FRINK Linked Data Fragments server

Matches in SemOpenAlex for { <https://semopenalex.org/work/W2213456243> ?p ?o ?g. }

• W2213456243 endingPage "477" @default.
• W2213456243 startingPage "464" @default.
• W2213456243 abstract "Comprehensive genomic analyses of common nervous system cancers provide new insights into their pathogenesis, diagnosis, and treatment. Although analogous studies of rare nervous system tumors are needed, there are major barriers to performing such studies. Cross-species comparative oncogenomics, identifying driver mutations in mouse cancer models and validating them in human tumors, is a promising alternative. Although still in its infancy, this approach is being applied to malignant peripheral nerve sheath tumors (MPNSTs), rare Schwann cell–derived malignancies that occur sporadically, after radiotherapy, and in neurofibromatosis type 1. Studies of human neurofibromatosis type 1–associated tumors suggest that NF1 tumor suppressor loss in Schwann cells triggers cell-autonomous and intercellular changes, resulting in development of benign neurofibromas; subsequent neurofibroma-MPNST progression is caused by aberrant growth factor signaling and mutations affecting the p16INK4A-cyclin D1-CDK4-Rb and p19ARF-Mdm2-p53 cell cycle pathways. Mice with Nf1, Trp53, and/or Cdkn2a mutations that overexpress the Schwann cell mitogen neuregulin-1 or overexpress the epidermal growth factor receptor validate observations in human tumors and, to various degrees, model human tumorigenesis. Genomic analyses of MPNSTs arising in neuregulin-1 and epidermal growth factor receptor-overexpressing mice and forward genetic screens with Sleeping Beauty transposons implicate additional signaling cascades in MPNST pathogenesis. These studies confirm the utility of mouse models for MPNST driver gene discovery and provide new insights into the complexity of MPNST pathogenesis. Comprehensive genomic analyses of common nervous system cancers provide new insights into their pathogenesis, diagnosis, and treatment. Although analogous studies of rare nervous system tumors are needed, there are major barriers to performing such studies. Cross-species comparative oncogenomics, identifying driver mutations in mouse cancer models and validating them in human tumors, is a promising alternative. Although still in its infancy, this approach is being applied to malignant peripheral nerve sheath tumors (MPNSTs), rare Schwann cell–derived malignancies that occur sporadically, after radiotherapy, and in neurofibromatosis type 1. Studies of human neurofibromatosis type 1–associated tumors suggest that NF1 tumor suppressor loss in Schwann cells triggers cell-autonomous and intercellular changes, resulting in development of benign neurofibromas; subsequent neurofibroma-MPNST progression is caused by aberrant growth factor signaling and mutations affecting the p16INK4A-cyclin D1-CDK4-Rb and p19ARF-Mdm2-p53 cell cycle pathways. Mice with Nf1, Trp53, and/or Cdkn2a mutations that overexpress the Schwann cell mitogen neuregulin-1 or overexpress the epidermal growth factor receptor validate observations in human tumors and, to various degrees, model human tumorigenesis. Genomic analyses of MPNSTs arising in neuregulin-1 and epidermal growth factor receptor-overexpressing mice and forward genetic screens with Sleeping Beauty transposons implicate additional signaling cascades in MPNST pathogenesis. These studies confirm the utility of mouse models for MPNST driver gene discovery and provide new insights into the complexity of MPNST pathogenesis. Our understanding of the mechanisms underlying the development of common types of nervous system tumors has expanded exponentially over the past decade. In large part, this is because a cadre of investigators and consortia such as The Cancer Genome Atlas have comprehensively identified the genomic abnormalities in large cohorts of neoplasms such as glioblastomas,1Cancer Genome Atlas Research NetworkComprehensive genomic characterization defines human glioblastoma genes and core pathways.Nature. 