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The presence of Alternative lengthening of telomeres (ALT) and/or ATRX loss, as well as the role of other telomere abnormalities, have not been formally studied across the spectrum of NF1-associated solid tumors. Utilizing a telomere-specific FISH assay, we classified tumors as either ALT-positive or having long (without ALT), short, or normal telomere lengths. A total of 426 tumors from 256 NF1 patients were evaluated, as well as 99 MPNST tumor samples that were sporadic or of unknown NF1 status. In the NF1-glioma dataset, ALT was present in the majority of high-grade gliomas: 14 (of 23; 60%) in contrast to only 9 (of 47; 19%) low-grade gliomas (p = 0.0009). In the subset of ALT-negative glioma cases, telomere lengths were estimated and we observed 17 (57%) cases with normal, 12 (40%) cases with abnormally long, and only 1 (3%) case with short telomeres. In the NF1-associated malignant nerve sheath tumor (NF1-MPNST) set (n = 75), ALT was present in 9 (12%). In the subset of ALT-negative NF1-MPNST cases, telomeres were short in 9 (38%), normal in 14 (58%) and long in 1 (3%). In the glioma set, overall survival was significantly decreased for patients with ALT-positive tumors (p

Organized and hosted by the Children's Tumor Foundation (CTF), the Neurofibromatosis (NF) conference is the premier annual gathering for clinicians and researchers interested in neurofibromatosis type 1 (NF1), neurofibromatosis type 2 (NF2), and schwannomatosis (SWN). The 2016 edition constituted a blend of clinical and basic aspects of NF research that helped in clarifying different advances in the field. The incorporation of next generation sequencing is changing the way genetic diagnostics is performed for NF and related disorders, providing solutions to problems like genetic heterogeneity, overlapping clinical manifestations, or the presence of mosaicism. The transformation from plexiform neurofibroma (PNF) to malignant peripheral nerve sheath tumor (MPNST) is being clarified, along with new management and treatments for benign and premalignant tumors. Promising new cellular and in vivo models for understanding the musculoskeletal abnormalities in NF1, the development of NF2 or SWN associated schwannomas, and clarifying the cells that give rise to NF1-associated optic pathway glioma were presented. The interaction of neurofibromin and SPRED1 was described comprehensively, providing functional insight that will help in the interpretation of pathogenicity of certain missense variants identified in NF1 and Legius syndrome patients. Novel promising imaging techniques are being developed, as well as new integrative and holistic management models for patients that take into account psychological, social, and biological factors. Importantly, new therapeutic approaches for schwannomas, meningiomas, ependymomas, PNF, and MPNST are being pursued. This report highlights the major advances that were presented at the 2016 CTF NF conference.

The neurofibromatoses (NF) are autosomal dominant genetic disorders that encompass the rare diseases NF1, NF2, and schwannomatosis. The NFs affect more people worldwide than Duchenne muscular dystrophy and Huntington's disease combined. NF1 and NF2 are caused by mutations of known tumor suppressor genes (NF1 and NF2, respectively). For schwannomatosis, although mutations in SMARCB1 were identified in a subpopulation of schwannomatosis patients, additional causative gene mutations are still to be discovered. Individuals with NF1 may demonstrate manifestations in multiple organ systems, including tumors of the nervous system, learning disabilities, and physical disfigurement. NF2 ultimately can cause deafness, cranial nerve deficits, and additional severe morbidities caused by tumors of the nervous system. Unmanageable pain is a key finding in patients with schwannomatosis. Although today there is no marketed treatment for NF-related tumors, a significant number of clinical trials have become available. In addition, significant preclinical efforts have led to a more rational selection of potential drug candidates for NF trials. An important element in fueling this progress is the sharing of knowledge. For over 20 years the Children's Tumor Foundation has convened an annual NF Conference, bringing together NF professionals to share novel findings, ideas, and build collaborations. The 2012 NF Conference held in New Orleans hosted over 350 NF researchers and clinicians. This article provides a synthesis of the highlights presented at the conference and as such, is a "state-of-the-field" for NF research in 2012.

