| January Neurofibromatosis Research Roundup |
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This is a digest of some neurofibromatosis-related papers that appeared in the literature recently. For full abstracts and the latest NF-related publications visit http://www.ncbi.nlm.nih.gov/pubmed/ and search ‘neurofibromatosis’, ‘schwannomatosis’, or author name. To keep abreast of breaking NF research news, sign up to receive the CTF blog in your inbox! https://www.ctf.org/blog Molecular Advances in NF2 Understanding how merlin actually works in the cell will help figure out how to develop effective drug therapies for NF2. Children’s Tumor Foundation Young Investigator Awardee Timmy Mani (University of Cincinnati) provides in Hennigan et al. a new and unique view of merlin that might advance this area. It has long been known that merlin is related to proteins from the Ezrin Radixin-Moesin (ERM) protein family. ERM proteins are regulated by switching from a ‘closed’ to an ‘open’ conformation, and it has been thought merlin is the same. Mani and colleagues developed a series of probes that allowed them to ‘visualize’ merlin by fluorescence resonance energy transfer (FRET), as purified protein and in living cells. They found something new and unexpected: merlin exists in a stable, closed conformation but when activated undergoes a more subtle change than previously thought. These studies add to a recently growing body of evidence that challenge the standard thinking in the NF2 field. Also, though early stage, this type of research can inform the development of drug therapies aimed at targeting and restoring merlin function, and providing tumor treatments. To examine genotype/phenotype correlations in NF2, Selvanathan et al. present a comparison between the clinical presentations of patients with mutations predicted to produce truncated protein (nonsense/frameshift mutations) or loss of protein (large deletions). Nonsense/frameshift patients have more severe NF2 symptoms: they are typically diagnosed younger and have a higher risk of meningioma, spinal tumors, additional cranial nerve tumors, skin lesions, and spinal tumors; younger age of hearing loss onset, tinnitus, paraesthesiae, wasting, weakness and headaches. Patients with nonsense/frameshift mutations therefore need to be particularly closely monitored. Molecular Advances in NF1 Phoenix and Temple begin to unravel the molecular role of the gene Spred1, mutations of which was recently identified as Legius Syndrome, an NF1-like syndrome but with apparently milder features. It turns out that the Spred1 gene is present in developing brain in regions where neurons are bearing made and seems to have a role in controlling the proliferation and maturing of developing neurons. When the Spred1 gene is knocked down (suppressed), the organization of cells in the brain does not properly establish or mature. Looking ahead, it will be interesting to see if this impact of Spred1 on brain development contributes to learning disabilities seen in Legius Syndrome. Arima et al. highlighted the role of the Ras pathway in regulating epithelial-to-mesenchymal transition (EMT) which are involved in many normal biological functions such as embryonic development and wound healing, as well as abnormal processes such as cancer. This study focused in on the role of neurofibromin protein – which intimately regulates Ras signaling – in EMT and found that EMT-related transcription factors Snail, Slug, Twist, ZEB1 and ZEB2 are increased in human neurofibromas and Schwann cells. When the NF1 gene is silenced in normal cells, these gene are also increased in expression. Therefore loss of neurofibromin as occurs I NF1 tumors activates EMT-related signaling, and may drive tumor growth. A comprehensive article by Gottfried et al. provides a valuable review of NF1 tumor signaling pathways and the current status of candidate drug targets. Verdijk et al. examined the role of TP53 mutations in 145 cases – some NF1 patients - on human malignant peripheral nerve sheath tumors (MPNSTs). TP53 mutations were found to be relatively rare and not seen in NF1 patients. Pasmant et al. examined gene expression in dermal and plexiform neurofibromas using a 22,000-oligonucleotide microarray transcriptomic approach to examine a series of plexiform neurofibromas and dermal neurofibromas. Several members of the CCN gene family - which regulates cell adhesion, migration, proliferation, and survival - were dysregulated in NF1 tumorigenesis. S100A8, S100A9, and CD36 were also upregulated. These might be useful diagnostic or prognostic markers or inform future novel therapeutic strategies. Padmanabhan et al. describe characterization of two zebrafish gene orthologs of the human NF1 gene called nf1a and nf1b and are able to knock down the gene and create zebrafish with vascular and cardiac valve abnormalities. The group will use the fish models for structure-function analysis and genetic screens. Molecular Advances in Schwannomatosis Dagar et al. provide the first report of using high resolution melting (HRM), for a rapid and sensitive diagnostic screening method for detecting sequence variations in SMARCB1, the candidate causal gene in familial schwannomatosis (as well as rhabdoid tumor and epitheloid sarcoma). 