2008; 455: 1061-1068Crossref PubMed Scopus (5792) Google Scholar, 2Parsons D.W. Jones S. Zhang X. Lin J.C. Leary R.J. Angenendt P. Mankoo P. Carter H. Siu I.M. Gallia G.L. Olivi A. McLendon R. Rasheed B.A. Keir S. Nikolskaya T. Nikolsky Y. Busam D.A. Tekleab H. Diaz Jr., L.A. Hartigan J. Smith D.R. Strausberg R.L. Marie S.K. Shinjo S.M. Yan H. Riggins G.J. Bigner D.D. Karchin R. Papadopoulos N. Parmigiani G. Vogelstein B. Velculescu V.E. Kinzler K.W. An integrated genomic analysis of human glioblastoma multiforme.Science. 2008; 321: 1807-1812Crossref PubMed Scopus (4527) Google Scholar ependymomas,3Johnson R.A. Wright K.D. Poppleton H. Mohankumar K.M. Finkelstein D. Pounds S.B. Rand V. Leary S.E. White E. Eden C. Hogg T. Northcott P. Mack S. Neale G. Wang Y.D. Coyle B. Atkinson J. DeWire M. Kranenburg T.A. Gillespie Y. Allen J.C. Merchant T. Boop F.A. Sanford R.A. Gajjar A. Ellison D.W. Taylor M.D. Grundy R.G. Gilbertson R.J. Cross-species genomics matches driver mutations and cell compartments to model ependymoma.Nature. 2010; 466: 632-636Crossref PubMed Scopus (285) Google Scholar, 4Modena P. Lualdi E. Facchinetti F. Veltman J. Reid J.F. Minardi S. Janssen I. Giangaspero F. Forni M. Finocchiaro G. Genitori L. Giordano F. Riccardi R. Schoenmakers E.F. Massimino M. Sozzi G. Identification of tumor-specific molecular signatures in intracranial ependymoma and association with clinical characteristics.J Clin Oncol. 2006; 24: 5223-5233Crossref PubMed Scopus (178) Google Scholar, 5Witt H. Mack S.C. Ryzhova M. Bender S. Sill M. Isserlin R. et al.Delineation of two clinically and molecularly distinct subgroups of posterior fossa ependymoma.Cancer Cell. 2011; 20: 143-157Abstract Full Text Full Text PDF PubMed Scopus (378) Google Scholar, 6Wani K. Armstrong T.S. Vera-Bolanos E. Raghunathan A. Ellison D. Gilbertson R. Vaillant B. Goldman S. Packer R.J. Fouladi M. Pollack I. Mikkelsen T. Prados M. Omuro A. Soffietti R. Ledoux A. Wilson C. Long L. Gilbert M.R. Aldape K. Collaborative Ependymoma Research NetworkA prognostic gene expression signature in infratentorial ependymoma.Acta Neuropathol. 2012; 123: 727-738Crossref PubMed Scopus (119) Google Scholar, 7Mack S.C. Witt H. Piro R.M. Gu L. Zuyderduyn S. Stutz A.M. et al.Epigenomic alterations define lethal CIMP-positive ependymomas of infancy.Nature. 2014; 506: 445-450Crossref PubMed Scopus (436) Google Scholar, 8Pajtler K.W. Witt H. Sill M. Jones D.T. Hovestadt V. Kratochwil F. et al.Molecular classification of ependymal tumors across all CNS compartments, histopathological grades, and age groups.Cancer Cell. 2015; 27: 728-743Abstract Full Text Full Text PDF PubMed Scopus (699) Google Scholar medulloblastomas,9Parsons D.W. Li M. Zhang X. Jones S. Leary R.J. Lin J.C. et al.The genetic landscape of the childhood cancer medulloblastoma.Science. 2011; 331: 435-439Crossref PubMed Scopus (582) Google Scholar, 10Jones D.T. Jager N. Kool M. Zichner T. Hutter B. Sultan M. et al.Dissecting the genomic complexity underlying medulloblastoma.Nature. 2012; 488: 100-105Crossref PubMed Scopus (643) Google Scholar and diffuse intrinsic pontine gliomas.11Khuong-Quang D.A. Buczkowicz P. Rakopoulos P. Liu X.Y. Fontebasso A.M. Bouffet E. Bartels U. Albrecht S. Schwartzentruber J. Letourneau L. Bourgey M. Bourque G. Montpetit A. Bourret G. Lepage P. Fleming A. Lichter P. Kool M. von Deimling A. Sturm D. Korshunov A. Faury D. Jones D.T. Majewski J. Pfister S.M. Jabado N. Hawkins C. K27M mutation in histone H3.3 defines clinically and biologically distinct subgroups of pediatric diffuse intrinsic pontine gliomas.Acta Neuropathol. 2012; 124: 439-447Crossref PubMed Scopus (636) Google Scholar, 12Schwartzentruber J. Korshunov A. Liu X.Y. Jones D.T. Pfaff E. Jacob K. et al.Driver mutations in histone H3.3 and chromatin remodelling genes in paediatric glioblastoma.Nature. 2012; 482: 226-231Crossref PubMed Scopus (1706) Google Scholar, 13Wu G. Broniscer A. McEachron T.A. Lu C. Paugh B.S. Becksfort J. Qu C. Ding L. Huether R. Parker M. Zhang J. Gajjar A. Dyer M.A. Mullighan C.G. Gilbertson R.J. Mardis E.R. Wilson R.K. Downing J.R. Ellison D.W. Baker S.J. St. Jude Children's Research Hospital—Washington University Pediatric Cancer Genome ProjectSomatic histone H3 alterations in pediatric diffuse intrinsic pontine gliomas and non-brainstem glioblastomas.Nat Genet. 