Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

A RASopathy gene commonly mutated in cancer: the neurofibromatosis type 1 tumour suppressor

Key Points

  • The neurofibromatosis type 1 (NF1) research community has identified the NF1 gene and has developed mouse models of plexiform neurofibroma, optic pathway glioma, malignant peripheral nerve sheath tumours and juvenile myelomonocytic leukaemia, all of which are tumours that are found in patients with NF1.

  • The NF1 gene encodes a RAS GTPase-activating protein known as neurofibromin and is one of several genes that (when mutant) affect RAS–MAPK signalling, causing related diseases collectively known as RASopathies.

  • Preclinical and clinical testing consortia have found that inhibition of MEK shrinks benign tumours but that combinatorial therapies are likely to be needed for NF1-related malignancies. These may include targeting of other RAS effector pathways. Treatments that target NF1 could also be tested as treatments for other RASopathies.

  • The neurofibromin protein has been studied, and many potential interacting partners have been identified. However, many questions remain concerning the functional importance of possible interaction partners and roles of neurofibromin protein domains, and the interactions between neurofibromin and cyclic AMP signalling pathways.

  • NF1 mutations are common in most sporadic tumour types and can mediate resistance to therapy.

Abstract

Neurofibromatosis type 1 (NF1) is a common genetic disorder that predisposes affected individuals to tumours. The NF1 gene encodes a RAS GTPase-activating protein called neurofibromin and is one of several genes that (when mutant) affect RAS–MAPK signalling, causing related diseases collectively known as RASopathies. Several RASopathies, beyond NF1, are cancer predisposition syndromes. Somatic NF1 mutations also occur in 5–10% of human sporadic cancers and may contribute to resistance to therapy. To highlight areas for investigation in RASopathies and sporadic tumours with NF1 mutations, we summarize current knowledge of NF1 disease, the NF1 gene and neurofibromin, neurofibromin signalling pathways and recent developments in NF1 therapeutics.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Neurofibromatosis type 1 historical developments.
Figure 2: Disease manifestations in patients with neurofibromatosis type 1: epochs in which they develop.
Figure 3: Neurofibromatosis type 1 signalling pathways.
Figure 4: Neurofibromin protein structure and interacting proteins.

Similar content being viewed by others

References

  1. Crowe, F. W., Schull, W. J. & Neel, J. V. A Clinical, Pathological and Genetic Study of Multiple Neurofibromatosis (Charles C. Thomas, 1956).

  2. Evans, D. G. et al. Birth incidence and prevalence of tumor-prone syndromes: estimates from a UK family genetic register service. Am. J. Med. Genet. A 152A, 327–332 (2010).

    Article  CAS  PubMed  Google Scholar 

  3. Huson, S. M., Compston, D. A., Clark, P. & Harper, P. S. A genetic study of von Recklinghausen neurofibromatosis in south east Wales. I. Prevalence, fitness, mutation rate, and effect of parental transmission on severity. J. Med. Genet. 26, 704–711 (1989).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Friedman, J. M. & Birch, P. H. Type 1 neurofibromatosis: a descriptive analysis of the disorder in 1,728 patients. Am. J. Med. Genet. 70, 138–143 (1997).

    Article  CAS  PubMed  Google Scholar 

  5. Huson, S. M., Compston, D. A. & Harper, P. S. A genetic study of von Recklinghausen neurofibromatosis in south east Wales. II. Guidelines for genetic counselling. J. Med. Genet. 26, 712–721 (1989).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Evans, D. G. et al. Mortality in neurofibromatosis 1: in North West England: an assessment of actuarial survival in a region of the UK since 1989. Eur. J. Hum. Genet. 19, 1187–1191 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  7. Listernick, R., Charrow, J., Greenwald, M. & Mets, M. Natural history of optic pathway tumors in children with neurofibromatosis type 1: a longitudinal study. J. Pediatr. 125, 63–66 (1994).

    Article  CAS  PubMed  Google Scholar 

  8. [No authors listed.] Neurofibromatosis. Conference statement. National Institutes of Health Consensus Development Conference. Arch. Neurol. 45, 575–578 (1988).

  9. Gutmann, D. H. et al. The diagnostic evaluation and multidisciplinary management of neurofibromatosis 1 and neurofibromatosis 2. JAMA 278, 51–57 (1997).

    Article  CAS  PubMed  Google Scholar 

  10. Stiller, C. A., Chessells, J. M. & Fitchett, M. Neurofibromatosis and childhood leukaemia/lymphoma: a population-based UKCCSG study. Br. J. Cancer 70, 969–972 (1994).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Walther, M. M., Herring, J., Enquist, E., Keiser, H. R. & Linehan, W. M. von Recklinghausen's disease and pheochromocytomas. J. Urol. 162, 1582–1586 (1999).

    Article  CAS  PubMed  Google Scholar 

  12. Miettinen, M., Fetsch, J. F., Sobin, L. H. & Lasota, J. Gastrointestinal stromal tumors in patients with neurofibromatosis 1: a clinicopathologic and molecular genetic study of 45 cases. Am. J. Surg. Pathol. 30, 90–96 (2006).

    Article  PubMed  Google Scholar 

  13. Stewart, D. R. et al. Diagnosis, management, and complications of glomus tumours of the digits in neurofibromatosis type 1. J. Med. Genet. 47, 525–532 (2010).

    Article  PubMed  Google Scholar 

  14. Sung, L. et al. Neurofibromatosis in children with rhabdomyosarcoma: a report from the Intergroup Rhabdomyosarcoma Study IV. J. Pediatr. 144, 666–668 (2004).

    Article  PubMed  Google Scholar 

  15. Oktenli, C. et al. Unusual features in a patient with neurofibromatosis type 1: multiple subcutaneous lipomas, a juvenile polyp in ascending colon, congenital intrahepatic portosystemic venous shunt, and horseshoe kidney. Am. J. Med. Genet. A 127A, 298–301 (2004).

    Article  PubMed  Google Scholar 

  16. Viskochil, D. et al. Deletions and a translocation interrupt a cloned gene at the neurofibromatosis type 1 locus. Cell 62, 187–192 (1990).

    Article  CAS  PubMed  Google Scholar 

  17. Cawthon, R. M. et al. A major segment of the neurofibromatosis type 1 gene: cDNA sequence, genomic structure, and point mutations. Cell 62, 193–201 (1990).

    Article  CAS  PubMed  Google Scholar 

  18. Wallace, M. R. et al. Type 1 neurofibromatosis gene: identification of a large transcript disrupted in three NF1 patients. Science 249, 181–186 (1990).

