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 theNF1 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 secondNF1 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 theNF1+/– heterozygous mast cell. In general, for malignant transformation to occur, there must be accumulation of additional mutations of multiple genes includingINK4A/ARF andP53, with resulting abnormalities of their respective signal cascades. Further, abnormalities of theNF1 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 is a common autosomal dominant disease and is characterized by neural crest-derived tumors.18,101 The key feature of NF1, neurofibromas, are complex tumors arising from peripheral nerve sheaths.59,101 Neurofibromas consist primarily of Schwann cells, fibroblasts, and a large amount of extracellular matrix with collagen surrounding an axon, but they also contain many other cell types including perineural cells, mast cells, pericytes, and endothelial cells.9,59,80,85,101 Malignant tumors can arise in either childhood or adulthood, with MPNSTs being most common.16 In addition to the lesions associated with the peripheral nervous system, patients with NF1 are also at risk for CNS tumors, specifically gliomas.2,42 In childhood, these gliomas are primarily located in the optic pathway and less frequently in the hypothalamus and brainstem; adults are more likely to develop highergrade gliomas.2
Our group has previously published an overview of the genetics and pathogenesis of neurofibromas in NF1.38 In the present paper, we update the relevant information related to the genetic alterations that predispose individuals to this tumor and also discuss the mechanisms involved in the tumorigenesis of MPNSTs and optic nerve gliomas, with attention on implications for targeted therapies (not previously presented).
Genetics
As background information, we include here a brief summary of the genetics of this disease. In this autosomal dominant–inherited condition, in which homozygosity is lethal to embryos,15,46 all affected individuals are heterozygous for anNF1 mutation.35 OneNF1 allele carries a genetic alteration in all cells of a patient with NF1, and therefore, a loss of the secondNF1 allele (loss of heterozygosity, LOH) results in complete functional loss of neurofibromin31,52,86,87 and risk of tumor formation.31,32,47,86 Point mutations affecting the correct splicing of theNF1 gene are a common cause of NF1,4,33,73 responsible for both somatic and germline mutations.87 Many mutations in theNF1 gene result in truncation of the protein product, neurofibromin.96 Approximately half of cases represent new mutations,35 and a mutation at a given locus may provide a selective and proliferative advantage in a germ-cell precursor.84
Positional cloning identified theNF1 gene at 17q11.2.19,97,103 It produces an mRNA9,67 that is expressed in almost all tissues103 but most highly in brain, spinal cord, and the peripheral nervous system.24,98 Neurofibromin, the protein product of theNF1 gene, is found in neurons, oligodendrocytes, and Schwann cells in adults,24,98 and is also expressed in other cell types, such as keratinocytes, adrenal medulla, and white blood cells.40,98 Neurofibromin is reduced or absent in neurofibroma cells,39,55 which are composed principally of Schwann cells without functional neurofibromin.77
Signal Transduction Pathways
Although it only occupies a small area of the protein (360 amino acids), the Ras-GTPase activating protein (GAP)-related domain (GRD) is an important functional region of neurofibromin17,106,107 that stimulates the intrinsic GTPase of p21-Ras-GTP to hydrolyze GTP to GDP, inactivating p21-Ras (Fig. 1).1,6,14,68,93,106 Inactivation of the active Ras-GTP is the main function of neurofibromin.
Fig. 1.
Illustration depicting the signal transduction pathways involved in NF1 tumorigenesis. Growth factors (gf) interact with receptors at the cell surface, activating guanine nucleotide exchange factors and resulting in activated Ras. Activated Ras sends intracellular signals activating the phosphoinositol 3′ kinase (PI3K), AKT, and mTOR pathway. Activated Ras also activates the Raf-MAK (mitogen-activated kinase)/MEK pathway to stimulate ERK (extracellular signal–related kinase), which can enter the nucleus and promote transcription. Normally, neurofibromin downregulates Ras through its GAP-related domain, and therefore in its absence or at decreased levels in NF1, signaling is increased through all of these pathways resulting in cell proliferation and inhibited apoptosis. Adapted by permission from Macmillan Publishers Ltd:Oncogene 26: 4609–4616, copyright 2007.