2012; 44: 251-253Crossref PubMed Scopus (1094) Google Scholar These studies have provided key insights that are fundamentally altering both the diagnosis and treatment of central nervous system tumors. For diagnosis, it is now clear that for some tumor types, mutational status is more predictive of prognosis than classic pathologic criteria.14Aldape K. Zadeh G. Mansouri S. Reifenberger G. von Deimling A. Glioblastoma: pathology, molecular mechanisms and markers.Acta Neuropathol. 2015; 129: 829-848Crossref PubMed Scopus (410) Google Scholar As a result, the International Society of Neuropathology-Haarlem Working Group, which is developing the upcoming version of the Diagnostic Manual for Tumours of the Central Nervous System, has proposed a diagnostic approach that integrates pathologic and molecular findings to better predict patient outcomes.15Louis D.N. Perry A. Burger P. Ellison D.W. Reifenberger G. von Deimling A. Aldape K. Brat D. Collins V.P. Eberhart C. Figarella-Branger D. Fuller G.N. Giangaspero F. Giannini C. Hawkins C. Kleihues P. Korshunov A. Kros J.M. Beatriz Lopes M. Ng H.K. Ohgaki H. Paulus W. Pietsch T. Rosenblum M. Rushing E. Soylemezoglu F. Wiestler O. Wesseling P. International Society of Neuropathology--HaarlemInternational Society Of Neuropathology–Haarlem consensus guidelines for nervous system tumor classification and grading.Brain Pathol. 2014; 24: 429-435Crossref PubMed Scopus (458) Google Scholar It is also now evident that there are several molecular subtypes of glioblastomas,16Verhaak R.G. Hoadley K.A. Purdom E. Wang V. Qi Y. Wilkerson M.D. Miller C.R. Ding L. Golub T. Mesirov J.P. Alexe G. Lawrence M. O'Kelly M. Tamayo P. Weir B.A. Gabriel S. Winckler W. Gupta S. Jakkula L. Feiler H.S. Hodgson J.G. James C.D. Sarkaria J.N. Brennan C. Kahn A. Spellman P.T. Wilson R.K. Speed T.P. Gray J.W. Meyerson M. Getz G. Perou C.M. Hayes D.N. Cancer Genome Atlas Research NetworkIntegrated genomic analysis identifies clinically relevant subtypes of glioblastoma characterized by abnormalities in PDGFRA, IDH1, EGFR, and NF1.Cancer Cell. 2010; 17: 98-110Abstract Full Text Full Text PDF PubMed Scopus (4980) Google Scholar ependymomas,5Witt H. Mack S.C. Ryzhova M. Bender S. Sill M. Isserlin R. et al.Delineation of two clinically and molecularly distinct subgroups of posterior fossa ependymoma.Cancer Cell. 2011; 20: 143-157Abstract Full Text Full Text PDF PubMed Scopus (378) Google Scholar, 6Wani K. Armstrong T.S. Vera-Bolanos E. Raghunathan A. Ellison D. Gilbertson R. Vaillant B. Goldman S. Packer R.J. Fouladi M. Pollack I. Mikkelsen T. Prados M. Omuro A. Soffietti R. Ledoux A. Wilson C. Long L. Gilbert M.R. Aldape K. Collaborative Ependymoma Research NetworkA prognostic gene expression signature in infratentorial ependymoma.Acta Neuropathol. 2012; 123: 727-738Crossref PubMed Scopus (119) Google Scholar, 7Mack S.C. Witt H. Piro R.M. Gu L. Zuyderduyn S. Stutz A.M. et al.Epigenomic alterations define lethal CIMP-positive ependymomas of infancy.Nature. 2014; 506: 445-450Crossref PubMed Scopus (436) Google Scholar, 8Pajtler K.W. Witt H. Sill M. Jones D.T. Hovestadt V. Kratochwil F. et al.Molecular classification of ependymal tumors across all CNS compartments, histopathological grades, and age groups.Cancer Cell. 2015; 27: 728-743Abstract Full Text Full Text PDF PubMed Scopus (699) Google Scholar diffuse intrinsic pontine gliomas,11Khuong-Quang D.A. Buczkowicz P. Rakopoulos P. Liu X.Y. Fontebasso A.M. Bouffet E. Bartels U. Albrecht S. Schwartzentruber J. Letourneau L. Bourgey M. Bourque G. Montpetit A. Bourret G. Lepage P. Fleming A. Lichter P. Kool M. von Deimling A. Sturm D. Korshunov A. Faury D. Jones D.T. Majewski J. Pfister S.M. Jabado N. Hawkins C. K27M mutation in histone H3.3 defines clinically and biologically distinct subgroups of pediatric diffuse intrinsic pontine gliomas.Acta Neuropathol. 2012; 124: 439-447Crossref PubMed Scopus (636) Google Scholar, 17Paugh B.S. Broniscer A. Qu C. Miller C.P. Zhang J. Tatevossian R.G. Olson J.M. Geyer J.R. Chi S.N. da Silva N.S. Onar-Thomas A. Baker J.N. Gajjar A. Ellison D.W. Baker S.J. Genome-wide analyses identify recurrent amplifications of receptor tyrosine kinases and cell-cycle regulatory genes in diffuse intrinsic pontine glioma.J Clin Oncol. 