    Article  CAS  PubMed  Google Scholar 

  19. Maertens, O. et al. Molecular pathogenesis of multiple gastrointestinal stromal tumors in NF1 patients. Hum. Mol. Genet. 15, 1015–1023 (2006).

    Article  PubMed  Google Scholar 

  20. Brems, H. et al. Glomus tumors in neurofibromatosis type 1: genetic, functional, and clinical evidence of a novel association. Cancer Res. 69, 7393–7401 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Madden, J. R., Rush, S. Z., Stence, N., Foreman, N. K. & Liu, A. K. Radiation-induced gliomas in 2 pediatric patients with neurofibromatosis type 1: case study and summary of the literature. J. Pediatr. Hematol. Oncol. 36, e105–e108 (2014).

    Article  PubMed  Google Scholar 

  22. Seminog, O. O. & Goldacre, M. J. Risk of benign tumours of nervous system, and of malignant neoplasms, in people with neurofibromatosis: population-based record-linkage study. Br. J. Cancer 108, 193–198 (2013). This paper suggests that individuals with NF1 are at risk of many types of cancer.

    Article  CAS  PubMed  Google Scholar 

  23. Ballester, R. et al. The NF1 locus encodes a protein functionally related to mammalian GAP and yeast IRA proteins. Cell 63, 851–859 (1990).

    Article  CAS  PubMed  Google Scholar 

  24. Martin, G. A. et al. The GAP-related domain of the neurofibromatosis type 1 gene product interacts with ras p21. Cell 63, 843–849 (1990).

    Article  CAS  PubMed  Google Scholar 

  25. Xu, G. F. et al. The neurofibromatosis type 1 gene encodes a protein related to GAP. Cell 62, 599–608 (1990).

    Article  CAS  PubMed  Google Scholar 

  26. Bos, J. L., Rehmann, H. & Wittinghofer, A. GEFs and GAPs: critical elements in the control of small G proteins. Cell 129, 865–877 (2007).

    Article  CAS  PubMed  Google Scholar 

  27. Ohba, Y. et al. Regulatory proteins of R-Ras, TC21/R-Ras2, and M-Ras/R-Ras3. J. Biol. Chem. 275, 20020–20026 (2000). This paper characterizes neurofibromin as an off signal for all RAS proteins.

    Article  CAS  PubMed  Google Scholar 

  28. Cox, A. D. & Der, C. J. Ras history: the saga continues. Small GTPases 1, 2–27 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  29. Simsek-Kiper, P. O. et al. Clinical and molecular analysis of RASopathies in a group of Turkish patients. Clin. Genet. 83, 181–186 (2013).

    Article  CAS  PubMed  Google Scholar 

  30. Kratz, C. P., Rapisuwon, S., Reed, H., Hasle, H. & Rosenberg, P. S. Cancer in Noonan, Costello, cardiofaciocutaneous and LEOPARD syndromes. Am. J. Med. Genet. C Semin. Med. Genet. 157C, 83–89 (2011).

    Article  PubMed  Google Scholar 

  31. Brems, H. et al. Germline loss-of-function mutations in SPRED1 cause a neurofibromatosis 1-like phenotype. Nature Genet. 39, 1120–1126 (2007).

    Article  CAS  PubMed  Google Scholar 

  32. Ding, L. et al. Somatic mutations affect key pathways in lung adenocarcinoma. Nature 455, 1069–1075 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. The Cancer Genome Atlas Research Network. Comprehensive genomic characterization defines human glioblastoma genes and core pathways. Nature 455, 1061–1068 (2008).

  34. The Cancer Genome Atlas Research Network. Integrated genomic analyses of ovarian carcinoma. Nature 474, 609–615 (2011).

  35. Meric-Bernstam, F. et al. Concordance of genomic alterations between primary and recurrent breast cancer. Mol. Cancer Ther. 13, 1382–1389 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Boudry-Labis, E. et al. Neurofibromatosis-1 gene deletions and mutations in de novo adult acute myeloid leukemia. Am. J. Hematol. 88, 306–311 (2013).

    Article  CAS  PubMed  Google Scholar 

  37. Shen, M. H., Harper, P. S. & Upadhyaya, M. Molecular genetics of neurofibromatosis type 1 (NF1). J. Med. Genet. 33, 2–17 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Messiaen, L. M. 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. Mutat. 15, 541–555 (2000).

    Article  CAS  PubMed  Google Scholar 

  39. Klose, A. et al. Selective disactivation of neurofibromin GAP activity in neurofibromatosis type 1. Hum. Mol. Genet. 7, 1261–1268 (1998). This study identifies a point mutation that affects the neurofibromin RASGAP domain in a patient with NF1, which supports a key role for neurofibromin RASGAP activity in NF1.

    Article  CAS  PubMed  Google Scholar 

  40. Fahsold, R. et al. Minor lesion mutational spectrum of the entire NF1 gene does not explain its high mutability but points to a functional domain upstream of the GAP-related domain. Am. J. Hum. Genet. 66, 790–818 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Balla, B. et al. Fast and robust next-generation sequencing technique using ion torrent personal genome machine for the screening of neurofibromatosis type 1 (NF1) gene. J. Mol. Neurosci. 53, 204–210 (2014).

    Article  CAS  PubMed  Google Scholar 

  42. Ko, J. M., Sohn, Y. B., Jeong, S. Y., Kim, H. J. & Messiaen, L. M. Mutation spectrum of NF1 and clinical characteristics in 78 Korean patients with neurofibromatosis type 1. Pediatr. Neurol. 48, 447–453 (2013).

    Article  PubMed  Google Scholar 

  43. Alkindy, A., Chuzhanova, N., Kini, U., Cooper, D. N. & Upadhyaya, M. Genotype–phenotype associations in neurofibromatosis type 1 (NF1): an increased risk of tumor complications in patients with NF1 splice-site mutations? Hum. Genomics 6, 12 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. De Raedt, T. et al. Elevated risk for MPNST in NF1 microdeletion patients. Am. J. Hum. Genet. 72, 1288–1292 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Upadhyaya, M. et al. An absence of cutaneous neurofibromas associated with a 3-bp inframe deletion in exon 17 of the NF1 gene (c.2970–2972 delAAT): evidence of a clinically significant NF1 genotype–phenotype correlation. Am. J. Hum. Genet. 80, 140–151 (2007).

    Article  CAS  PubMed  Google Scholar 

  46. Rieley, M. B. et al. Variable expression of neurofibromatosis 1 in monozygotic twins. Am. J. Med. Genet. A 155A, 478–485 (2011).