The functional domain of neurofibromin, Ras, acts as part of a signal transduction pathway that is activated by growth factors and their receptors.8 Increased Ras-GTP leads to increased signaling through Raf kinase, which activates a kinase cascade involving MEK kinase and the Erk1 and Erk2 isoforms of MAPK resulting in cell proliferation.13,27,91 Increased Ras-GTP also protects cells from apoptosis by activating mTOR.10,51 Studies confirm that neurofibromin negatively regulates this mTOR pathway with loss of neurofibromin expression in established human neurofibroma cell lines associated with high levels of mTOR activity.10,51 The mTOR pathway is constitutively activated in both NF1-deficient primary cells and human tumor, is dependent on Ras and PI3K activation, and is mediated by the phosphorylation and inactivation of the TSC2-encoded protein tuberin by AKT.51 Overall, Ras is a key component of many growth factor signaling pathways, and in the absence of neurofibromin it is constitutively activated, resulting in increased cell proliferation and survival.98
The Ras/MAPK pathway is critical to normal development by its regulation of cell proliferation, differentiation, motility, growth, apoptosis, and cell senescence.92 Interestingly, there are multiple developmental syndromes in addition to NF1 that form tumors by abnormalities in the Ras pathway, and they are referred to as the “RASopathies” or “neuro-cardio-facial-cutaneous syndromes.”26,92 These diseases include Noonan syndrome, LEOPARD syndrome, Costello syndrome, capillary malformation–arteriovenous malformation, and cardio-facio-cutaneous syndrome; these syndromes and their relation to the Ras/MAPK pathway are reviewed in detail in Tidyman and Rauen (Fig. 2).92 They are related by germline mutations in genes that encode protein components of the Ras/MAPK pathway, and these mutations may result in increased signal transduction.92 Each syndrome exhibits unique phenotypic features; however, there are overlapping clinical features including characteristic facial features, cardiac defects, skin abnormalities, developmental delay, and a risk of malignancy.92 Interestingly, there are several NF1-related pathways that are significant in the pathogenesis of other developmental syndromes, including mTOR, which contributes to tuberous sclerosis.30,44,74,75 Denayer and colleagues26 noted that these syndromes with common molecular pathways demonstrated the important roles for evolutionarily conserved pathways not only in oncogenesis, but also in cognition, growth, and development.
Fig. 2.
Drawing demonstrating the common Ras/MAPK pathways responsible for multiple developmental syndromes, including NF1. In addition to similar molecular origins, these Ras-related diseases, including Noonan syndrome, LEOPARD syndrome, hereditary gingival fibromatosis 1, capillary malformation–arteriovenous malformation (CM-AVM) syndrome, Costello syndrome, autoimmune lymphoproliferative syndrome (ALPS), cardio-facio-cutaneous (CFC) syndrome, and Legius syndrome, have considerable phenotypic overlap. Thus, targeted molecular treatment may be effective for multiple diseases. Figure reproduced with permission from Tidyman and Rauen.92
Malignant Peripheral Nerve Sheath Tumors
Additional molecular cascades may be involved in tumorigenesis for malignant NF1 tumors.12 For example, Ral overactivation is a novel cell signaling abnormality in MPNSTs.12 Of note, overactivation of Ras and many of its downstream effectors occurred in only a fraction of MPNST cell lines, but Ral was overactivated in all MPNST cells and tumor samples.12 Silencing Ral or inhibiting it with a dominant-negative Ral caused a significant reduction in proliferation, invasiveness, and in vivo tumorigenicity of MPNST cells.12 Also, neurofibromin is shown to regulate Ral activation, and NF1-GRD treatment caused a significant decrease in proliferation, invasiveness, and cell cycle progression, and increased cell death.12 The mTOR pathway has also been shown to have an important role in NF1-associated malignancies including MPNST.50
Among the genetic abnormalities previously reported to be involved in the transformation to malignancy in NF1,39 the loss or mutation of theP53 gene in NF1-related MPNSTs (but never in benign neurofibromas)11,37,49,58,63,64,66,72,78,82,95,105 is associated with a poor prognosis.65 The loss of theP53 gene results in abnormalities in DNA damage–induced cell cycle arrest and apoptosis.95 Approximately half of MPNSTs in patients with NF1 show homozygous deletions at theCDKN2A (also known asINK4A orINK4A/ARF) gene, which contributes to increasing cellular proliferation.95 Also, MPNSTs demonstrate a high frequency of microsatellite instability, and thus, additional loci become targets for mutations during the malignant transformation.
