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Special Issue "Frontiers in Neurofibromatosis"

A special issue of Cancers (ISSN 2072-6694).

Deadline for manuscript submissions: 25 March 2023 | Viewed by 3008

Special Issue Editors

Dr. Staci Martin
E-Mail Website
Guest Editor
Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, 9030 Old Georgetown Road, #107, Bethesda, MD 20892, USA
Interests: pain; acceptance and commitment therapy; cognitive functioning; medication adherence
Dr. Geraldine O'Sullivan Coyne
E-Mail Website
Guest Editor
Developmental Therapeutics Clinics, Division of Cancer Treatment and Diagnosis, National Cancer Institute, 31 Center Drive, Room 3A44, Bethesda, MD 20892, USA
Interests: developmental therapeutics; biomarkers; rare tumors
Dr. Miriam Bornhorst
E-Mail Website
Guest Editor
Children’s National Health System, 111 Michigan Avenue Northwest, Washington, DC 20010, USA
Interests: optic pathway gliomas; metabolism; NF1, neurofibromas

Special Issue Information

Dear Colleagues, 

Neurofibromatoses (NF1, NF2, and schwannomatosis) are a group of genetic disorders that can cause cancerous and noncancerous tumors in addition to a variety of other physical, cognitive, and neurobehavioral manifestations. While recent treatment advances have been made for some NF-related symptoms, basic and clinical researchers should strive towards further progress in areas such as cutaneous neurofibromas, optic pathway gliomas, schwannomas, and others. Interventions for helping patients in coping with NF-associated learning disabilities, social impairments, and pain are also warranted. What is also of importance is understanding the most up-to-date techniques for measuring tumor volume and the relationship between tumor volume and functional outcomes. 

The goal of this Special Issue in Cancers is to highlight innovations in diagnosis, assessment, and treatment for neurofibromatoses and to point readers towards future research directions. We welcome original research, reviews, and editorials This may be an excellent opportunity for senior researchers to partner up with early-career investigators. We also encourage authors to consider healthcare disparities and/or how their findings apply to diverse patient populations.

Dr. Staci Martin
Dr. Geraldine O'Sullivan Coyne
Dr. Miriam Bornhorst
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Cancers is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2400 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • neurofibromatosis type 1
  • neurofibromatosis type 2
  • schwannomatosis
  • pain
  • psychosocial functioning
  • mouse models
  • optic pathway gliomas

Published Papers (4 papers)