    Article  PubMed  Google Scholar 

  47. Easton, D. F., Ponder, M. A., Huson, S. M. & Ponder, B. A. An analysis of variation in expression of neurofibromatosis (NF) type 1 (NF1): evidence for modifying genes. Am. J. Hum. Genet. 53, 305–313 (1993).

    CAS  PubMed  PubMed Central  Google Scholar 

  48. De Raedt, T. et al. PRC2 loss amplifies Ras-driven transcription and confers sensitivity to BRD4-based therapies. Nature 514, 247–251 (2014).

    Article  CAS  PubMed  Google Scholar 

  49. Lee, W. et al. PRC2 is recurrently inactivated through EED or SUZ12 loss in malignant peripheral nerve sheath tumors. Nature Genet. 46, 1227–1232 (2014).

    Article  CAS  PubMed  Google Scholar 

  50. Zhang, M. et al. Somatic mutations of SUZ12 in malignant peripheral nerve sheath tumors. Nature Genet. 46, 1170–1172 (2014). References 48–50 show that Polycomb repressive complex genes are commonly inactivated in MPNSTs and support sensitivity of MPNSTs to bromodomain-containing protein 4 inhibition in combination with MEK inhibition.

    Article  CAS  PubMed  Google Scholar 

  51. Amlin-Van Schaick, J., Kim, S., Broman, K. W. & Reilly, K. M. Scram1 is a modifier of spinal cord resistance for astrocytoma on mouse chr 5. Mamm. Genome 23, 277–285 (2012).

    Article  CAS  PubMed  Google Scholar 

  52. Amlin-Van Schaick, J. C. et al. Arlm1 is a male-specific modifier of astrocytoma resistance on mouse chr 12. Neuro Oncol. 14, 160–174 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Saal, H. M. et al. Racial differences in the prevalence of optic nerve gliomas in neurofibromatosis type 1. Am. J. Hum. Genet. Abstr. 57, A54 (1995).

    Google Scholar 

  54. Diggs-Andrews, K. A. et al. Sex is a major determinant of neuronal dysfunction in neurofibromatosis type 1. Ann. Neurol. 75, 309–316 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Sun, T. et al. Sexually dimorphic RB inactivation underlies mesenchymal glioblastoma prevalence in males. J. Clin. Invest. 124, 4123–4133 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Ling, J. Q. et al. CTCF mediates interchromosomal colocalization between Igf2/H19 and Wsb1/Nf1. Science 312, 269–272 (2006).

    Article  CAS  PubMed  Google Scholar 

  57. Parsons, D. W. et al. An integrated genomic analysis of human glioblastoma multiforme. Science 321, 1807–1812 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Holzel, M. et al. NF1 is a tumor suppressor in neuroblastoma that determines retinoic acid response and disease outcome. Cell 142, 218–229 (2010). This study is the first in a series of papers to demonstrate that NF1 mutation confers resistance to therapy.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Kan, Z. et al. Diverse somatic mutation patterns and pathway alterations in human cancers. Nature 466, 869–873 (2010).

    Article  CAS  PubMed  Google Scholar 

  60. Kim, H. A., Ling, B. & Ratner, N. Nf1-deficient mouse Schwann cells are angiogenic and invasive and can be induced to hyperproliferate: reversion of some phenotypes by an inhibitor of farnesyl protein transferase. Mol. Cell. Biol. 17, 862–872 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Gutmann, D. H. et al. Heterozygosity for the neurofibromatosis 1 (NF1) tumor suppressor results in abnormalities in cell attachment, spreading and motility in astrocytes. Hum. Mol. Genet. 10, 3009–3016 (2001).

    Article  CAS  PubMed  Google Scholar 

  62. Ingram, D. A. et al. Genetic and biochemical evidence that haploinsufficiency of the Nf1 tumor suppressor gene modulates melanocyte and mast cell fates in vivo. J. Exp. Med. 191, 181–188 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. McGillicuddy, L. T. et al. Proteasomal and genetic inactivation of the NF1 tumor suppressor in gliomagenesis. Cancer Cell 16, 44–54 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Bajenaru, M. L. et al. Optic nerve glioma in mice requires astrocyte Nf1 gene inactivation and Nf1 brain heterozygosity. Cancer Res. 63, 8573–8577 (2003).

    CAS  PubMed  Google Scholar 

  65. Zhu, Y. et al. Early inactivation of p53 tumor suppressor gene cooperating with NF1 loss induces malignant astrocytoma. Cancer Cell 8, 119–130 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Verhaak, R. G. et al. Integrated genomic analysis identifies clinically relevant subtypes of glioblastoma characterized by abnormalities in PDGFRA, IDH1, EGFR, and NF1. Cancer Cell 17, 98–110 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Daston, M. M. et al. The protein product of the neurofibromatosis type 1 gene is expressed at highest abundance in neurons, Schwann cells, and oligodendrocytes. Neuron 8, 415–428 (1992).

    Article  CAS  PubMed  Google Scholar 

  68. Hinman, M. N., Sharma, A., Luo, G. & Lou, H. Neurofibromatosis type 1 alternative splicing is a key regulator of Ras signaling in neurons. Mol. Cell. Biol. 34, 2188–2197 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Bollag, G. & McCormick, F. Differential regulation of rasGAP and neurofibromatosis gene product activities. Nature 351, 576–579 (1991).

    Article  CAS  PubMed  Google Scholar 

  70. Vallee, B. et al. Nf1 RasGAP inhibition of LIMK2 mediates a new cross-talk between Ras and Rho pathways. PLoS ONE 7, e47283 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Stowe, I. B. et al. A shared molecular mechanism underlies the human rasopathies Legius syndrome and neurofibromatosis-1. Genes Dev. 26, 1421–1426 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Oliveira, A. F. & Yasuda, R. Neurofibromin is the major Ras inactivator in dendritic spines. J. Neurosci. 34, 776–783 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Wang, H. F. et al. Valosin-containing protein and neurofibromin interact to regulate dendritic spine density. J. Clin. Invest. 121, 4820–4837 (2011). References 71–73 provide the first strong evidence that specific neurofibromin-interacting proteins — SPRED1 and VCP — are crucial for neurofibromin function.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Tokuo, H. et al. Phosphorylation of neurofibromin by cAMP-dependent protein kinase is regulated via a cellular association of NG,NG-dimethylarginine dimethylaminohydrolase. FEBS Lett. 494, 48–53 (2001).