2011; 29: 3999-4006Crossref PubMed Scopus (227) Google Scholar, 18Puget S. Philippe C. Bax D.A. Job B. Varlet P. Junier M.P. Andreiuolo F. Carvalho D. Reis R. Guerrini-Rousseau L. Roujeau T. Dessen P. Richon C. Lazar V. Le Teuff G. Sainte-Rose C. Geoerger B. Vassal G. Jones C. Grill J. Mesenchymal transition and PDGFRA amplification/mutation are key distinct oncogenic events in pediatric diffuse intrinsic pontine gliomas.PLoS One. 2012; 7: e30313Crossref PubMed Scopus (172) Google Scholar, 19Saratsis A.M. Kambhampati M. Snyder K. Yadavilli S. Devaney J.M. Harmon B. Hall J. Raabe E.H. An P. Weingart M. Rood B.R. Magge S.N. MacDonald T.J. Packer R.J. Nazarian J. Comparative multidimensional molecular analyses of pediatric diffuse intrinsic pontine glioma reveals distinct molecular subtypes.Acta Neuropathol. 2014; 127: 881-895Crossref PubMed Scopus (69) Google Scholar and medulloblastomas,20Pugh T.J. Weeraratne S.D. Archer T.C. Pomeranz Krummel D.A. Auclair D. Bochicchio J. et al.Medulloblastoma exome sequencing uncovers subtype-specific somatic mutations.Nature. 2012; 488: 106-110Crossref PubMed Scopus (585) Google Scholar, 21Northcott P.A. Shih D.J. Peacock J. Garzia L. Morrissy A.S. Zichner T. et al.Subgroup-specific structural variation across 1,000 medulloblastoma genomes.Nature. 2012; 488: 49-56Crossref PubMed Scopus (628) Google Scholar, 22Kool M. Korshunov A. Remke M. Jones D.T. Schlanstein M. Northcott P.A. Cho Y.J. Koster J. Schouten-van Meeteren A. van Vuurden D. Clifford S.C. Pietsch T. von Bueren A.O. Rutkowski S. McCabe M. Collins V.P. Backlund M.L. Haberler C. Bourdeaut F. Delattre O. Doz F. Ellison D.W. Gilbertson R.J. Pomeroy S.L. Taylor M.D. Lichter P. Pfister S.M. Molecular subgroups of medulloblastoma: an international meta-analysis of transcriptome, genetic aberrations, and clinical data of WNT, SHH, Group 3, and Group 4 medulloblastomas.Acta Neuropathol. 2012; 123: 473-484Crossref PubMed Scopus (719) Google Scholar each of which depends on distinct signaling cascades and thus potentially sensitive to different therapeutic agents. As a result, many academic centers are now performing oncogenomic testing to predict which drugs are potentially effective against a patient's tumor. It is reasonable to expect that globally defining the genomic abnormalities that occur in large cohorts of rare nervous system cancers would similarly affect the care of patients with those neoplasms. However, there are important barriers to performing such analyses. The Cancer Genome Atlas typically tries to study 500 examples of each tumor type, using frozen tissue and a matched germline DNA; this cohort size will capture driver mutations present in at least 5% of that tumor type. In practice, the number of tumor samples that must be collected is much larger, because many samples will be rejected during quality assurance. In addition, The Cancer Genome Atlas prefers tumors from patients who have not yet received chemotherapy or radiotherapy, which reduces the pool of available tumor samples. Because large numbers of samples are needed and rare cancers that meet these criteria are encountered only a few times annually even in large medical centers, it is likely that investigators from different institutions will have to pool their tumor collections if these studies are to be performed. However, assembling even a small collection of rare tumor specimens requires several years, and many investigators are reluctant to donate their tumor collections to large consortia because of a concern that the effort invested in their collection will not be recognized. Consequently, human factors will also impede the collection of large numbers of rare human cancer specimens. This should not dissuade us from performing comprehensive genomic analyses on all of the rare nervous system tumors we can collect; the information we will derive from these studies will undoubtedly be invaluable. However, to maximize the value of information derived from relatively small numbers of human tumors, we will need to partner these studies with other approaches. Recognizing this, many investigators are beginning to use genetically engineered mouse models to identify driver genes potentially relevant to the pathogenesis of rare tumor types. Here, I review how this approach has been used to probe the pathogenesis of malignant peripheral nerve sheath tumors (MPNSTs). MPNSTs are rare Schwann cell–derived neoplasms that represent approximately 5% of the soft tissue sarcomas diagnosed annually.23Lewis J.J. Brennan