9 distinct pathogenic SMARCB1 mutations were identified in a total of 19 rhabdoid tumors. Two tumors had two distinct mutations and two harbored SMARCB1 deletion. Other mutations were nonsense or frame-shifts. HRM is rapid, sensitive and inexpensive and could be widely adopted in diagnostic laboratories to facilitate whole gene mutation screening. Most cases of schwannomatosis are thought to be first case in a family due to a new mutation; to date the candidate schwannomatosis gene SMARCB1/INI1 has moreso been associated with familial, inherited schwannomatosis. Hulsebos et al. examine this gene in a family with two schwannomatosis affected children, but with apparently clinically unaffected parents. Both affected individuals carried a constitutional SMARCB1 mutation not seen in constitutional DNA of the parents. Haplotyping revealed that the chromosome 22 segment that carries the mutant SMARCB1 allele originated from the mother. She transferred the same chromosome 22 segment, however, with a wild-type SMARCB1 copy, to a third unaffected child. The mother was therefore identified as a germ line mosaic for the SMARCB1 mutation and shows for the first time that germ line mosaicism may occur in schwannomatosis. NF2 Clinical Management Reports Suryanarayanan et al. highlighted to role of conservative management in NF2 vestibular schwannomas in a study of 436 patients, 109 of whom had NF2. Though the NF2 schwannomas were significantly larger than the sporadic vestibular schwannomas at commencement of study, two thirds of tumors overall did not grow with growth being inversely related to patient age. The group noted that if a tumor is greater than 1.5cm, it needed more aggressive monitoring; and that NF2 vestibular schwannomas are inherently more challenging and less predictable to manage that sporadic vestibular schwannomas. Yeung et al. examined mechanisms of radioresistance that occur in vestibular schwannomas, and explore the complex path toward understanding why some of these tumors become radioresistant and how this information can guide selection of therapy for individuals.
NF1 Clinical Management Reports
Karabatsou et al. assessed the use of 18Fluorodeoxyglucose (18FDG)-positron emission tomography (PET) as a malignancy detection tool in a pilot study of 9 NF1 patients with plexiform neurofibromas suspected to have undergone transformation to an MPNST. Patients were preoperatively evaluated pre-surgery and this tool was found to be useful in predicting malignant transformation and facilitating targeting of biopsies to metabolic hot spots, to further augment diagnostic sensitivity. Rosenfeld et al. examine the incidence of aggressive CNS lesions in NF1 via a retrospective review of 145 NF1 patients with CNS tumors. Over two-thirds of these patients had optic pathway tumors. 5 patients had high grade tumors - one anaplastic medulloblastoma and 4 high grade glioma - with 3 of these patients having an optic pathway tumor first. The group recommends close monitoring of young NF1 patients with tumors are in an unusual location or behaving in an uncharacteristically aggressive manner. Broekman et al. present a case of high-grade astrocytoma in an NF1 patient and possible underlying pathophysiology. Jett and Friedman present a new clinical review of NF1 management approaches and recommendations for care of individual NF1 manifestations. Onesti et al. described surgical management 29 neurofibromas in NF1 patients and established that subtotal and total resection without functional destruction is often possible for superficial plexiform neurofibromas. Faruque et al. report on a case of NF1 where the patient developed massive haemothorax as a result of spontaneous rupture of the left vertebral artery and left subclavian artery and review the diagnostic and management challenge of the case. NF1 may be associated with a variety of speech deviations, and Alivuotila et al. review the variety of speech characteristics that can occur in NF1. Various speech problems were observed - problems in regulating pitch, deviant nasality, misarticulation, and disfluency. These were more common and severe in children than in adults; while men had more speech problems than women. The study highlights components of speech requiring particular speech therapy in NF1. Gresham et al. present a case of a pregnant patient with NF1 and the unique challenges presented to the care team by caring for this individual.
...and Some Updates from Beyond NF
Dr. Kate Rauen (UCSF) organized a stellar meeting last summer bringing together physicians, researchers, families and medical foundations with an interest in the spectrum of ‘Ras/MAPK’ disorders including NF1, Legius Syndrome, Noonan’s Sydrome, Costello Syndrome amongst other conditions. Now Rauen et al. have published a report of highlights from the meeting. The molecular commonalities of these disorders and might each help inform the clinical management of, and drug therapy. Broader insights into the spread of malignant tumors came from Kim et al. that ‘circulating tumor cells’ (CTCs) can not only spread and start new tumors but also return to their tumor of origin to re-seed and perpetuate that tumor’s growth. CTCs may even take ‘refuge’ in the bone marrow for a time before reappearing to seed or re-seed a malignant tumor. In migrating to a tumor, the CTCs seem to be responding to interleukins, secreted by the tumor. The finds may help explain why tumors grow back after surgical removal and drug therapy and hopefully help inform development of future treatment approaches for malignant tumors.