    Article  CAS  PubMed  Google Scholar 

  75. Zhang, P. et al. DDAH1 deficiency attenuates endothelial cell cycle progression and angiogenesis. PLoS ONE 8, e79444 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Tan, M. et al. SAG/RBX2/ROC2 E3 ubiquitin ligase is essential for vascular and neural development by targeting NF1 for degradation. Dev. Cell 21, 1062–1076 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Hollstein, P. E. & Cichowski, K. Identifying the ubiquitin ligase complex that regulates the NF1 tumor suppressor and Ras. Cancer Discov. 3, 880–893 (2013).

    Article  CAS  PubMed  Google Scholar 

  78. Rodenhiser, D. I., Andrews, J. D., Mancini, D. N., Jung, J. H. & Singh, S. M. Homonucleotide tracts, short repeats and CpG/CpNpG motifs are frequent sites for heterogeneous mutations in the neurofibromatosis type 1 (NF1) tumour-suppressor gene. Mutat. Res. 373, 185–195 (1997).

    Article  CAS  PubMed  Google Scholar 

  79. Gutmann, D. H. et al. Somatic neurofibromatosis type 1 (NF1) inactivation characterizes NF1-associated pilocytic astrocytoma. Genome Res. 23, 431–439 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Lenarduzzi, M. et al. MicroRNA-193b enhances tumor progression via down regulation of neurofibromin 1. PLoS ONE 8, e53765 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Paschou, M. & Doxakis, E. Neurofibromin 1 is a miRNA target in neurons. PLoS ONE 7, e46773 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Birnbaum, R. A. et al. Nf1 and Gmcsf interact in myeloid leukemogenesis. Mol. Cell 5, 189–195 (2000).

    Article  CAS  PubMed  Google Scholar 

  83. Rizvi, T. A. et al. A novel cytokine pathway suppresses glial cell melanogenesis after injury to adult nerve. J. Neurosci. 22, 9831–9840 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Gouzi, J. Y. et al. The receptor tyrosine kinase Alk controls neurofibromin functions in Drosophila growth and learning. PLoS Genet. 7, e1002281 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Bollag, G. et al. Loss of NF1 results in activation of the Ras signaling pathway and leads to aberrant growth in haematopoietic cells. Nature Genet. 12, 144–148 (1996).

    Article  CAS  PubMed  Google Scholar 

  86. Jessen, W. J. et al. MEK inhibition exhibits efficacy in human and mouse neurofibromatosis tumors. J. Clin. Invest. 123, 340–347 (2013). This study shows that, in a mouse model, inhibition of MEK shrinks neurofibromas, which supports ongoing clinical trials.

    Article  CAS  PubMed  Google Scholar 

  87. Dai, C. et al. Loss of tumor suppressor NF1 activates HSF1 to promote carcinogenesis. J. Clin. Invest. 122, 3742–3754 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Brundage, M. E. et al. MAF mediates crosstalk between Ras–MAPK and mTOR signaling in NF1. Oncogene 33, 5626–5636 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Bodempudi, V. et al. Ral overactivation in malignant peripheral nerve sheath tumors. Mol. Cell. Biol. 29, 3964–3974 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Dasgupta, B., Yi, Y., Chen, D. Y., Weber, J. D. & Gutmann, D. H. Proteomic analysis reveals hyperactivation of the mammalian target of rapamycin pathway in neurofibromatosis 1-associated human and mouse brain tumors. Cancer Res. 65, 2755–2760 (2005).

    Article  CAS  PubMed  Google Scholar 

  91. Johannessen, C. M. et al. TORC1 is essential for NF1-associated malignancies. Curr. Biol. 18, 56–62 (2008).

    Article  CAS  PubMed  Google Scholar 

  92. Patmore, D. M. et al. In vivo regulation of TGFβ by R-Ras2 revealed through loss of the RasGAP protein Nf1. Cancer Res. 72, 5317–5327 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Keng, V. W. et al. PTEN and NF1 inactivation in Schwann cells produces a severe phenotype in the peripheral nervous system that promotes the development and malignant progression of peripheral nerve sheath tumors. Cancer Res. 72, 3405–3413 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Farrer, R. G., Farrer, J. R. & DeVries, G. H. Platelet-derived growth factor-BB activates calcium/calmodulin-dependent and -independent mechanisms that mediate Akt phosphorylation in the neurofibromin-deficient human Schwann cell line ST88-14. J. Biol. Chem. 288, 11066–11073 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Tanaka, K., Matsumoto, K. & Toh, E. A. IRA1, an inhibitory regulator of the RAS–cyclic AMP pathway in Saccharomyces cerevisiae. Mol. Cell. Biol. 9, 757–768 (1989).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Tanaka, K. et al. IRA2, a second gene of Saccharomyces cerevisiae that encodes a protein with a domain homologous to mammalian ras GTPase-activating protein. Mol. Cell. Biol. 10, 4303–4313 (1990).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Colombo, S., Paiardi, C., Pardons, K., Winderickx, J. & Martegani, E. Evidence for adenylate cyclase as a scaffold protein for Ras2–Ira interaction in Saccharomyces cerevisie. Cell. Signal. 26, 1147–1154 (2014).

    Article  CAS  PubMed  Google Scholar 

  98. Hegedus, B. et al. Neurofibromatosis-1 regulates neuronal and glial cell differentiation from neuroglial progenitors in vivo by both cAMP- and Ras-dependent mechanisms. Cell Stem Cell 1, 443–457 (2007).

    Article  CAS  PubMed  Google Scholar 

  99. Tong, J., Hannan, F., Zhu, Y., Bernards, A. & Zhong, Y. Neurofibromin regulates G protein-stimulated adenylyl cyclase activity. Nature Neurosci. 5, 95–96 (2002).

    Article  CAS  PubMed  Google Scholar 

  100. Wolman, M. A. et al. Modulation of cAMP and Ras signaling pathways improves distinct behavioral deficits in a zebrafish model of neurofibromatosis type 1. Cell Rep. 5, 1265–1270 (2014). This recent study demonstrates that RAS and cAMP signalling, both altered by loss of neurofibromin function, are crucial for specific behavioural deficits in a model system.

    Article  CAS  Google Scholar 

  101. Kim, H. A., Ratner, N., Roberts, T. M. & Stiles, C. D. Schwann cell proliferative responses to cAMP and Nf1 are mediated by cyclin D1. J. Neurosci. 21, 1110–1116 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Anastasaki, C. & Gutmann, D. H. Neuronal NF1/RAS regulation of cyclic AMP requires atypical PKC activation. Hum. Mol. Genet. 23, 6712–6721 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Tan, X. et al. The CREB–miR-9 negative feedback minicircuitry coordinates the migration and proliferation of glioma cells. PLoS ONE 7, e49570 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Warrington, N. M. et al. Cyclic AMP suppression is sufficient to induce gliomagenesis in a mouse model of neurofibromatosis-1. Cancer Res. 70, 5717–5727 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Rodriguez, F. J. et al. Gliomas in neurofibromatosis type 1: a clinicopathologic study of 100 patients. J. Neuropathol. Exp. Neurol. 67, 240–249 (2008).