M.F. Soft tissue sarcomas.Curr Probl Surg. 1996; 33: 817-872Abstract Full Text PDF PubMed Google Scholar Although MPNSTs occur sporadically, after radiotherapy and in individuals with the autosomal dominant tumor susceptibility syndrome neurofibromatosis type 1 (NF1), our current understanding of the mechanisms responsible for MPNST pathogenesis in humans is derived almost exclusively from studies of NF1-associated MPNSTs. I begin by discussing the mechanisms responsible for the pathogenesis of plexiform neurofibromas, the benign precursors that give rise to MPNSTs in NF1 patients, and their transformation into MPNSTs. I then consider key genetically engineered mouse models that were created to validate observations in human MPNSTs, what we have learned from these models, and their relative suitability for MPNST driver gene discovery. I finish by reviewing the initial genomic analyses that have been performed with these mouse MPNST models. NF1 is the most common genetic disease that affects the human nervous system, occurring in 1 in every 3500 newborn infants.24Carroll S.L. Molecular mechanisms promoting the pathogenesis of Schwann cell neoplasms.Acta Neuropathol. 2012; 123: 321-348Crossref PubMed Scopus (80) Google Scholar Although completely penetrant, the manifestations of NF1 are highly variable, even in the same family. NF1 patients commonly have learning disabilities, pigmentary lesions of the iris (Lisch nodules) and skin (axillary freckling, café-au-lait macules), bone dysplasias, and glial neoplasms in brain (optic gliomas, glioblastomas), large peripheral nerves (plexiform neurofibromas, MPNSTs), and skin (dermal neurofibromas). Less frequently, these individuals develop other tumors such as pheochromocytomas, rhabdomyosarcomas, leiomyosarcomas, and juvenile myelomonocytic leukemia. In NF1 patients, one allele of neurofibromin 1 (NF1), a tumor suppressor gene that contains 60 exons and spans 282,751 bp on chromosome 17 (17q11.2), is inactivated. Nonsense mutations,25Messiaen L.M. Callens T. Mortier G. Beysen D. Vandenbroucke I. Van Roy N. Speleman F. Paepe A.D. Exhaustive mutation analysis of the NF1 gene allows identification of 95% of mutations and reveals a high frequency of unusual splicing defects.Hum Mutat. 2000; 15: 541-555Crossref PubMed Scopus (418) Google Scholar missense mutations,25Messiaen L.M. Callens T. Mortier G. Beysen D. Vandenbroucke I. Van Roy N. Speleman F. Paepe A.D. Exhaustive mutation analysis of the NF1 gene allows identification of 95% of mutations and reveals a high frequency of unusual splicing defects.Hum Mutat. 2000; 15: 541-555Crossref PubMed Scopus (418) Google Scholar frameshift mutations,25Messiaen L.M. Callens T. Mortier G. Beysen D. Vandenbroucke I. Van Roy N. Speleman F. Paepe A.D. Exhaustive mutation analysis of the NF1 gene allows identification of 95% of mutations and reveals a high frequency of unusual splicing defects.Hum Mutat. 2000; 15: 541-555Crossref PubMed Scopus (418) Google Scholar or mutations that affect RNA splicing26Wimmer K. Roca X. Beiglbock H. Callens T. Etzler J. Rao A.R. Krainer A.R. Fonatsch C. Messiaen L. Extensive in silico analysis of NF1 splicing defects uncovers determinants for splicing outcome upon 5' splice-site disruption.Hum Mutat. 2007; 28: 599-612Crossref PubMed Scopus (102) Google Scholar are the usual means of NF1 inactivation; these mutations tend to cluster in exons 10a to 10c and 37, but they can be found anywhere in the NF1 coding sequence. Complete deletion of the NF1 gene also occurs, but is rare, being seen in only 5% of NF1 patients.27Wimmer K. Yao S. Claes K. Kehrer-Sawatzki H. Tinschert S. De Raedt T. Legius E. Callens T. Beiglbock H. Maertens O. Messiaen L. Spectrum of single- and multiexon NF1 copy number changes in a cohort of 1,100 unselected NF1 patients.Genes Chromosomes Cancer. 2006; 45: 265-276Crossref PubMed Scopus (121) Google Scholar Although the NF1 gene was cloned in 1990, the functions performed by neurofibromin, the 2818-amino acid polypeptide encoded by this gene, are still incompletely understood. We do know that neurofibromin inactivates members of the Ras family of small GTP-binding proteins.24Carroll S.L. Molecular mechanisms promoting the pathogenesis of Schwann cell neoplasms.Acta Neuropathol. 