Gliomas
There is evidence that theNF1 gene is involved in the tumorigenesis of both NF1-related and sporadically occurring gliomas.70,79,112 For example, a genomic analysis of human glioblastoma multiforme identified that theNF1 gene was mutated in 15% of tumors.79 As in other NF1 tumors, biallelicNF1 gene inactivation is observed in NF1-associated gliomas and the heterozygous supporting cell or astrocyte is also important for tumorigenesis.5 Of note, McGillicuddy et al.70 found thatNF1 function is inactivated in sporadic gliomas, and it occurs by both proteasomal degradation and genetic loss. For example, neurofibromin protein destabilization is triggered by the hyperactivation of protein kinase C (PKC) and thus, these tumors may be sensitive to PKC inhibitors. They found that complete genetic loss ofNF1 occurs when p53 is inactivated and allows sensitivity to mTOR inhibitors.70 Yeh et al.112 found that there is variability inNF1 gene expression in distinct populations of glia and increased glial cell proliferation in the optic nerve and brainstem but not in other areas afterNF1 inactivation in vitro and in vivo, and thus differences inNF1 gene expression might contribute to the regional localization of brain tumors. Recent studies also demonstrated that the mTOR pathway is involved in tumorigenesis of gliomas in NF1,16,42,50,51,70 and its inhibitor rapamycin is effective in decreasing tumor proliferation in an animal model.42
Neurofibromas
Neurofibromas are unique among tumors because they exhibit extensive cellular heterogeneity.85,89 Reciprocal signaling among the many cell types is known to occur in normal peripheral nerve sheath and in neurofibromas,48,56 and decreased neurofibromin in neurofibromas may result in altered responses. Despite this heterogeneity, the Schwann cell lineage has been recognized as the primary cell type for neurofibroma formation. This cell type is the major one amplified in neurofibromas and is the primary target of growth factors stimulating neurofibroma formation.81,90,102 In addition, the loss of bothNF1 alleles occurs exclusively in the Schwann cell, whereas a wild-type gene is retained in the other neurofibroma cells, including fibroblasts.57,88 This Schwann cell, which lacks functional neurofibromin, has a substantial growth advantage77 and a loss of negative autocrine growth control.76
The stage of differentiation of the Schwann cell as the progenitor cell for NF1 tumors is still the subject of some debate.53,61 In 2009, Le and coworkers61 proposed that the neural crest stem cell is the cell of origin for cutaneous neurofibromas after identifying a population of stem/progenitor cells residing in the dermis (called skin-derived precursors) that, through loss ofNF1, form neurofibromas. Interestingly, in another study, Joseph et al.53 showed that stem cells did not persist postnatally in the location of future neurofibromas or MPNSTs and proposed that the cell of origin is a more differentiated glial cell. Finally, Zheng and coworkers113 noted that plexiform neurofibroma results fromNF1 deficiency in progenitor cells of peripheral nerves. These cells did not cause hyperproliferation or tumorigenesis in the early postnatal period and peripheral nerve development appeared largely normal except for abnormal Remak bundles, the nonmyelinated axon-Schwann cell unit, identified in postnatal mutant nerves. Subsequent degeneration of abnormal Remak bundles occurred concurrently with expansion of nonmyelinating Schwann cells. These findings led the authors to suggest that abnormally differentiated Remak bundles might be the cell of origin for plexiform neurofibroma.
Haploinsufficiency of theNF1 gene in the microenvironment of neurofibromas contributes to its tumorigenicity.71 The single activeNF1 allele in the heterozygous supporting cell does not generate enough functional protein to achieve an appropriate biological response,29 and this confers a growth advantage that contributes to tumorigenesis.45 The neurofibromin-deficient NF1+/– Schwann cell and other heterozygous supporting cells are absolutely necessary for tumor formation and are critically involved in the pathogenesis of neurofibromas.77,114 Also, inflammatory cells, including mast cells, are important to tumor initiation, progression, and angiogenesis.22,23,41 Neurofibromin-deficient Schwann cells secrete increased kit ligand, which serves as a chemoattractant for mast cells expressing c-kit receptor. Also, heterozygous inactivation of NF1+/– promotes migration of mast cells on α4β1 integrins (mast cell surface proteins), in response to the kit ligand. Overall, the loss ofNF1 in Schwann cells results in an increase in growth factor production that initiates a paracrine loop, and it is important for tumor initiation and progression.109
Normally, growth factors cooperate to suppress cell death in Schwann cell precursors,36 but growth factor dysregulation is thought to be involved in tumorigenesis.83 Changes in growth factor expression may be the direct result ofNF1 gene loss or from secondary genetic events.69 Abnormal growth factor receptor expression also has a role in tumorigenesis, progression, and malignant transformation.