    Article  PubMed  Google Scholar 

  106. Jones, D. T. et al. Recurrent somatic alterations of FGFR1 and NTRK2 in pilocytic astrocytoma. Nature Genet. 45, 927–932 (2013).

    Article  CAS  PubMed  Google Scholar 

  107. Zhu, Y. et al. Inactivation of NF1 in CNS causes increased glial progenitor proliferation and optic glioma formation. Development 132, 5577–5588 (2005).

    Article  CAS  PubMed  Google Scholar 

  108. Lee, Y. D., Gianino, S. M. & Gutmann, D. H. Innate neural stem cell heterogeneity determines the patterning of glioma formation in children. Cancer Cell 22, 131–138 (2012). This important paper suggests that the restricted localization of benign OPGs in children with NF1 occurs owing to the loss of NF1 in spatially restricted developing cells.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Shin, J. et al. Zebrafish neurofibromatosis type 1 genes have redundant functions in tumorigenesis and embryonic development. Dis. Model. Mech. 5, 881–894 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Mayes, D. A. et al. Nf1 loss and Ras hyperactivation in oligodendrocytes induce NOS-driven defects in myelin and vasculature. Cell Rep. 4, 1197–1212 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Serra, E. et al. Schwann cells harbor the somatic NF1 mutation in neurofibromas: evidence of two different Schwann cell populations. Hum. Mol. Genet. 9, 3055–3064 (2000).

    Article  CAS  PubMed  Google Scholar 

  112. Le, L. Q., Shipman, T., Burns, D. K. & Parada, L. F. Cell of origin and microenvironment contribution for NF1-associated dermal neurofibromas. Cell Stem Cell 4, 453–463 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Dugoff, L. & Sujansky, E. Neurofibromatosis type 1 and pregnancy. Am. J. Med. Genet. 66, 7–10 (1996).

    Article  CAS  PubMed  Google Scholar 

  114. Prada, C. E. et al. Pediatric plexiform neurofibromas: impact on morbidity and mortality in neurofibromatosis type 1. J. Pediatr. 160, 461–467 (2012).

    Article  PubMed  Google Scholar 

  115. Wu, J. et al. Plexiform and dermal neurofibromas and pigmentation are caused by Nf1 loss in desert hedgehog-expressing cells. Cancer Cell 13, 105–116 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Le, L. Q. et al. Susceptible stages in Schwann cells for NF1-associated plexiform neurofibroma development. Cancer Res. 71, 4686–4695 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Mayes, D. A. et al. Perinatal or adult Nf1 inactivation using tamoxifen-inducible PlpCre each cause neurofibroma formation. Cancer Res. 71, 4675–4685 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Zheng, H. et al. Induction of abnormal proliferation by nonmyelinating Schwann cells triggers neurofibroma formation. Cancer Cell 13, 117–128 (2008).

    Article  CAS  PubMed  Google Scholar 

  119. Yang, F. C. et al. Nf1-dependent tumors require a microenvironment containing Nf1+/−- and c-kit-dependent bone marrow. Cell 135, 437–448 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Chen, Z. et al. Cells of origin in the embryonic nerve roots for NF1-associated plexiform neurofibroma. Cancer Cell 26, 695–706 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. Williams, J. P. et al. Nf1 mutation expands an EGFR-dependent peripheral nerve progenitor that confers neurofibroma tumorigenic potential. Cell Stem Cell 3, 658–669 (2008). References 115–121 indicate that the neurofibroma cell of origin remains uncertain.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. Muir, D., Neubauer, D., Lim, I. T., Yachnis, A. T. & Wallace, M. R. Tumorigenic properties of neurofibromin-deficient neurofibroma Schwann cells. Am. J. Pathol. 158, 501–513 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  123. Tucker, T., Wolkenstein, P., Revuz, J., Zeller, J. & Friedman, J. M. Association between benign and malignant peripheral nerve sheath tumors in NF1. Neurology 65, 205–211 (2005).

    Article  CAS  PubMed  Google Scholar 

  124. Carli, M. et al. Pediatric malignant peripheral nerve sheath tumor: the Italian and German soft tissue sarcoma cooperative group. J. Clin. Oncol. 23, 8422–8430 (2005).

    Article  PubMed  Google Scholar 

  125. Evans, D. G. et al. Malignant peripheral nerve sheath tumours in neurofibromatosis 1. J. Med. Genet. 39, 311–314 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  126. Perrone, F. et al. PDGFRA, PDGFRB, EGFR, and downstream signaling activation in malignant peripheral nerve sheath tumor. Neuro Oncol. 11, 725–736 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  127. Bottillo, I. et al. Germline and somatic NF1 mutations in sporadic and NF1-associated malignant peripheral nerve sheath tumours. J. Pathol. 217, 693–701 (2009).

    Article  CAS  PubMed  Google Scholar 

  128. Miller, S. J. et al. Large-scale molecular comparison of human Schwann cells to malignant peripheral nerve sheath tumor cell lines and tissues. Cancer Res. 66, 2584–2591 (2006).

    Article  CAS  PubMed  Google Scholar 

  129. Beert, E. et al. Atypical neurofibromas in neurofibromatosis type 1 are premalignant tumors. Genes Chromosomes Cancer 50, 1021–1032 (2011). This is a key paper demonstrating that mutations in CDKN2A are the only common chromosomal changes, apart from NF1 mutations, that are consistently detectable by single-nucleotide polymorphism analysis during plexiform neurofibroma transition to MPNST.

    Article  CAS  PubMed  Google Scholar 

  130. Legius, E. et al. TP53 mutations are frequent in malignant NF1 tumors. Genes Chromosomes Cancer 10, 250–255 (1994).

    Article  CAS  PubMed  Google Scholar 

  131. Menon, A. G. et al. Chromosome 17p deletions and p53 gene mutations associated with the formation of malignant neurofibrosarcomas in von Recklinhausen neurofibromatosis. Proc. Natl Acad. Sci. USA 87, 5435–5439 (1990).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  132. Birindelli, S. et al. Rb and TP53 pathway alterations in sporadic and NF1-related malignant peripheral nerve sheath tumors. Lab. Invest. 81, 833–844 (2001).