2012; 123: 321-348Crossref PubMed Scopus (80) Google Scholar This function is mediated by a centrally located domain (amino acids 1203 to 1549) within neurofibromin that is homologous to the Saccharomyces cerevisiae GTPase-activating proteins (GAPs) IRA1 and IRA2. Ras proteins are activated on binding GTP; the neurofibromin Ras GAP domain stimulates an intrinsic GTPase activity in Ras proteins, causing them to cleave a phosphate from the bound GTP and inactivate themselves. Other domains in neurofibromin, namely the cysteine/serine-rich domain and a tubulin-binding domain located amino terminal to the Ras GAP domain, modulate its Ras GAP activity.24Carroll S.L. Molecular mechanisms promoting the pathogenesis of Schwann cell neoplasms.Acta Neuropathol. 2012; 123: 321-348Crossref PubMed Scopus (80) Google Scholar The cysteine/serine-rich domain and TBD have opposing actions; phosphorylation of the cysteine/serine-rich domain by protein kinase Cα results in enhanced Ras GAP activity, whereas the interaction of tubulin with the tubulin-binding domain inhibits neurofibromin's Ras GAP function. A bipartite domain that contains both a region analogous to the yeast protein Sec14p and a pleckstrin homology domain is present carboxy terminal to the Ras GAP domain. Although it was suggested that this domain binds glycerophospholipids and interacts with other as yet unidentified proteins, the biological significance of these hypothetical interactions remains unknown. The carboxy terminus of neurofibromin also contains a focal adhesion kinase (FAK)–interacting domain that allows neurofibromin to modulate substrate interactions. Curiously, although neurofibromin has no known nuclear functions, a nuclear localization signal is present within the FAK-interacting domain. Conversely, some neurofibromin functions are not yet linked to specific domains in this protein. For example, although neurofibromin loss results in changes in cAMP and calcium signaling, it is not yet known which neurofibromin domains regulate these events. Most investigators examining neurofibromin's tumor suppressor function have focused on the role of the Ras GAP domain. However, there is reason to think that other domains in neurofibromin also contribute to tumor suppression. For instance, neurofibromin is a member of a family of Ras GAPs that includes RASA1 (p120GAP), PLXNB2, RASA2 (Gap1m), RASA3 (GAP1IP4BP), RASA4 (CAPRI), RASAL1, SYNGAP (p135SynGAP), DAB2IP, RASAL2, and IQGAP1-3. Although several of these proteins are expressed ubiquitously, they do not compensate for neurofibromin loss in NF1-null tumors. Further, none of these other Ras GAPs produce a tumor susceptibility syndrome when mutated, indicating that loss of their Ras GAP activity is not sufficient for tumorigenesis. A comparison of the structure of neurofibromin to that of other Ras GAPs shows that, other than their Ras GAP domains, the domains present in other members of this protein family differ from those in neurofibromin. Given the structural and functional differences between neurofibromin and other Ras GAPs, it is thus possible that both the Ras GAP and other domains in neurofibromin are required for tumor suppression. Shortly after the cloning of the NF1 gene, it was recognized that plexiform neurofibroma pathogenesis is initiated when a second-hit mutation inactivates the remaining functional NF1 gene in a cell within the Schwann cell lineage,24Carroll S.L. Molecular mechanisms promoting the pathogenesis of Schwann cell neoplasms.Acta Neuropathol. 2012; 123: 321-348Crossref PubMed Scopus (80) Google Scholar resulting in a loss of neurofibromin expression and Ras hyperactivation.24Carroll S.L. Molecular mechanisms promoting the pathogenesis of Schwann cell neoplasms.Acta Neuropathol. 2012; 123: 321-348Crossref PubMed Scopus (80) Google Scholar This led to the prediction that drugs targeting Ras signaling would be effective against NF1-null nerve sheath tumors. Unexpectedly, however, the farnesyltransferase inhibitor tipifarnib, which blocks a post-translational modification critical for Ras activity, did not inhibit the progression of plexiform neurofibromas.28Widemann B.C. Dombi E. Gillespie A. Wolters P.L. Belasco J. Goldman S. Korf B.R. Solomon J. Martin S. Salzer W. Fox E. Patronas N. Kieran M.W. Perentesis J.P. Reddy A. Wright J.J. Kim A. Steinberg S.M. Balis F.M. Phase 2 randomized, flexible crossover, double-blinded, placebo-controlled trial of the farnesyltransferase inhibitor tipifarnib in children and young adults with neurofibromatosis type 1 and progressive plexiform neurofibromas.Neuro Oncol. 