated which resulted in a 22% reduction in tumor volume after 6 months of therapy and finally enabled surgery. These data show that MEK inhibitors may not lead to complete disappearance of NF1-associated plexiform neurofibromas but can be an essential step in a multimodal therapeutic approach for these tumors. The course of our patient suggests that MEK inhibitors are likely to play a significant role in providing a cure for one of the most devastating manifestations of NF1.

scholarly journals Neurofibromatosis Type 1 and tumorigenesis: molecular mechanisms and therapeutic implications

2010 ◽  
Vol 28 (1) ◽  
pp. E8 ◽  
Author(s):  
Oren N. Gottfried ◽  
David H. Viskochil ◽  
William T. Couldwell
Keyword(s):  
Neurofibromatosis Type 1 ◽  
Molecular Mechanisms ◽  
Mapk Pathway ◽  
Neurofibromatosis Type ◽  
Germline Mutations ◽  
Tumor Formation ◽  
Mitogen Activated Protein Kinase ◽  
Ras Signaling ◽  
Peripheral Nerve Sheath Tumors

Neurofibromatosis Type 1 (NF1) is a common autosomal dominant disease characterized by complex and multicellular neurofibroma tumors, and less frequently by malignant peripheral nerve sheath tumors (MPNSTs) and optic nerve gliomas. Significant advances have been made in elucidating the cellular, genetic, and molecular biology involved in tumor formation in NF1. Neurofibromatosis Type 1 is caused by germline mutations of the NF1 tumor suppressor gene, which generally result in decreased intracellular neurofibromin protein levels, leading to increased cascade Ras signaling to its downstream effectors. Multiple key pathways are involved with the development of tumors in NF1, including Ras/mitogen-activated protein kinase (MAPK) and Akt/mammalian target of rapamycin (mTOR). Interestingly, recent studies demonstrate that multiple other developmental syndromes (in addition to NF1) share phenotypic features resulting from germline mutations in genes responsible for components of the Ras/MAPK pathway. In general, a somatic loss of the second NF1 allele, also referred to as loss of heterozygosity, in the progenitor cell, either the Schwann cell or its precursor, combined with haploinsufficiency in multiple supporting cells is required for tumor formation. Importantly, a complex series of interactions with these other cell types in neurofibroma tumorigenesis is mediated by abnormal expression of growth factors and their receptors and modification of gene expression, a key example of which is the process of recruitment and involvement of the NF1+/– heterozygous mast cell. In general, for malignant transformation to occur, there must be accumulation of additional mutations of multiple genes including INK4A/ARF and P53, with resulting abnormalities of their respective signal cascades. Further, abnormalities of the NF1 gene and molecular cascade described above have been implicated in the tumorigenesis of NF1 and some sporadically occurring gliomas, and thus, these treatment options may have wider applicability. Finally, increased knowledge of molecular and cellular mechanisms involved with NF1 tumorigenesis has led to multiple preclinical and clinical studies of targeted therapy, including the mTOR inhibitor rapamycin, which is demonstrating promising preclinical results for treatment of MPNSTs and gliomas.

Neurofibromatosis Type 1: Cognitive and Behavioral Phenotype: Diagnosis and Treatment

2010 ◽  
Author(s):  
Maria T. Acosta
Keyword(s):  
Peripheral Nerve ◽  
Neurofibromatosis Type 1 ◽  
Clinical Manifestations ◽  
Neurofibromatosis Type ◽  
Academic Difficulties ◽  
Plexiform Neurofibromas ◽  
Nerve Sheath Tumors ◽  
Peripheral Nerve Sheath Tumors ◽  
Nerve Sheath

Neurofibromatosis type 1 (Nf1) is a neurocutaneous disorder with a prevalence of approximately 1 in 2,500–3,500 individuals (Ferner et al. 2007). The physical manifestations of Nf1, such as café au lait spots, axillary freckling, iris hamartomas (Lisch nodules), osseous lesions (sphenoid wing dysplasia, pseudoarthrosis), and benign as well as malignant neural tumors (neurofibromas, optic gliomas), are well recognized (Castle et al. 2003; Ferner et al. 2007). National Institutes of Health (NIH) criteria are currently used for clinical diagnosis (1988) (Table 31.1). The clinical severity of this disorder is quite variable, and approximately 20% of children with Nf1 will later have considerable physical complications (Castle et al. 2003; Ferner et al. 2007; Williams et al. 2009). Other clinical manifestations are abnormalities of the cardiovascular, gastrointestinal, renal, and endocrine systems, facial and body disfigurement, cognitive deficit, and malignancies of the peripheral nerve sheath and central nervous system. The tumors that occur in Nf1 are dermal and plexiform neurofibromas, optic gliomas, malignant peripheral nerve sheath tumors (MPNSTs), pheochromocytomas, and rhabdomyosarcomas (Castle et al. 2003). Children with Nf1 have an increased risk of developing myeloid disease, particularly juvenile chronic myeloid leukemia. Some 30%–40% of Nf1 patients develop plexiform neurofibromas (Szudek, Evans, and Friedman 2003). Malignant peripheral nerve sheath tumors are present in 5%–10% of cases (Evans et al. 2002), often in preexisting plexiform neurofibromas (Castle et al. 2003). Although many see the predisposition to cancer as the major concern regarding Nf1, some of the more prevalent features are not directly related to tumors (Acosta, Gioia, and Silva 2006). Cognitive dysfunction, academic difficulties, and school failure, occur in 40%–80% (Hyman, Arthur, and North 2006; Krab et al. 2008; North et al. 1997). These complications affect the day-to-day life of these children, and are the largest cause of lifetime morbidity in the pediatric Nf1 population (Acosta et al. 2006). These deficits impact on long-term adaptation to society (Acosta et al. 2006; Barton and North 2007; Krab et al. 2008; Krab et al. 2009).