    Article  CAS  PubMed  Google Scholar 

  133. De Raedt, T. et al. Exploiting cancer cell vulnerabilities to develop a combination therapy for Ras-driven tumors. Cancer Cell 20, 400–413 (2011). This is the first paper to identify a combination of therapies that target MPNSTs. The authors show that increasing proteotoxic stress causes tumour regression but only if combined with inhibition of the mTOR pathway.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  134. Mawrin, C. et al. Immunohistochemical and molecular analysis of p53, RB, and PTEN in malignant peripheral nerve sheath tumors. Virchows Arch. 440, 610–615 (2002).

    Article  CAS  PubMed  Google Scholar 

  135. Mantripragada, K. K. et al. High-resolution DNA copy number profiling of malignant peripheral nerve sheath tumors using targeted microarray-based comparative genomic hybridization. Clin. Cancer Res. 14, 1015–1024 (2008).

    Article  CAS  PubMed  Google Scholar 

  136. Haferlach, C. et al. AML with CBFB–MYH11 rearrangement demonstrate RAS pathway alterations in 92% of all cases including a high frequency of NF1 deletions. Leukemia 24, 1065–1069 (2010).

    Article  CAS  PubMed  Google Scholar 

  137. Holtkamp, N. et al. EGFR and erbB2 in malignant peripheral nerve sheath tumors and implications for targeted therapy. Neuro Oncol. 10, 946–957 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  138. Borrego-Diaz, E. et al. Overactivation of Ras signaling pathway in CD133+ MPNST cells. J. Neurooncol. 108, 423–434 (2012).

    Article  CAS  PubMed  Google Scholar 

  139. Spyra, M. et al. Cancer stem cell-like cells derived from malignant peripheral nerve sheath tumors. PLoS ONE 6, e21099 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  140. Cichowski, K. et al. Mouse models of tumor development in neurofibromatosis type 1. Science 286, 2172–2176 (1999).

    Article  CAS  PubMed  Google Scholar 

  141. Vogel, K. S. et al. Mouse tumor model for neurofibromatosis type 1. Science 286, 2176–2179 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  142. Dodd, R. D. et al. NF1 deletion generates multiple subtypes of soft-tissue sarcoma that respond to MEK inhibition. Mol. Cancer Ther. 12, 1906–1917 (2013).

    Article  CAS  PubMed  Google Scholar 

  143. Joseph, N. M. et al. The loss of Nf1 transiently promotes self-renewal but not tumorigenesis by neural crest stem cells. Cancer Cell 13, 129–140 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  144. Buchstaller, J., McKeever, P. E. & Morrison, S. J. Tumorigenic cells are common in mouse MPNSTs but their frequency depends upon tumor genotype and assay conditions. Cancer Cell 21, 240–252 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  145. Zhang, G. et al. Comparative oncogenomic analysis of copy number alterations in human and zebrafish tumors enables cancer driver discovery. PLoS Genet. 9, e1003734 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  146. Rahrmann, E. P. et al. Forward genetic screen for malignant peripheral nerve sheath tumor formation identifies new genes and pathways driving tumorigenesis. Nature Genet. 45, 756–766 (2013).

    Article  CAS  PubMed  Google Scholar 

  147. MacInnes, A. W., Amsterdam, A., Whittaker, C. A., Hopkins, N. & Lees, J. A. Loss of p53 synthesis in zebrafish tumors with ribosomal protein gene mutations. Proc. Natl Acad. Sci. USA 105, 10408–10413 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  148. Kumar, M. G., Emnett, R. J., Bayliss, S. J. & Gutmann, D. H. Glomus tumors in individuals with neurofibromatosis type 1. J. Am. Acad. Dermatol. 71, 44–48 (2014).

    Article  PubMed  Google Scholar 

  149. Jacks, T. et al. Tumor predisposition in mice heterozygous for a targeted mutation in NF1. Nature Genet. 7, 353–361 (1994).

    Article  CAS  PubMed  Google Scholar 

  150. Yoshimi, A., Kojima, S. & Hirano, N. Juvenile myelomonocytic leukemia: epidemiology, etiopathogenesis, diagnosis, and management considerations. Paediatr. Drugs 12, 11–21 (2010).

    Article  PubMed  Google Scholar 

  151. Chang, T. et al. Sustained MEK inhibition abrogates myeloproliferative disease in Nf1 mutant mice. J. Clin. Invest. 123, 335–339 (2013). This paper shows that, in a GEM JMML model, single-agent MEK inhibition significantly reduces disease, laying the foundation for human clinical trials.

    Article  CAS  PubMed  Google Scholar 

  152. Robertson, K. A. et al. Imatinib mesylate for plexiform neurofibromas in patients with neurofibromatosis type 1: a phase 2 trial. Lancet Oncol. 13, 1218–1224 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  153. Marcus, L. et al. Phase I study of the MEK1/2 inhibitor selumetinib (AZD6244) hydrogen sulfate in children and young adults with neurofibromatosis type 1 (NF1) and inoperable plexiform neurofibromas (PNs). J. Clin. Oncol. Abstr. 32, 10018 (2014).

    Article  Google Scholar 

  154. Katz, D., Lazar, A. & Lev, D. Malignant peripheral nerve sheath tumour (MPNST): the clinical implications of cellular signalling pathways. Expert Rev. Mol. Med. 11, e30 (2009).

    Article  PubMed  Google Scholar 

  155. Patel, A. J. et al. BET bromodomain inhibition triggers apoptosis of NF1-associated malignant peripheral nerve sheath tumors through Bim induction. Cell Rep. 6, 81–92 (2014).

    Article  CAS  PubMed  Google Scholar 

  156. Patel, A. V. et al. Ras-driven transcriptome analysis identifies aurora kinase A as a potential malignant peripheral nerve sheath tumor therapeutic target. Clin. Cancer Res. 18, 5020–5030 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  157. Mo, W. et al. CXCR4/CXCL12 mediate autocrine cell cycle progression in NF1-associated malignant peripheral nerve sheath tumors. Cell 152, 1077–1090 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  158. Watson, A. L. et al. Canonical Wnt/β-catenin signaling drives human Schwann cell transformation, progression, and tumor maintenance. Cancer Discov. 3, 674–689 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  159. Luscan, A. et al. The activation of the WNT signaling pathway is a hallmark in neurofibromatosis type 1 tumorigenesis. Clin. Cancer Res. 20, 358–371 (2014). References 157–159 show the activation of WNT signalling in human MPNSTs and provide preclinical evidence that supports the importance of WNT signalling in MPNSTs.