2014; 16: 707-718Crossref PubMed Scopus (71) Google Scholar In retrospect, this clinical trial likely failed because the Ras activation that follows neurofibromin loss is more complex than that seen in tumors with an activating mutation of a single Ras protein. Neurofibromin inhibits both the classic Ras (H-, N-, and K-Ras) and R-Ras (R-Ras, R-Ras2/TC21, and M-Ras) subfamilies.24Carroll S.L. Molecular mechanisms promoting the pathogenesis of Schwann cell neoplasms.Acta Neuropathol. 2012; 123: 321-348Crossref PubMed Scopus (80) Google Scholar As it happens, multiple members of both subfamilies (H-Ras, N-Ras, K-Ras, R-Ras, and R-Ras2) are simultaneously expressed and activated in MPNST cells. Further, these subfamilies have both overlapping and distinct functions in MPNST cells (Figure 1). Classic Ras and R-Ras proteins both contribute to MPNST proliferation. However, only classic Ras proteins promote the survival of MPNST cells, whereas R-Ras proteins drive their migration.29Brossier N.M. Prechtl A.M. Longo J.F. Barnes S. Wilson L.S. Byer S.J. Brosius S.N. Carroll S.L. Classic Ras proteins promote proliferation and survival via distinct phosphoproteome alterations in neurofibromin-null malignant peripheral nerve sheath tumor cells.J Neuropathol Exp Neurol. 2015; 74: 568-586Crossref Scopus (12) Google Scholar Within the classic Ras subfamily, though, there appears to be functional redundancy; ablation of one subfamily member results in increased expression and activation of another subfamily member with little, if any, effect on proliferation. Tipifarnib inhibits only H-Ras, because other post-translational modifications such as geranylgeranylation allow K-Ras and N-Ras to be appropriately activated30Appels N.M. Beijnen J.H. Schellens J.H. Development of farnesyl transferase inhibitors: a review.Oncologist. 2005; 10: 565-578Crossref PubMed Scopus (234) Google Scholar and thus circumvent inhibition by tipifarnib. Consequently, treatment with this drug likely resulted in compensatory activation of other, tipifarnib-resistant Ras proteins. Indeed, the simultaneous activation and intrafamily functional redundancy of Ras proteins in NF1-null MPNST cells suggests that it will be difficult to target these proteins therapeutically. Consequently, some laboratories have asked whether targeting signaling pathways downstream of Ras such as mitogen-activated protein extracellular signal-related kinase (ERK) kinase (MEK)31Jessen W.J. Miller S.J. Jousma E. Wu J. Rizvi T.A. Brundage M.E. Eaves D. Widemann B. Kim M.O. Dombi E. Sabo J. Hardiman Dudley A. Niwa-Kawakita M. Page G.P. Giovannini M. Aronow B.J. Cripe T.P. Ratner N. MEK inhibition exhibits efficacy in human and mouse neurofibromatosis tumors.J Clin Invest. 2013; 123: 340-347Crossref PubMed Scopus (224) Google Scholar, 32Watson A.L. Anderson L.K. Greeley A.D. Keng V.W. Rahrmann E.P. Halfond A.L. Powell N.M. Collins M.H. Rizvi T. Moertel C.L. Ratner N. Largaespada D.A. Co-targeting the MAPK and PI3K/AKT/mTOR pathways in two genetically engineered mouse models of schwann cell tumors reduces tumor grade and multiplicity.Oncotarget. 2014; 5: 1502-1514Crossref PubMed Scopus (58) Google Scholar and the phosphatidylinositol 3-kinase (PI3K)-Akt-TSC2-mammalian target of rapamycin (mTOR)-S6 kinase33Johannessen C.M. Reczek E.E. James M.F. Brems H. Legius E. Cichowski K. The NF1 tumor suppressor critically regulates TSC2 and mTOR.Proc Natl Acad Sci U S A. 2005; 102: 8573-8578Crossref PubMed Scopus (470) Google Scholar, 34Johannessen C.M. Johnson B.W. Williams S.M. Chan A.W. Reczek E.E. Lynch R.C. Rioth M.J. McClatchey A. Ryeom S. Cichowski K. TORC1 is essential for NF1-associated malignancies.Curr Biol. 2008; 18: 56-62Abstract Full Text Full Text PDF PubMed Scopus (173) Google Scholar would be more effective therapeutically. Although initial results indicate that this is the case, note that the full repertoire of Ras-dependent signaling pathways activated in NF1-null peripheral nerve sheath tumors has not yet been defined. Indeed, a re" @default.