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Research

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Article
Demographic and Disease-Related Predictors of Socioemotional Development in Children with Neurofibromatosis Type 1 and Plexiform Neurofibromas: An Exploratory Study
Cancers 2022, 14(23), 5956; https://doi.org/10.3390/cancers14235956 (registering DOI) - 01 Dec 2022
Abstract
Individuals with neurofibromatosis type 1 (NF1) and plexiform neurofibromas (PNs) have a higher risk for socioemotional problems. The current study aims to identify the socioemotional developmental pattern and its predictors across childhood and adolescence in individuals with NF1 and PNs. Participants included 88 [...] Read more.
Individuals with neurofibromatosis type 1 (NF1) and plexiform neurofibromas (PNs) have a higher risk for socioemotional problems. The current study aims to identify the socioemotional developmental pattern and its predictors across childhood and adolescence in individuals with NF1 and PNs. Participants included 88 children with NF1 and PNs (aged 6–18 years old, M = 12.05, SD = 3.62, 57% male) in a natural history study. Neuropsychological assessments were administered three times over six years. There are large variabilities in socioemotional development in the study participants. Developmental patterns varied across socioemotional domains, respondent type (parent-report [PR] vs. child-report [CR]), demographic factors, and NF1 disease-related factors. For instance, lower parental education was associated with a greater decline in internalizing problems (PR) but a greater increase in school disconnectedness (CR) over time. Non-White (vs. White) children were more likely to experience increased adaptive skills (PR) but decreased personal adjustment (CR). Children with more visible tumors experienced a greater decrease in school disconnectedness (CR). Children with more NF1 complications experienced a greater decrease in externalizing problems (PR). These findings indicate the necessity of using multi-informants and investigating subdomains of socioemotional functions. They also highlight the importance of developing individualized approaches to patient care and interventions. Full article
(This article belongs to the Special Issue Frontiers in Neurofibromatosis)
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Article
Knockdown of NCOR2 Inhibits Cell Proliferation via BDNF/TrkB/ERK in NF1-Derived MPNSTs
Cancers 2022, 14(23), 5798; https://doi.org/10.3390/cancers14235798 - 24 Nov 2022
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Abstract
(1) Background: malignant peripheral nerve sheath tumours (MPNSTs) are aggressive Schwann cell-derived sarcomas with dismal prognoses. Previous studies have shown that nuclear receptor corepressor 2 (NCOR2) plays a vital role in neurodevelopment and in various tumours. However, the impact of NCOR2 on the [...] Read more.
(1) Background: malignant peripheral nerve sheath tumours (MPNSTs) are aggressive Schwann cell-derived sarcomas with dismal prognoses. Previous studies have shown that nuclear receptor corepressor 2 (NCOR2) plays a vital role in neurodevelopment and in various tumours. However, the impact of NCOR2 on the progression of MPNST remains unclear. (2) Methods: by GEO database, MPNST tissue microarray, and NF1-related tumour tissues and cell lines were used to explore NCOR2 expression level in the MPNSTs. The role and mechanism of NCOR2 in NF1-derived MPNSTs were explored by experiments in vivo and in vitro and by transcriptome high-throughput sequencing. (3) Results: NCOR2 expression is significantly elevated in NF1-derived MPNSTs and is associated with patient 10-year survival time. Knockdown of NCOR2 suppressed NF1-derived MPNST cell proliferation by blocking the cell cycle in the G0/G1 phase. Moreover, decreased NCOR2 expression could down-regulate MAPK signal activity through the BDNF/TrkB pathway. (4) Conclusions: our findings demonstrated that NCOR2 expression is significantly elevated in NF1-derived MPNSTs. NCOR2 knockdown can inhibit NF1-derived MPNST cell proliferation by weakened BDNF/TrkB/ERK signalling. Targeting NF1-derived MPNSTs with TrkB inhibitors, or in combination with ERK inhibitors, may be a novel therapeutic strategy for clinical trials. Full article
(This article belongs to the Special Issue Frontiers in Neurofibromatosis)
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Article
Mutation of PTPN11 (Encoding SHP-2) Promotes MEK Activation and Malignant Progression in Neurofibromin-Deficient Cells in a Manner Sensitive to BRAP Mutation
Cancers 2022, 14(10), 2377; https://doi.org/10.3390/cancers14102377 - 12 May 2022
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Abstract
Germline mutations of NF1 cause neurofibromatosis type 1 (NF1) through the activation of the RAS signaling pathway, and some NF1 patients develop malignant peripheral nerve sheath tumors (MPNSTs). Here, we established subclones of the human NF1-MPNST cell line sNF96.2 that [...] Read more.
Germline mutations of NF1 cause neurofibromatosis type 1 (NF1) through the activation of the RAS signaling pathway, and some NF1 patients develop malignant peripheral nerve sheath tumors (MPNSTs). Here, we established subclones of the human NF1-MPNST cell line sNF96.2 that manifest increased tumorigenic activity and increased phosphorylation of the protein kinases MEK and Akt relative to the parental cells. Genomic DNA sequencing identified 14 additional heterozygous mutations within the coding regions of 13 cancer- and other disease-related genes in these subclones. One of these genes, PTPN11, encodes SHP-2, and the forced expression of the identified G503V mutant of SHP-2 increased both tumorigenic activity and MEK phosphorylation in parental sNF96.2 cells, suggesting that the combination of PTPN11 and NF1 mutations induces the pathological activation of the RAS pathway. These effects of SHP-2 (G503V) were inhibited by the coexpression of the G370A mutant of BRAP, which was also detected in the highly malignant subclones, and this inhibition was accompanied by the calpain-dependent cleavage of SHP-2 (G503V). The cleavage of SHP-2 (G503V) and suppression of MEK phosphorylation mediated by BRAP (G370A) were not detected in NF1-intact (HeLa) cells. Tumor promotion by SHP-2 (G503V) and its suppression by BRAP (G370A) may serve as a basis for the development of new treatment strategies for NF1. Full article
(This article belongs to the Special Issue Frontiers in Neurofibromatosis)
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Review