    Article  CAS  PubMed  Google Scholar 

  160. Kolberg, M. et al. Survival meta-analyses for >1800 malignant peripheral nerve sheath tumor patients with and without neurofibromatosis type 1. Neuro Oncol. 15, 135–147 (2013).

    Article  CAS  PubMed  Google Scholar 

  161. de Bruin, E. C. et al. Reduced NF1 expression confers resistance to EGFR inhibition in lung cancer. Cancer Discov. 4, 606–619 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  162. Maertens, O. et al. Elucidating distinct roles for NF1 in melanomagenesis. Cancer Discov. 3, 338–349 (2013).

    Article  CAS  PubMed  Google Scholar 

  163. Nissan, M. H. et al. Loss of NF1 in cutaneous melanoma is associated with RAS activation and MEK dependence. Cancer Res. 74, 2340–2350 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  164. Whittaker, S. R. et al. A genome-scale RNA interference screen implicates NF1 loss in resistance to RAF inhibition. Cancer Discov. 3, 350–362 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  165. Straussman, R. et al. Tumour micro-environment elicits innate resistance to RAF inhibitors through HGF secretion. Nature 487, 500–504 (2012). References 161–165 show that NF1 mutation causes resistance to therapy through multiple mechanisms.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  166. Reuss, D. E. et al. Functional MHC class II is upregulated in neurofibromin-deficient Schwann cells. J. Invest. Dermatol. 133, 1372–1375 (2013).

    Article  CAS  PubMed  Google Scholar 

  167. Carr, N. J. & Warren, A. Y. Mast cell numbers in melanocytic naevi and cutaneous neurofibromas. J. Clin. Pathol. 46, 86–87 (1993).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  168. Prada, C. E. et al. Neurofibroma-associated macrophages play roles in tumor growth and response to pharmacological inhibition. Acta Neuropathol. 125, 159–168 (2013).

    Article  CAS  PubMed  Google Scholar 

  169. Yang, F. C., Staser, K. & Clapp, D. W. The plexiform neurofibroma microenvironment. Cancer Microenviron. 5, 307–310 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  170. Ribeiro, S. et al. Injury signals cooperate with Nf1 loss to relieve the tumor-suppressive environment of adult peripheral nerve. Cell Rep. 5, 126–136 (2013).

    Article  CAS  PubMed  Google Scholar 

  171. Pong, W. W., Higer, S. B., Gianino, S. M., Emnett, R. J. & Gutmann, D. H. Reduced microglial CX3CR1 expression delays neurofibromatosis-1 glioma formation. Ann. Neurol. 73, 303–308 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  172. Patwardhan, P. P. et al. Sustained inhibition of receptor tyrosine kinases and macrophage depletion by PLX3397 and rapamycin as a potential new approach for the treatment of MPNSTs. Clin. Cancer Res. 20, 3146–3158 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  173. Chau, V. et al. Preclinical therapeutic efficacy of a novel pharmacologic inducer of apoptosis in malignant peripheral nerve sheath tumors. Cancer Res. 74, 586–597 (2014).

    Article  CAS  PubMed  Google Scholar 

  174. Wood, M. et al. Discovery of a small molecule targeting IRA2 deletion in budding yeast and neurofibromin loss in malignant peripheral nerve sheath tumor cells. Mol. Cancer Ther. 10, 1740–1750 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  175. Peacock, J. D. et al. Molecular-guided therapy predictions reveal drug resistance phenotypes and treatment alternatives in malignant peripheral nerve sheath tumors. J. Transl Med. 11, 213 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  176. Hummel, T. R. et al. Gene expression analysis identifies potential biomarkers of neurofibromatosis type 1 including adrenomedullin. Clin. Cancer Res. 16, 5048–5057 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  177. Park, S. J. et al. Serum biomarkers for neurofibromatosis type 1 and early detection of malignant peripheral nerve-sheath tumors. BMC Med. 11, 109 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  178. Weng, Y., Chen, Y., Chen, J., Liu, Y. & Bao, T. Identification of serum microRNAs in genome-wide serum microRNA expression profiles as novel noninvasive biomarkers for malignant peripheral nerve sheath tumor diagnosis. Med. Oncol. 30, 531 (2013).

    Article  CAS  PubMed  Google Scholar 

  179. Gutmann, D. H., Blakeley, J. O., Korf, B. R. & Packer, R. J. Optimizing biologically targeted clinical trials for neurofibromatosis. Expert Opin. Investig. Drugs 22, 443–462 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  180. Flex, E. et al. Activating mutations in RRAS underlie a phenotype within the RASopathy spectrum and contribute to leukaemogenesis. Hum. Mol. Genet. 23, 4315–4327 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  181. Aoki, Y. et al. Gain-of-function mutations in RIT1 cause Noonan syndrome, a RAS/MAPK pathway syndrome. Am. J. Hum. Genet. 93, 173–180 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  182. Chen, P. C. et al. Next-generation sequencing identifies rare variants associated with Noonan syndrome. Proc. Natl Acad. Sci. USA 111, 11473–11478 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  183. von Recklinghausen, F. Ueber die multiplen Fibrome der Haut und ihre Beziehung zu den multiplen Neuromen (August Hirschwald, 1882).

    Google Scholar 

  184. Sorensen, S. A., Mulvihill, J. J. & Nielsen, A. Long-term follow-up of von Recklinghausen neurofibromatosis. Survival and malignant neoplasms. N. Engl. J. Med. 314, 1010–1015 (1986).

    Article  CAS  PubMed  Google Scholar 

  185. Riccardi, V. M. Mast-cell stabilization to decrease neurofibroma growth. Preliminary experience with ketotifen. Arch. Dermatol. 123, 1011–1016 (1987).

    Article  CAS  PubMed  Google Scholar 

  186. Huson, S. M., Harper, P. S. & Compston, D. A. Von Recklinghausen neurofibromatosis. A clinical and population study in south-east Wales. Brain 111, 1355–1381 (1988).

    Article  PubMed  Google Scholar 

  187. Buchberg, A. M., Cleveland, L. S., Jenkins, N. A. & Copeland, N. G. Sequence homology shared by neurofibromatosis type-1 gene and IRA-1 and IRA-2 negative regulators of the RAS cyclic AMP pathway. Nature 347, 291–294 (1990).

    Article  CAS  PubMed  Google Scholar 

  188. Brannan, C. I. et al. Targeted disruption of the neurofibromatosis type-1 gene leads to developmental abnormalities in heart and various neural crest-derived tissues. Genes Dev. 8, 1019–1029 (1994).