Preclinical Models
The development of animal models for preclinical testing in NF1 is key to identifying novel targets for future therapies.43 Early xenograft models for studying neurofibroma formation produced tumors by injecting human neurofibroma tissue or Schwann cell preparations into the sciatic nerve of immunodeficient mice.3,62,89 Subsequently,Nf1 transgene mouse models were developed based on a mutation identified in patients with NF1.15,46 It was hoped that transgene mouse models would prove to be a suitable model for human NF1, but mice heterozygous for theNf1 mutation (Nf1+/Nf1n31) do not develop the classic phenotype of NF1 disease including neurofibromas,46 and mice that are homozygous for theNf1 mutation die in utero.15,46 Later, chimeric mice (Nf1–/–:Nf1+/+) were developed by injection ofNf1–/– homozygous mutant embryonic stem cells at an early developmental stage (blastocysts) to overcome the lethality of the germline homozygous genotype with some success.20 Although the mice developed multiple neurofibromas resembling human plexiform neurofibromas, the cell type in which theNf1 was deleted could not be controlled.71 Next, a conditional mouse model was developed that resulted in somatic inactivation ofNf1 and ablation of neurofibromin function specifically in Schwann cells.114 This animal model,Nf1flox/−;Krox20-cre, provided evidence for the necessity for haploinsufficient supporting cells in neurofibroma formation,114 and all mice developed plexiform neurofibromas with all of the typical supporting cells (Nf1+/–).
A mouse model was developed for MPNSTs by generating mice with mutations in bothNf1 andp53 genes.20,100 These mice (Nf1+/–:p53+/–) developed soft-tissue sarcomas and MPNSTs in neural crest–derived tissue.20,100 This model demonstrates that a mutation in thep53 gene in addition to that inNf1 is required for malignant transformation of cells of neural crest origin.20,100
There are alsoNF1-deficient animal models of NF1 that produce gliomas.5,42 In contrast to astrocyte-restrictedNF1 conditional knockout mice, heterozygous mice lackingNF1 in astrocytes develop optic nerve gliomas. Thus, NF1 glioma formation requires additional cellular or genetic conditions. This mouse model demonstrates thatNF1+/– cells contribute to the pathogenesis of gliomas in NF1 and provides a tool for the preclinical evaluation of potential therapeutic interventions.
Targeted Treatment
Targeted therapy will have a great impact for patients with numerous neurofibromas, very massive plexiform neurofibromas, or MPNSTs for which surgery and radiation have not been widely successful,54,94 and as an adjunct or primary treatment of gliomas. Currently, the principal mode of therapy for spinal neurofibromas or plexiform neurofibromas is surgery. Although isolated single–nerve root neurofibromas can be resected without significant morbidity, patients with multiple spinal neurofibromas often require multiple surgeries during their lifetime. Also, patients with large plexiform neurofibromas represent a surgical challenge; have a high recurrence rate if tumors are subtotally resected, intense adherence, and invasion into local tissue; and have a risk of malignant transformation.54,94 Many preclinical studies, as well as a few clinical trials using biological-based therapeutic approaches to target specific genetic or molecular events involved in NF1 tumorigenesis are in progress. In the future, these medical therapies may be useful for treatment of residual tumors, or as a measure to reduce tumor size prior to surgery, or even to decrease the development of tumors. It may also be possible to apply new therapeutic agents to the local tumor environment to reduce the incidence of recurrences.
Preclinical or clinical studies have targeted various aspects of mast cell functioning, the Ras signaling pathways, rapamycin, and growth factors and receptors, but future therapies may be targeted at almost any molecule involved in tumorigenesis (Fig. 1). A number of strategies were discussed in our previous review. Proposed treatments that reduce the mast cell activity, migration, or numbers within neurofibromas and mast cell stabilizers have been considered as possible therapeutic strategies.109,110 Options for treatment include pharmacological inhibition of PI3K, kit activity, or α4β1 adhesion.109,110 The Ras signal transduction pathways have also been targeted for treatments.104,108 Anti-Ras therapies are an ideal target, becauseRAS is one of the most common oncogenes mutated in human malignancies,104 and Ras-GTP is elevated for both benign and malignant NF1 neurofibromas.39 Treatment options include the delivery of gene therapy vectors with functional NF1 GRD proteins or with dominant negative Ras, which blocks Ras activity.60,98 Other options include the injection of neutralizing Ras antibodies, which inhibits cell proliferation,7,25 or viruses that target and infect cells with activated Ras signaling.21 For example, the human reovirus requires an activated Ras signaling pathway for infection of cultured cells and has been shown to cause tumor regression in mouse models.21 The downstream effectors of the Ras signaling pathway,104 including agents that inhibit MEK28,34 and PI3K,99,111 are promising targets for future neurofibroma treatment.