Neurofibromatosis type 1 (NF1), the most common tumor predisposition syndrome, occurs when NF1 gene variants result in loss of neurofibromin, a negative regulator of RAS activity. Plexiform neurofibromas (PN) are peripheral nerve sheath tumors that develop in patients with NF1 and are associated with substantial morbidity and for which, until recently, the only treatment was surgical resection. However, surgery carries several risks and a proportion of PN are considered inoperable. Understanding the genetic underpinnings of PN led to the investigation of targeted therapies as medical treatment options, and the MEK1/2 inhibitor selumetinib has shown promising efficacy in pediatric patients with NF1 and symptomatic, inoperable PN. In a phase I/II trial, most children (approximately 70%) achieved reduction in tumor volume accompanied by improvements in patient-reported outcomes (decreased tumor-related pain and improvements in quality of life, strength, and range of motion). Selumetinib is currently the only licensed medical therapy indicated for use in pediatric patients with symptomatic, inoperable NF1-PN, with approval based on the results of this pivotal clinical study. Several other MEK inhibitors (binimetinib, mirdametinib, trametinib) and the tyrosine kinase inhibitor cabozantinib are also being investigated as medical therapies for NF1-PN. Careful consideration of multiple aspects of both disease and treatments is vital to reduce morbidity and improve outcomes in patients with this complex and heterogeneous disease, and clinicians should be fully aware of the risks and benefits of available treatments. There is no single treatment pathway for patients with NF1-PN; surgery, watchful waiting, and/or medical treatment are options. Treatment should be individualized based on recommendations from a multidisciplinary team, considering the size and location of PN, effects on adjacent tissues, and patient and family preferences. This review outlines the treatment strategies currently available for patients with NF1-PN and the evidence supporting the use of MEK inhibitors, and discusses key considerations in clinical decision-making. [ABSTRACT FROM AUTHOR]

Nerve sheath tumors occur as a heterogeneous group of neoplasms in patients with neurofibromatosis type 1 (NF1). The malignant form represents the most common cause of death in people with NF1, and even when benign, these tumors can result in significant disfigurement, neurologic dysfunction, and a range of profound symptoms. Lack of human tissue across the peripheral nerve tumors common in NF1 has been a major limitation in the development of new therapies. To address this unmet need, we have created an annotated collection of patient tumor samples, patient-derived cell lines, and patient-derived xenografts, and carried out high-throughput genomic and transcriptomic characterization to serve as a resource for further biologic and preclinical therapeutic studies. In this work, we release genomic and transcriptomic datasets comprised of 55 tumor samples derived from 23 individuals, complete with clinical annotation. All data are publicly available through the NF Data Portal and at http://synapse.org/jhubiobank. Measurement(s) gene expression • gene_variant Technology Type(s) RNA sequencing • exome sequencing • DNA sequencing Factor Type(s) tumor type Sample Characteristic - Organism Homo sapiens • Homo sapiens/Mus musculus xenograft Machine-accessible metadata file describing the reported data: 10.6084/m9.figshare.12037599 [ABSTRACT FROM AUTHOR]