    Article  CAS  PubMed  Google Scholar 

  189. Guo, H. F., The, I., Hannan, F., Bernards, A. & Zhong, Y. Requirement of Drosophila NF1 for activation of adenylyl cyclase by PACAP38-like neuropeptides. Science 276, 795–798 (1997).

    Article  CAS  PubMed  Google Scholar 

  190. The, I. et al. Rescue of a Drosophila NF1 mutant phenotype by protein kinase A. Science 276, 791–794 (1997).

    Article  CAS  PubMed  Google Scholar 

  191. Zhu, Y. et al. Ablation of NF1 function in neurons induces abnormal development of cerebral cortex and reactive gliosis in the brain. Genes Dev. 15, 859–876 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  192. Nguyen, R. et al. Plexiform neurofibromas in children with neurofibromatosis type 1: frequency and associated clinical deficits. J. Pediatr. 159, 652–655.e2 (2011).

    Article  PubMed  Google Scholar 

  193. DeBella, K., Szudek, J. & Friedman, J. M. Use of the National Institutes of Health criteria for diagnosis of neurofibromatosis 1 in children. Pediatrics 105, 608–614 (2000).

    Article  CAS  PubMed  Google Scholar 

  194. Stevenson, D. A. et al. Descriptive analysis of tibial pseudarthrosis in patients with neurofibromatosis 1. Am. J. Med. Genet. 84, 413–419 (1999).

    Article  CAS  PubMed  Google Scholar 

  195. Alivuotila, L. et al. Speech characteristics in neurofibromatosis type 1. Am. J. Med. Genet. A 152A, 42–51 (2010).

    Article  PubMed  Google Scholar 

  196. Feldmann, R., Denecke, J., Grenzebach, M., Schuierer, G. & Weglage, J. Neurofibromatosis type 1: motor and cognitive function and T2-weighted MRI hyperintensities. Neurology 61, 1725–1728 (2003).

    Article  CAS  PubMed  Google Scholar 

  197. Nicolin, G. et al. Natural history and outcome of optic pathway gliomas in children. Pediatr. Blood Cancer 53, 1231–1237 (2009).

    Article  PubMed  Google Scholar 

  198. Hyman, S. L., Shores, E. A. & North, K. N. Learning disabilities in children with neurofibromatosis type 1: subtypes, cognitive profile, and attention-deficit-hyperactivity disorder. Dev. Med. Child Neurol. 48, 973–977 (2006).

    Article  PubMed  Google Scholar 

  199. Garg, S. et al. Autism and other psychiatric comorbidity in neurofibromatosis type 1: evidence from a population-based study. Dev. Med. Child Neurol. 55, 139–145 (2013).

    Article  PubMed  Google Scholar 

  200. Friedman, J. M. et al. Cardiovascular disease in neurofibromatosis 1: report of the NF1 Cardiovascular Task Force. Genet. Med. 4, 105–111 (2002).

    Article  CAS  PubMed  Google Scholar 

  201. Ferner, R. E. et al. Guidelines for the diagnosis and management of individuals with neurofibromatosis 1. J. Med. Genet. 44, 81–88 (2007).

    Article  CAS  PubMed  Google Scholar 

  202. Aravind, L., Neuwald, A. F. & Ponting, C. P. Sec14p-like domains in NF1 and Dbl-like proteins indicate lipid regulation of Ras and Rho signaling. Curr. Biol. 9, R195–R197 (1999).

    Article  CAS  PubMed  Google Scholar 

  203. Welti, S., Fraterman, S., D'Angelo, I., Wilm, M. & Scheffzek, K. The sec14 homology module of neurofibromin binds cellular glycerophospholipids: mass spectrometry and structure of a lipid complex. J. Mol. Biol. 366, 551–562 (2007). This study shows that crystallization of the neurofibromin lipid-binding domain supports the relevance of lipid interaction to neurofibromin function.

    Article  CAS  PubMed  Google Scholar 

  204. D'Angelo, I., Welti, S., Bonneau, F. & Scheffzek, K. A novel bipartite phospholipid-binding module in the neurofibromatosis type 1 protein. EMBO Rep. 7, 174–179 (2006).

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

The authors apologize to colleagues whose work they were unable to cite owing to space limitations or inadvertent omission. They have attempted to emphasize remaining questions and the most recent data in the field. They thank K. M. Cichowski (Brigham and Women's Hospital, Massachusetts, USA), E. Schorry and N. Nassar (Cincinnati Children's Hospital, Ohio, USA), and B. Widemann (US National Cancer Institute) for reviewing the draft manuscript. N.R. is supported by grants from the US National Institutes of Health, the Department of Defense Program on Neurofibromatosis, the Children's Tumor Foundation and the Neurofibromatosis Therapeutic Acceleration Programs.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Nancy Ratner.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Related links

PowerPoint slides

Supplementary information

Glossary

Café-au-lait macules

Hyperpigmented spots on the skin of patients with neurofibromatosis type 1 (NF1). They are used as an NF1 diagnostic criterion, particularly in young children.

Polycomb repressive complex 2

A complex that regulates epigenetic silencing of chromatin and includes the subunits SUZ12, EED, EZH1 or EZH2 and RBAP48. It also has histone methyltransferase activity.

Astrocytes

The most abundant type of glial cell in the central nervous system. Astrocytes regulate the extracellular neuronal environment.

Imprinting control region

A regulatory element (a segment of DNA) that is modified by methylation to regulate gene expression.

Schwann cells

Glial cells derived from neural crest cells that ensheathe and myelinate axons in the peripheral nervous system.

Oligodendrocytes

Glial cells derived from neuroepithelial cells that ensheathe and myelinate axons in the central nervous system.

NG2 cells

Oligodendrocyte progenitor cells that may have additional functions in the mature brain.

Aurora kinase

A serine/threonine kinase that functions during mitosis and is required for correct function of centrosomes.

Bromodomain inhibitors

A new class of epigenetic modulators of gene expression.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Ratner, N., Miller, S. A RASopathy gene commonly mutated in cancer: the neurofibromatosis type 1 tumour suppressor. Nat Rev Cancer 15, 290–301 (2015). https://doi.org/10.1038/nrc3911

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrc3911

This article is cited by

Search

Quick links

Nature Briefing: Cancer

Sign up for the Nature Briefing: Cancer newsletter — what matters in cancer research, free to your inbox weekly.

Get what matters in cancer research, free to your inbox weekly. Sign up for Nature Briefing: Cancer