Newer studies are focusing on the mTOR pathway and its inhibitor rapamycin.10,16,42,50,51,70 Importantly, tumor cell lines derived from patients with NF1, and a genetically engineered cell system that requiresNf1-deficiency for transformation, are highly sensitive to rapamycin. For example, Bhola et al.10 developed and characterized a human NF1-MPNST explant grown subcutaneously in mice to evaluate the effect of rapamycin. Rapamycin significantly inhibited human NF1-MPNST mTOR pathway activation and growth without systemic toxicities. It was effective at reducing NF1-MPNST proliferation and angiogenesis, but did not increase apoptosis. Rapamycin effectively decreased activation downstream of mTOR, but there was increased AKT activation. This study therefore demonstrated the therapeutic potential and limits of rapamycin in NF1-associated and possibly sporadic MPNST. Johannessen et al.50 demonstrated that rapamycin suppresses the growth of aggressive NF1-associated malignancies in a murine model. Interestingly, they demonstrated that rapamycin does not function via mechanisms generally assumed to mediate tumor suppression, including inhibition of HIF-1α and indirect suppression of AKT, but does suppress the mTOR target Cyclin D1. Finally, in a genetically engineered mouse model of low-grade optic glioma resulting from inactivation of theNF1 gene, pharmacological mTOR inhibition in vivo led to decreased tumor cell proliferation in a dose-dependent fashion associated with a decrease in tumor volume.42 It is important to realize that rapamycin is an effective treatment in other developmental syndromes with abnormalities of the mTOR pathway, including tuberous sclerosis, where it may be efficacious in the management of cognitive or developmental disorders and epilepsy and in preventing or limiting tumor development.30,44,74,75
Overall, these medical therapies targeting specific genetic or molecular events involved in NF1 tumorigenesis may be useful for treatment of residual tumors, to reduce tumor size prior to surgery, to decrease the incidence of tumor formation, or to apply to the local tumor environment at the time of resection.
Conclusions
Remarkable progress has been made toward understanding the pathogenesis of neurofibromas since the cloning of theNF1 gene in 1990. Neurofibromatosis Type 1 is caused by germline mutations of theNF1 tumor suppressor gene, which generally results in decreased intracellular neurofibromin protein, leading to increased cascade Ras signaling to its downstream effectors, including Ras/MAPK and Akt/mTOR. In general, a somatic loss of the secondNF1 allele in the progenitor cell, either the Schwann cell or its precursor, combined with haploinsufficiency in multiple supporting cells is required for tumor formation. Importantly, there is a complex series of interactions with these other cell types, such asNF1+/– heterozygous mast cells, in neurofibroma tumorigenesis. In general, for malignant transformation to occur there must be accumulation of additional mutations of multiple genes includingINK4A/ARF andP53. Increased knowledge of molecular and cellular mechanisms involved with NF1 tumorigenesis has led to more accurate animal models of NF1 tumors to evaluate new agents for targeted molecular therapy, including the mTOR inhibitor rapamycin, which are demonstrating promising preclinical results for treatment of MPNSTs and gliomas.
Disclosure
The authors report no conflict of interest concerning the materials or methods used in this study or the findings specified in this paper.
Author contributions to the study and manuscript preparation include the following. Conception and design: WT Couldwell, ON Gottfried, DH Viskochil. Drafting the article: ON Gottfried. Critically revising the article: WT Couldwell, ON Gottfried, DH Viskochil. Reviewed final version of the manuscript and approved it for submission: WT Couldwell, ON Gottfried. Study supervision: WT Couldwell, DH Viskochil.
Acknowledgment
The authors thank Kristin Kraus, M.Sc., for editorial assistance preparing this paper.