Schwannomatosis, a rare form of neurofibromatosis, is characterized predominantly by multiple, often painful, schwannomas throughout the peripheral nervous system. The current standard of care for schwannomatosis is surgical resection. A major obstacle to schwannomatosis research is the lack of robust tumor cell lines. There is a great need for mechanistic and drug discovery studies of schwannomatosis, yet appropriate tools are not currently available. Schwannomatosis tumors are difficult to grow in culture as they survive only a few passages before senescence. Our lab has extensive experience in establishing primary and immortalized human Schwann cell cultures from normal tissue that retain their phenotypes after immortalization. Therefore we took on the challenge of creating immortalized human Schwann cell lines derived from tumors from schwannomatosis patients. We have established and fully characterized 2 schwannomatosis cell lines from 2 separate patients using SV40 virus large T antigen. One patient reported pain and the other did not. The schwannomatosis cell lines were stained with S100B antibodies to confirm Schwann cell identity. The schwannomatosis cells also expressed the Schwann cell markers, p75NTR, S100B, and NGF after multiple passages. Cell morphology was retained following multiple passaging and freeze/ thaw cycles. Gene expression microarray analysis was used to compare the cell lines with their respective parent tumors. No differences in key genes were detected, with the exception that several cell cycle regulators were upregulated in the schwannomatosis cell lines when compared to their parent tumors. This upregulation was apparently a product of cell culturing, as the schwannomatosis cells exhibited the same expression pattern of cell cycle regulatory genes as normal primary human Schwann cells. Cell growth was also similar between normal primary and immortalized tumor cells in culture. Accurate cell lines derived directly from human tumors will serve as invaluable tools for advancing schwannomatosis research, including drug screening. [ABSTRACT FROM AUTHOR]

Neurofibromatosis type 1 (NF1) is a neurocutaneous syndrome characterized by the development of multiple peripheral nerve sheath tumors, the majority of which are benign neurofibromas. However, malignant peripheral nerve sheath tumors (MPNSTs) occur with a 10 % lifetime risk in patients with NF1, often developing within a neurofibroma. When clinical suspicion for an MPNST arises, imaging with FDG PET and MRI is performed to characterize a peripheral tumor for potential malignancy. In this report, we describe a patient with NF-1 who had two peripheral tumors with similar features by PET, both suspicious for MPNST, but differing features by MRI, one of which was subsequently determined to be an MPNST and the second to be a schwannoma. [ABSTRACT FROM AUTHOR]

Sciatic nerve mass-like enlargement caused by peripheral nerve sheath tumors or neurocutaneous syndromes such as neurofibromatosis or schwannomatosis has been widely reported. Other causes of enlargement, such as from perineuroma, fibromatosis, neurolymphoma, amyloidosis, endometriosis, intraneural ganglion cyst, Charcot-Marie-Tooth disease, and chronic inflammatory demyelinating polyneuropathy are relatively rare. High-resolution magnetic resonance imaging (MRI) is an excellent non-invasive tool for the evaluation of such lesions. In this article, the authors discuss normal anatomy of the sciatic nerve and MRI findings of the above-mentioned lesions. [ABSTRACT FROM AUTHOR]

Malignant peripheral nerve sheath tumors (MPNST) are the deadliest cancer that arises in individuals diagnosed with neurofibromatosis and account for nearly 5% of the 15,000 soft tissue sarcomas diagnosed in the United States each year. Comprised of neoplastic Schwann cells, primary risk factors for developing MPNST include existing plexiform neurofibromas (PN), prior radiotherapy treatment, and expansive germline mutations involving the entire NF1 gene and surrounding genes. PN develop in nearly 30-50% of patients with neurofibromatosis type 1 (NF1) and most often grow rapidly in the first decade of life. One of the most important aspects of clinical care for NF1 patients is monitoring PN for signs of malignant transformation to MPNST that occurs in 10-15% of patients. We perform aneuploidy analysis on ctDNA from 883 ostensibly healthy individuals and 28 patients with neurofibromas, including 7 patients with benign neurofibroma, 9 patients with PN and 12 patients with MPNST. Overall sensitivity for detecting MPNST using genome wide aneuploidy scoring was 33%, and analysis of sub-chromosomal copy number alterations (CNAs) improved sensitivity to 50% while retaining a high specificity of 97%. In addition, we performed mutation analysis on plasma cfDNA for a subset of patients and identified mutations in NF1, NF2, RB1, TP53BP2, and GOLGA2. Given the high throughput and relatively low sequencing coverage required by our assay, liquid biopsy represents a promising technology to identify incipient MPNST. [ABSTRACT FROM AUTHOR]