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Review
Neurofibroma Development in Neurofibromatosis Type 1: Insights from Cellular Origin and Schwann Cell Lineage Development
Cancers 2022, 14(18), 4513; https://doi.org/10.3390/cancers14184513 - 17 Sep 2022
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Abstract
Background: Neurofibromatosis type 1 (NF1), a genetic tumor predisposition syndrome that affects about 1 in 3000 newborns, is caused by mutations in the NF1 gene and subsequent inactivation of its encoded neurofibromin. Neurofibromin is a tumor suppressor protein involved in the downregulation of [...] Read more.
Background: Neurofibromatosis type 1 (NF1), a genetic tumor predisposition syndrome that affects about 1 in 3000 newborns, is caused by mutations in the NF1 gene and subsequent inactivation of its encoded neurofibromin. Neurofibromin is a tumor suppressor protein involved in the downregulation of Ras signaling. Despite a diverse clinical spectrum, one of several hallmarks of NF1 is a peripheral nerve sheath tumor (PNST), which comprises mixed nervous and fibrous components. The distinct spatiotemporal characteristics of plexiform and cutaneous neurofibromas have prompted hypotheses about the origin and developmental features of these tumors, involving various cellular transition processes. Methods: We retrieved published literature from PubMed, EMBASE, and Web of Science up to 21 June 2022 and searched references cited in the selected studies to identify other relevant papers. Original articles reporting the pathogenesis of PNSTs during development were included in this review. We highlighted the Schwann cell (SC) lineage shift to better present the evolution of its corresponding cellular origin hypothesis and its important effects on the progression and malignant transformation of neurofibromas. Conclusions: In this review, we summarized the vast array of evidence obtained on the full range of neurofibroma development based on cellular and molecular pathogenesis. By integrating findings relating to tumor formation, growth, and malignancy, we hope to reveal the role of SC lineage shift as well as the combined impact of additional determinants in the natural history of PNSTs. Full article
(This article belongs to the Special Issue Frontiers in Neurofibromatosis)
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Planned Papers

The below list represents only planned manuscripts. Some of these manuscripts have not been received by the Editorial Office yet. Papers submitted to MDPI journals are subject to peer-review.

Title: Neurofibromatosis- and Schwannomatosis- Associated Tumors: Approaches to Genetic Testing and Counseling
Authors: Allison Goetsch Weisman1,2; Shelly Weiss McQuaid1,2; Heather B. Radtke3,4; Jessica Stoll5; Bryce Brown6; Alicia Gomes6
Affiliation: 1 Ann & Robert H. Lurie Children’s Hospital of Chicago 2 Northwestern University Feinberg School of Medicine 3 Medical College of Wisconsin 4 Children’s Tumor Foundation 5 Tempus Labs, Inc. 6 University of Alabama at Birmingham
Abstract: Neurofibromatosis (NF) and schwannomatosis (SWN) are genetic conditions characterized by the development of nervous system tumors. Recently revised diagnostic criteria include the addition of genetic testing to confirm a pathogenic variant, as well as to detect the presence of mosaicism. Therefore, the use and interpretation of both germline and tumor-based testing have increasing importance in the diagnostic approach, treatment decisions, and risk stratification of these conditions. This focused review discusses approaches to genetic testing of NF- and SWN-related tumor types including gastrointestinal stromal tumors, plexiform neurofibromas with or without transformation to malignant peripheral nerve sheath tumors, and schwannomas, and emphasizes the need for appropriate pre- and post-test genetic counseling

Title: Pharmacologic Inhibition of Anaplastic Lymphoma Kinase to Treat Neurofibromatosis 1: Murine studies support improvement in cognitive function and sleep
Authors: Jacob Raber
Affiliation: Departments of Neurology and Radiation Medicine, Division of Neuroscience, ONPRC, Oregon Health & Science University, Portland, OR 97239, USA
Abstract: Neurofibromatosis 1, the most common single gene disease in humans, is caused by loss of function mutations in Neurofibromin. Genetic and biochemical investigations have established that Neurofibromin functions as a negative regulator of the ras-map kinase signaling cascade by catalyzing the inactivation of ras as a ras associated GTPase. The signaling pathways in which NF1 acts have been difficult to identify as the ras-map kinase cascade transduces signals via a variety of receptor tyrosine kinases. In the last decade, it has become clear that one of the signaling pathways critically regulated by NF1 is activation of the receptor tyrosine kinase Anaplastic Lymphoma Kinase (Alk). Studies initially in Drosophila and subsequently in mice have shown genetic and biochemical interactions between Alk signaling and NF1 in cognitive function, sleep, and regulation of body size. These interactions are pertinent to both developmental and adult phenotypes. We have studied the genetic interactions between Alk and NF1 in mice as well as the potential value of Alk inhibition in adults to reduce or even reverse behavioral phenotypes of Neurofibromatosis 1. We have shown that orally available small molecule inhibitors of Alk improve cognitive function and disordered sleep in heterozygous NF1 mice mutants. These data support the therapeutic potential of Alk inhibition to treat Neurofibromatosis in humans.

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