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MashourGA,,RatnerN,,KhanGA,,WangHL,,MartuzaRL, &KurtzA:The angiogenic factor midkine is aberrantly expressed in NF1-deficient Schwann cells and is a mitogen for neurofibroma-derived cells.Oncogene20:97–105,2001
McGillicuddyLT,,FrommJA,,HollsteinPE,,KubekS,,BeroukhimR, &De RaedtT, et al.:Proteasomal and genetic inactivation of the NF1 tumor suppressor in gliomagenesis.Cancer Cell16:44–54,2009
MenonAG,,AndersonKM,,RiccardiVM,,ChungRY,,WhaleyJM, &YandellDW, et al.:Chromosome 17p deletions and p53 gene mutations associated with the formation of malignant neurofibrosarcomas in von Recklinghausen neurofibromatosis.Proc Natl Acad Sci U S A87:5435–5439,1990
MessiaenLM,,CallensT,,MortierG,,BeysenD,,VandenbrouckeI, &Van RoyN, et al.:Exhaustive mutation analysis of the NF1 gene allows identification of 95% of mutations and reveals a high frequency of unusual splicing defects.Hum Mutat15:541–555,2000
MiR,,MaJ,,ZhangD,,LiL, &ZhangH:Efficacy of combined inhibition of mTOR and ERK/MAPK pathways in treating a tuberous sclerosis complex cell model.J Genet Genomics36:355–361,2009
MozaffariM,,Hoogeveen-WesterveldM,,KwiatkowskiD,,SampsonJ,,EkongR, &PoveyS, et al.:Identification of a region required for TSC1 stability by functional analysis of TSC1 missense mutations found in individuals with tuberous sclerosis complex.BMC Med Genet10:88,2009
MuirD:Differences in proliferation and invasion by normal, transformed and NF1 Schwann cell cultures are influenced by matrix metalloproteinase expression.Clin Exp Metastasis13:303–314,1995
NigroJM,,BakerSJ,,PreisingerAC,,JessupJM,,HostetterR, &ClearyK, et al.:Mutations in the p53 gene occur in diverse human tumour types.Nature342:705–708,1989
ParsonsDW,,JonesS,,ZhangX,,LinJC,,LearyRJ, &AngenendtP, et al.:An integrated genomic analysis of human glioblastoma multiforme.Science321:1807–1812,2008
PeltonenJ,,JaakkolaS,,LebwohlM,,RenvallS,,RisteliL, &VirtanenI, et al.:Cellular differentiation and expression of matrix genes in type 1 neurofibromatosis.Lab Invest59:760–771,1988
RasmussenSA,,OvermanJ,,ThomsonSA,,ColmanSD,,AbernathyCR, &TrimpertRE, et al.:Chromosome 17 loss-of-heterozygosity studies in benign and malignant tumors in neurofibromatosis type 1.Genes Chromosomes Cancer28:425–431,2000
RodenhiserDI,,AndrewsJD,,ManciniDN,,JungJH, &SinghSM:Homonucleotide tracts, short repeats and CpG/CpNpG motifs are frequent sites for heterogeneous mutations in the neurofibromatosis type 1 (NF1) tumour-suppressor gene.Mutat Res373:185–195,1997
SanguinettiC,,GrecoF,,de PalmaL,,SpecchiaN,,ToescaA, &NoriS:The ultrastructure of schwannoma and neurofibroma of the peripheral nerves.Ital J Orthop Traumatol17:237–246,1991
SawadaS,,FlorellS,,PurandareSM,,OtaM,,StephensK, &ViskochilD:Identification of NF1 mutations in both alleles of a dermal neurofibroma.Nat Genet14:110–112,1996
SerraE,,ArsE,,RavellaA,,SánchezA,,PuigS, &RosenbaumT, et al.:Somatic NF1 mutational spectrum in benign neurofibromas: mRNA splice defects are common among point mutations.Hum Genet108:416–429,2001
SerraE,,RosenbaumT,,WinnerU,,AledoR,,ArsE, &EstivillX, et al.:Schwann cells harbor the somatic NF1 mutation in neurofibromas: evidence of two different Schwann cell subpopulations.Hum Mol Genet9:3055–3064,2000