scholarly journals NFB-14. PSYCHOSOCIAL OUTCOMES IN CHILDREN WITH NEUROFIBROMATOSIS TYPE 1 AND PLEXIFORM NEUROFIBROMAS

2020 ◽  
Vol 22 (Supplement_3) ◽  
pp. iii420-iii420
Author(s):  
Sudarshawn Damodharan ◽  
Paige Mission ◽  
Diane Puccetti
Keyword(s):  
Neurofibromatosis Type 1 ◽  
Phenotypic Variability ◽  
Case Series ◽  
Neurofibromatosis Type ◽  
Attention Problems ◽  
Social Emotional ◽  
Plexiform Neurofibromas ◽  
Peripheral Nerve Sheath Tumors ◽  
Wide Range

Abstract OBJECTIVE This case series seeks to examine neurocognitive outcomes, social-emotional functioning, and family burden in young children diagnosed with Neurofibromatosis, type 1 (NF1) with early growing plexiform neurofibromas (PNFs). BACKGROUND Neurofibromatosis, type 1 (NF1) is a common predisposing chronic disease arising in early childhood, with an incidence of approximately 1:3000. Though NF1 displays a wide range of phenotypic variability, the primary feature of the disease is peripheral nerve sheath tumors called neurofibromas. Less is well known regarding the broader neurocognitive and social-emotional profile in presentations with more complex tumor growths, namely PNFs, which are present in at least half of the NF1-affected population. METHODS Participants with NF1 and PNFs (n=2) aged 6-7years completed comprehensive neuropsychological evaluations and parents completed measures of quality of life, social-emotional/behavioral functioning of child, parental stress, family adaptability, and family cohesion. RESULTS Outcomes suggest broad neurocognitive dysfunction (e.g., executive functioning deficits, attention problems, visual-motor delays, and poor motor coordination), social-emotional challenges (e.g., symptoms of anxiety and depression, and poor social skills), and familial distress. CONCLUSIONS Findings indicate the value of early and frequent monitoring of children with PNFs in medical systems and multi-disciplinary teams, and the importance of early intervention for both children and families.

scholarly journals Whole-body MRI Evaluation in Neurofibromatosis type 1 Patients Younger than 3 Years Old and the Genetic Contribution to Disease Progression

2021 ◽  
Author(s):  
Eungu Kang ◽  
Yoon-Myung Kim ◽  
Yunha Choi ◽  
Yena Lee ◽  
JunYoung Kim ◽  
...  
Keyword(s):  
Disease Progression ◽  
Neurofibromatosis Type 1 ◽  
Neurofibromatosis Type ◽  
Whole Body ◽  
Optic Pathway Glioma ◽  
Optic Pathway ◽  
Genetic Contribution ◽  
Plexiform Neurofibromas ◽  
Peripheral Nerve Sheath Tumors

Abstract Background: Neurofibromatosis type 1 (NF1) is a common human genetic disease with age-dependent phenotype progression. The overview of clinical and radiological findings evaluated by whole-body magnetic resonance imaging (WBMRI) in NF1 patients <3 years old assessed with a genetic contribution to disease progression is presented herein.Methods: This study included 70 clinically or genetically diagnosed NF1 patients who received WBMRI before 3 years old. Clinical, genetic, and radiologic features were collected by retrospective chart review. In NF1+, widely spread diffuse cutaneous neurofibromas, developmental delay, autism, seizure, cardiac abnormalities, hearing defect, optic pathway glioma, severe plexiform neurofibromas (>3 cm in diameter, disfigurement, accompanying pain, bony destruction, or located para-aortic area), brain tumors, nerve root tumors, malignant peripheral nerve sheath tumors, moyamoya disease, and bony dysplasia were included.Results: The age at WBMRI was 1.6 ± 0.7 years old, and NF1 mutations were found in 66 patients (94.3%). Focal areas of signal intensity (FASI) were the most common WBMRI finding (66.1%), followed by optic pathway glioma (15.7%), spine dural ectasia (12.9%), and plexiform neurofibromas (10.0%). Plexiform neurofibromas and NF1+ were more prevalent in familial case (28.7% vs 5.7%, p = 0.030; 71.4% vs 30.2%, p = 0.011). Follow-up WBMRI was conducted in 42 patients (23 girls and 19 boys) after 1.21 ± 0.50 years. FASI and radiologic progression were more frequent in patients with mutations involving GTPase activating protein-related domain (77.8% vs 52.4%, p = 0.047; 46.2% vs 7.7%, p = 0.029).Conclusions: WBMRI provides important information for the clinical care for young pediatric NF1 patients. As NF1 progresses in even these young patients, and is related to family history and the affected NF1 domains, serial evaluation with WBMRI should be assessed based on the clinical and genetic features for the patients’ best care.