• W2213456243 created "2016-06-24" @default.
• W2213456243 creator A5071472484 @default.
• W2213456243 date "2016-03-01" @default.
• W2213456243 modified "2023-10-17" @default.
• W2213456243 title "The Challenge of Cancer Genomics in Rare Nervous System Neoplasms" @default.
• W2213456243 cites W1530069278 @default.
• W2213456243 cites W1561335447 @default.
• W2213456243 cites W1929585111 @default.
• W2213456243 cites W1949037014 @default.
• W2213456243 cites W1966503073 @default.
• W2213456243 cites W1969498974 @default.
• W2213456243 cites W1975063093 @default.
• W2213456243 cites W1976009942 @default.
• W2213456243 cites W1976570935 @default.
• W2213456243 cites W1979855662 @default.
• W2213456243 cites W1979856883 @default.
• W2213456243 cites W1980324442 @default.
• W2213456243 cites W1982767015 @default.
• W2213456243 cites W1983785189 @default.
• W2213456243 cites W1987186315 @default.
• W2213456243 cites W1987425587 @default.
• W2213456243 cites W1987937498 @default.
• W2213456243 cites W1990917913 @default.
• W2213456243 cites W1992013240 @default.
• W2213456243 cites W1993442838 @default.
• W2213456243 cites W1996539839 @default.
• W2213456243 cites W2000690172 @default.
• W2213456243 cites W2008471038 @default.
• W2213456243 cites W2009019945 @default.
• W2213456243 cites W2011530103 @default.
• W2213456243 cites W2012573463 @default.
• W2213456243 cites W2017444651 @default.
• W2213456243 cites W2019200309 @default.
• W2213456243 cites W2020277292 @default.
• W2213456243 cites W2022046879 @default.
• W2213456243 cites W2022887464 @default.
• W2213456243 cites W2025183726 @default.
• W2213456243 cites W2028643362 @default.
• W2213456243 cites W2030664470 @default.
• W2213456243 cites W2031047333 @default.
• W2213456243 cites W2031264513 @default.
• W2213456243 cites W2032969727 @default.
• W2213456243 cites W2036105130 @default.
• W2213456243 cites W2040827479 @default.
• W2213456243 cites W2041366584 @default.
• W2213456243 cites W2042552060 @default.
• W2213456243 cites W2053442386 @default.
• W2213456243 cites W2054051862 @default.
• W2213456243 cites W2054674800 @default.
• W2213456243 cites W2055729102 @default.
• W2213456243 cites W2055770801 @default.
• W2213456243 cites W2056731811 @default.
• W2213456243 cites W2058413149 @default.
• W2213456243 cites W2060362092 @default.
• W2213456243 cites W2062062519 @default.
• W2213456243 cites W2065833903 @default.
• W2213456243 cites W2067715727 @default.
• W2213456243 cites W2070604281 @default.
• W2213456243 cites W2073355522 @default.
• W2213456243 cites W2077203214 @default.
• W2213456243 cites W2077813502 @default.
• W2213456243 cites W2080294298 @default.
• W2213456243 cites W2082080058 @default.
• W2213456243 cites W2088202919 @default.
• W2213456243 cites W2089794529 @default.
• W2213456243 cites W2101095637 @default.
• W2213456243 cites W2101538557 @default.
• W2213456243 cites W2102763487 @default.
• W2213456243 cites W2105126628 @default.
• W2213456243 cites W2108247214 @default.
• W2213456243 cites W2113432767 @default.
• W2213456243 cites W2116316399 @default.
• W2213456243 cites W2118124054 @default.
• W2213456243 cites W2120931365 @default.
• W2213456243 cites W2121651129 @default.
• W2213456243 cites W2121733985 @default.
• W2213456243 cites W2122184474 @default.
• W2213456243 cites W2124555914 @default.
• W2213456243 cites W2125920909 @default.
• W2213456243 cites W2131291777 @default.
• W2213456243 cites W2134479723 @default.
• W2213456243 cites W2136640137 @default.
• W2213456243 cites W2140048538 @default.
• W2213456243 cites W2142662937 @default.
• W2213456243 cites W2145755261 @default.
• W2213456243 cites W2148810289 @default.
• W2213456243 cites W2149699507 @default.
• W2213456243 cites W2149724253 @default.
• W2213456243 cites W2153862284 @default.
• W2213456243 cites W2154151857 @default.
• W2213456243 cites W2154930876 @default.
• W2213456243 cites W2158233796 @default.
• W2213456243 cites W2159562139 @default.
• W2213456243 cites W2161289668 @default.
• W2213456243 cites W2163986236 @default.
• W2213456243 cites W2166947969 @default.
• W2213456243 cites W2167532631 @default.

• next