TuckerT,,FriedmanJM,,FriedrichRE,,WenzelR,,FünstererC, &MautnerVF:Longitudinal study of neurofibromatosis 1 associated plexiform neurofibromas.J Med Genet46:81–85,2009
UpadhyayaM,,HanS,,ConsoliC,,MajounieE,,HoranM, &ThomasNS, et al.:Characterization of the somatic mutational spectrum of the neurofibromatosis type 1 (NF1) gene in neurofibromatosis patients with benign and malignant tumors.Hum Mutat23:134–146,2004
UpadhyayaM,,MaynardJ,,OsbornM,,HusonSM,,PonderM, &PonderBA, et al.:Characterisation of germline mutations in the neurofibromatosis type 1 (NF1) gene.J Med Genet32:706–710,1995
ViskochilD,,BuchbergAM,,XuG,,CawthonRM,,StevensJ, &WolffRK, et al.:Deletions and a translocation interrupt a cloned gene at the neurofibromatosis type 1 locus.Cell62:187–192,1990
ViskochilDH,The structure and function of the NF1 gene: molecular pathophysiology.FriedmanJM,,GutmannDH,,MacCollinM, &RiccardiVM:Neurofibromatosis: Phenotype, Natural History, and Pathogenesised 3Baltimore,Johns Hopkins University Press,1999.119–141
von DeimlingA,,FosterR, &KroneW,Familial tumour syndromes involving the nervous system.KleihuesP, &CaveneeWK:Pathology and Genetics: Tumours of the Nervous SystemLyon,IARC Press,2000.216–218
WallaceMR,,MarchukDA,,AndersenLB,,LetcherR,,OdehHM, &SaulinoAM, et al.:Type 1 neurofibromatosis gene: identification of a large transcript disrupted in three NF1 patients.Science249:181–186,1990
XuGF,,LinB,,TanakaK,,DunnD,,WoodD, &GestelandR, et al.:The catalytic domain of the neurofibromatosis type 1 gene product stimulates ras GTPase and complements ira mutants of S. cerevisiae.Cell63:835–841,1990
XuGF,,O'ConnellP,,ViskochilD,,CawthonR,,RobertsonM, &CulverM, et al.:The neurofibromatosis type 1 gene encodes a protein related to GAP.Cell62:599–608,1990
YanN,,RiccaC,,FletcherJ,,GloverT,,SeizingerBR, &ManneV:Farnesyltransferase inhibitors block the neurofibromatosis type I (NF1) malignant phenotype.Cancer Res55:3569–3575,1995
YangFC,,IngramDA,,ChenS,,ZhuY,,YuanJ, &LiX, et al.:Nf1-dependent tumors require a microenvironment containing Nf1+/– and c-kit-dependent bone marrow.Cell135:437–448,2008
ZhengH,,ChangL,,PatelN,,YangJ,,LoweL, &BurnsDK, et al.:Induction of abnormal proliferation by nonmyelinating schwann cells triggers neurofibroma formation.Cancer Cell13:117–128,2008
Address correspondence to: William T. Couldwell, M.D., Ph.D., Department of Neurosurgery, University of Utah Medical Center, 175 North Medical Drive East, Suite 3B409, Salt Lake City, Utah 84132. email:neuropub@hsc.utah.edu.
Illustration depicting the signal transduction pathways involved in NF1 tumorigenesis. Growth factors (gf) interact with receptors at the cell surface, activating guanine nucleotide exchange factors and resulting in activated Ras. Activated Ras sends intracellular signals activating the phosphoinositol 3′ kinase (PI3K), AKT, and mTOR pathway. Activated Ras also activates the Raf-MAK (mitogen-activated kinase)/MEK pathway to stimulate ERK (extracellular signal–related kinase), which can enter the nucleus and promote transcription. Normally, neurofibromin downregulates Ras through its GAP-related domain, and therefore in its absence or at decreased levels in NF1, signaling is increased through all of these pathways resulting in cell proliferation and inhibited apoptosis. Adapted by permission from Macmillan Publishers Ltd:Oncogene 26: 4609–4616, copyright 2007.