References Alivuotila L, Hakokari J, Visnapuu V, Korpijaakko-Huuhka AM, Aaltonen O, Happonen RP, Peltonen S, Peltonen J. (2010) Speech characteristics in NF 1. Am J Med Genet A. 152A(1):42-51. Arima Y, Hayashi H, Kamata K, Goto TM, Sasaki M, Kuramochi A, Saya H. (2009) Decreased expression of neurofibromin contributes to epithelial-mesenchymal transition in NF1. Exp Dermatol. [Epub ahead of print] Broekman ML, Risselada R, Engelen-Lee J, Spliet WG, Verweij BH. (2009) Glioblastoma multiforme in the posterior cranial fossa in a patient with NF1. Case Report Med. 2009:757898. Epub 2009 Dec 16. Dagar V, Chow CW, Ashley DM, Algar EM. (2009) Rapid detection of SMARCB1 sequence variation using high resolution melting. BMC Cancer. 9:437. Faruque MO, Davidson F. (2009) Clinical challenges and serious vascular complications in neurofibromatosis. Emerg Med Australas. 2009 Dec;21(6):518-20. Gottfried ON, Viskochil DH, Couldwell WT. (2010) NF1 and tumorigenesis: molecular mechanisms and therapeutic implications. Neurosurg Focus. 28(1):E8. Gresham DD, Braunlin JL, Vuckovich SK. (2010) Caring for the pregnant woman with neurofibromatosis. MCN Am J Matern Child Nurs. 35(1):18-23 Hennigan RF, Foster LA, Chaiken MF, Mani T, Gomes MM, Herr AB, Ip W. (2010) Fluorescence resonance energy transfer analysis of merlin conformational changes. Mol Cell Biol. 30(1):54-67. Hulsebos TJ, Kenter SB, Jakobs ME, Baas F, Chong B, Delatycki MB. (2009) SMARCB1/INI1 maternal germ line mosaicism in schwannomatosis. Clin Genet. Nov 11. [Epub ahead of print] Jett K, Friedman JM. (2009) Clinical and genetic aspects of NF1. Genet Med. 2009 Dec 18. [Epub ahead of print] Karabatsou K, Kiehl TR, Wilson DM, Hendler A, Guha A. (2009) Potential role of 18fluorodeoxyglucose-positron emission tomography/computed tomography in differentiating benign neurofibroma from malignant peripheral nerve sheath tumor associated with NF1. Neurosurgery. 65(4 Suppl):160-70. Kim, M-Y et al. (2009) Tumor Self-Seeding by Circulating Cancer Cells. Cell, 139(7):1315-1326 Padmanabhan A, Lee JS, Ismat FA, Lu MM, Lawson ND, Kanki JP, Look AT, Epstein JA. (2009) Cardiac and vascular functions of the zebrafish orthologues of the type I neurofibromatosis gene NFI. Proc Natl Acad Sci U S A. 2009 Dec 4. [Epub ahead of print] Pasmant E. et al. (2010) Differential expression of CCN1/CYR61, CCN3/NOV, CCN4/WISP1, and CCN5/WISP2 in NF1 tumorigenesis. J Neuropathol Exp Neurol. 69(1):60-9. Phoenix TN, Temple S. (2010) Spred1, a negative regulator of Ras-MAPK-ERK, is enriched in CNS germinal zones, dampens NSC proliferation, and maintains ventricular zone structure. Genes Dev. 1;24(1):45-56. Rauen et al. (2010) Proceedings from the 2009 genetic syndromes of the Ras/MAPK pathway: From bedside to bench and back. Am J Med Genet A. 152A(1):4-24. Rosenfeld A, Listernick R, Charrow J, Goldman S.(2009) NF1 and high-grade tumors of the central nervous system. Childs Nerv Syst. Nov 25. [Epub ahead of pƒrint] Selvanathan SK, Shenton A, Ferner R, Wallace AJ, Huson SM, Ramsden RT, Evans DG. (2009) Further genotype - phenotype correlations in NF2. Clin Genet. 2009 Nov 23. [Epub ahead of print] Suryanarayanan R, Ramsden RT, Saeed SR, Aggarwal R, King AT, Rutherford SA, Evans DG, Gillespie JE. (2010) Vestibular schwannoma: role of conservative management. J Laryngol Otol.:1-7. [Epub ahead of print] Verdijk RM, den Bakker MA, Dubbink HJ, Hop WC, Dinjens WN, Kros JM. (2010) TP53 mutation analysis of malignant peripheral nerve sheath tumors. J Neuropathol Exp Neurol. 69(1):16-26. Yeung AH, Sughrue ME, Kane AJ, Tihan T, Cheung SW, Parsa AT. (2009) Radiobiology of vestibular schwannomas: mechanisms of radioresistance and potential targets for therapeutic sensitization. Neurosurg Focus. 27(6):E2. |