scholarly journals NCOG-14. PSYCHOSOCIAL OUTCOMES IN CHILDREN WITH NEUROFIBROMATOSIS TYPE 1 AND PLEXIFORM NEUROFIBROMAS

2020 ◽  
Vol 22 (Supplement_2) ◽  
pp. ii132-ii132
Author(s):  
Diane Puccetti ◽  
Paige Mission ◽  
Shawn Damodharan
Keyword(s):  
Neurofibromatosis Type 1 ◽  
Phenotypic Variability ◽  
Case Series ◽  
Neurofibromatosis Type ◽  
Attention Problems ◽  
Social Emotional ◽  
Plexiform Neurofibromas ◽  
Peripheral Nerve Sheath Tumors ◽  
Wide Range

Abstract OBJECTIVE This case series seeks to examine neurocognitive outcomes, social-emotional functioning, and family burden in young children diagnosed with Neurofibromatosis, type 1 (NF1) with early growing plexiform neurofibromas (PNFs). BACKGROUND Neurofibromatosis, type 1 (NF1) is a common predisposing chronic disease arising in early childhood, with an incidence of approximately 1:3000. Though NF1 displays a wide range of phenotypic variability, the primary feature of the disease is peripheral nerve sheath tumors called neurofibromas. Less is well known regarding the broader neurocognitive and social-emotional profile in presentations with more complex tumor growths, namely PNFs, which are present in at least half of the NF1-affected population. METHODS Participants with NF1 and PNFs (n=2) aged 6-7years completed comprehensive neuropsychological evaluations and parents completed measures of quality of life, social-emotional/behavioral functioning of child, parental stress, family adaptability, and family cohesion. RESULTS Outcomes suggest broad neurocognitive dysfunction (e.g., executive functioning deficits, attention problems, visual-motor delays, and poor motor coordination), social-emotional challenges (e.g., symptoms of anxiety and depression, and poor social skills), and familial distress. CONCLUSIONS Findings indicate the value of early and frequent monitoring of children with PNFs in medical systems and multi-disciplinary teams, and the importance of early intervention for both children and families.

scholarly journals EXTH-08. MINIPIG MODELS OF NEUROFIBROMATOSIS TYPE 1 FOR THERAPEUTIC DEVELOPMENT

2020 ◽  
Vol 22 (Supplement_2) ◽  
pp. ii88-ii88
Author(s):  
Adrienne Watson ◽  
Sara Osum ◽  
Mandy Taisto ◽  
Barbara Tschida ◽  
Dylan Duerre ◽  
...  
Keyword(s):  
Neurofibromatosis Type 1 ◽  
Nonsense Mutation ◽  
Plasma Concentrations ◽  
Neurofibromatosis Type ◽  
Mapk Signaling ◽  
Optic Pathway Glioma ◽  
Ras Signaling ◽  
Safety And Efficacy ◽  
Mek Inhibitors

Abstract Neurofibromatosis Type 1 (NF1) is a genetic disease caused by mutations in the neurofibromin 1 (NF1) gene. NF1 patients present with a variety of clinical manifestations and are predisposed to cancer development. Many NF1 animal models have been developed, yet none display the spectrum of disease seen in patients and the translational impact of these models has been limited. Using gene-editing technology, we have developed a minipig model of NF1 that exhibits clinical hallmarks of the disease, including café au lait macules, neurofibromas, and optic pathway glioma. We have conducted pharmacological studies in our NF1 minipigs to assess the pharmacokinetic and pharmacodynamic properties of MEK inhibitors for NF1. We have demonstrated that oral administration of several MEK inhibitors results in clinically relevant plasma concentrations and consequent inhibition of Ras signaling in immune cells, and certain MEK inhibitors can cross the blood brain barrier and have a pharmacodynamic effect, suggesting that they may be effective in treating NF1-associated brain tumors. Because over 20% of NF1 patients harbor NF1 nonsense mutations, we are assessing safety and efficacy of nonsense mutation suppressors that may be effective in treating NF1. We evaluated six drugs known to induce nonsense mutation suppression in several primary cell types isolated from NF1 minipigs and show that several of these drugs have the propensity to induce the production of full length neurofibromin protein, leading to a subsequent reduction in MAPK signaling. Information acquired from this NF1 minipig preclinical model will be leveraged towards initiating a clinical trial in NF1 patients. The NF1 minipig provides an unprecedented opportunity to study the complex biology and natural history of NF1 and could prove indispensable for development of imaging methods, biomarkers, and evaluation of safety and efficacy of NF1 therapies.

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