Drawing demonstrating the common Ras/MAPK pathways responsible for multiple developmental syndromes, including NF1. In addition to similar molecular origins, these Ras-related diseases, including Noonan syndrome, LEOPARD syndrome, hereditary gingival fibromatosis 1, capillary malformation–arteriovenous malformation (CM-AVM) syndrome, Costello syndrome, autoimmune lymphoproliferative syndrome (ALPS), cardio-facio-cutaneous (CFC) syndrome, and Legius syndrome, have considerable phenotypic overlap. Thus, targeted molecular treatment may be effective for multiple diseases. Figure reproduced with permission from Tidyman and Rauen.92
Illustration depicting the signal transduction pathways involved in NF1 tumorigenesis. Growth factors (gf) interact with receptors at the cell surface, activating guanine nucleotide exchange factors and resulting in activated Ras. Activated Ras sends intracellular signals activating the phosphoinositol 3′ kinase (PI3K), AKT, and mTOR pathway. Activated Ras also activates the Raf-MAK (mitogen-activated kinase)/MEK pathway to stimulate ERK (extracellular signal–related kinase), which can enter the nucleus and promote transcription. Normally, neurofibromin downregulates Ras through its GAP-related domain, and therefore in its absence or at decreased levels in NF1, signaling is increased through all of these pathways resulting in cell proliferation and inhibited apoptosis. Adapted by permission from Macmillan Publishers Ltd:Oncogene 26: 4609–4616, copyright 2007.
Drawing demonstrating the common Ras/MAPK pathways responsible for multiple developmental syndromes, including NF1. In addition to similar molecular origins, these Ras-related diseases, including Noonan syndrome, LEOPARD syndrome, hereditary gingival fibromatosis 1, capillary malformation–arteriovenous malformation (CM-AVM) syndrome, Costello syndrome, autoimmune lymphoproliferative syndrome (ALPS), cardio-facio-cutaneous (CFC) syndrome, and Legius syndrome, have considerable phenotypic overlap. Thus, targeted molecular treatment may be effective for multiple diseases. Figure reproduced with permission from Tidyman and Rauen.92
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1
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SawadaS,,FlorellS,,PurandareSM,,OtaM,,StephensK, &ViskochilD:Identification of NF1 mutations in both alleles of a dermal neurofibroma.Nat Genet14:110–112,1996
SerraE,,ArsE,,RavellaA,,SánchezA,,PuigS, &RosenbaumT, et al.:Somatic NF1 mutational spectrum in benign neurofibromas: mRNA splice defects are common among point mutations.Hum Genet108:416–429,2001
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TuckerT,,FriedmanJM,,FriedrichRE,,WenzelR,,FünstererC, &MautnerVF:Longitudinal study of neurofibromatosis 1 associated plexiform neurofibromas.J Med Genet46:81–85,2009
UpadhyayaM,,HanS,,ConsoliC,,MajounieE,,HoranM, &ThomasNS, et al.:Characterization of the somatic mutational spectrum of the neurofibromatosis type 1 (NF1) gene in neurofibromatosis patients with benign and malignant tumors.Hum Mutat23:134–146,2004
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ViskochilD,,BuchbergAM,,XuG,,CawthonRM,,StevensJ, &WolffRK, et al.:Deletions and a translocation interrupt a cloned gene at the neurofibromatosis type 1 locus.Cell62:187–192,1990
ViskochilDH,The structure and function of the NF1 gene: molecular pathophysiology.FriedmanJM,,GutmannDH,,MacCollinM, &RiccardiVM:Neurofibromatosis: Phenotype, Natural History, and Pathogenesised 3Baltimore,Johns Hopkins University Press,1999.119–141
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WallaceMR,,MarchukDA,,AndersenLB,,LetcherR,,OdehHM, &SaulinoAM, et al.:Type 1 neurofibromatosis gene: identification of a large transcript disrupted in three NF1 patients.Science249:181–186,1990
XuGF,,LinB,,TanakaK,,DunnD,,WoodD, &GestelandR, et al.:The catalytic domain of the neurofibromatosis type 1 gene product stimulates ras GTPase and complements ira mutants of S. cerevisiae.Cell63:835–841,1990
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YanN,,RiccaC,,FletcherJ,,GloverT,,SeizingerBR, &ManneV:Farnesyltransferase inhibitors block the neurofibromatosis type I (NF1) malignant phenotype.Cancer Res55:3569–3575,1995
YangFC,,IngramDA,,ChenS,,ZhuY,,YuanJ, &LiX, et al.:Nf1-dependent tumors require a microenvironment containing Nf1+/– and c-kit-dependent bone marrow.Cell135:437–448,2008
ZhengH,,ChangL,,PatelN,,YangJ,,LoweL, &BurnsDK, et al.:Induction of abnormal proliferation by nonmyelinating schwann cells triggers neurofibroma formation.Cancer Cell13:117–128,2008
