Advertisement

Molecular Medicine

, Volume 17, Issue 1–2, pp 79–87 | Cite as

Identification of Genes Potentially Involved in the Increased Risk of Malignancy in NF1-Microdeleted Patients

  • Eric Pasmant
  • Julien Masliah-Planchon
  • Pascale Lévy
  • Ingrid Laurendeau
  • Nicolas Ortonne
  • Béatrice Parfait
  • Laurence Valeyrie-Allanore
  • Karen Leroy
  • Pierre Wolkenstein
  • Michel Vidaud
  • Dominique Vidaud
  • Ivan Bièche
Research Article

Abstract

Patients with NF1 microdeletion develop more neurofibromas at a younger age, and have an increased risk of malignant peripheral nerve sheath tumors (MPNSTs). We postulated that the increased risk of malignancy could be due to inactivation, in addition to NF1, of a second tumor suppressor gene located in the typical 1.4-Mb microdeletion found in most of the microdeleted patients. We investigated the expression of NF1, the other 16 protein-coding genes and the 2 microRNAs located in the 1.4-Mb microdeletion by means of real-time quantitative reverse-transcription polymerase chain reaction (RT-PCR) in a large series of human dermal and plexiform neurofibromas and MPNSTs. Five genes were significantly upregulated: OMG and SUZ12 in plexiform neurofibromas and ATAD5, EVI2A and C17 orf79 in MPNSTs. More interestingly, two genes were significantly downregulated (RNF135 and CENTA2) in tumor Schwann cells from MPNST biopsies and in MPNST cell lines. This study points to the involvement of several genes (particularly RNF135 and CENTA2) in the increased risk of malignancy observed in NF1-microdeleted patients.

Notes

Acknowledgments

This work was supported by Association pour la Recherche sur le Cancer, Association Neurofibromatoses et Recklinghausen, Ligue Française Contre les Neurofibromatoses, the Clinical Research program (PHRC 2002), INSERM Projet NF1GeneModif and Ministère de L’Enseignement Supérieur et de la Recherche.

Supplementary material

10020_2011_1701079_MOESM1_ESM.pdf (649 kb)
Supplementary material, approximately 411 KB.

References

  1. 1.
    Friedman JM. (1999) Epidemiology of neurofibromatosis type 1. Am. J. Med. Genet. 89:1–6.CrossRefGoogle Scholar
  2. 2.
    Cawthon RM, et al. (1990) A major segment of the neurofibromatosis type 1 gene: cDNA sequence, genomic structure, and point mutations. Cell. 62:193–201.CrossRefGoogle Scholar
  3. 3.
    Wallace MR, et al. (1990) Type 1 neurofibromatosis gene: identification of a large transcript disrupted in three NF1 patients. Science 249:181–6.CrossRefGoogle Scholar
  4. 4.
    Ferner RE, Gutmann DH. (2002) International consensus statement on malignant peripheral nerve sheath tumors in neurofibromatosis. Cancer Res. 62:1573–7.PubMedGoogle Scholar
  5. 5.
    Evans DG, et al. (2002) Malignant peripheral nerve sheath tumours in neurofibromatosis 1. J. Med. Genet. 39:311–4.CrossRefGoogle Scholar
  6. 6.
    Kluwe L, et al. (2004) Screening 500 unselected neurofibromatosis 1 patients for deletions of the NF1 gene. Hum. Mutat. 23:111–6.CrossRefGoogle Scholar
  7. 7.
    Mantripragada KK, et al. (2006) Identification of novel deletion breakpoints bordered by segmental duplications in the NF1 locus using high resolution array-CGH. J. Med. Genet. 43:28–38.CrossRefGoogle Scholar
  8. 8.
    Wimmer K, et al. (2006) Spectrum of single- and multiexon NF1 copy number changes in a cohort of 1,100 unselected NF1 patients. Genes Chromosomes Cancer 45:265–76.CrossRefGoogle Scholar
  9. 9.
    Dorschner MO, Sybert VP, Weaver M, Pletcher BA, Stephens K. (2000) NF1 microdeletion breakpoints are clustered at flanking repetitive sequences. Hum. Mol. Genet. 9:35–46.CrossRefGoogle Scholar
  10. 10.
    Jenne DE, et al. (2003) Complete physical map and gene content of the human NF1 tumor suppressor region in human and mouse. Genes Chromosomes Cancer 37:111–20.CrossRefGoogle Scholar
  11. 11.
    Kozaki K, Imoto I, Mogi S, Omura K, Inazawa J. (2008) Exploration of tumor-suppressive microRNAs silenced by DNA hypermethylation in oral cancer. Cancer Res. 68:2094–105.CrossRefGoogle Scholar
  12. 12.
    Upadhyaya M, et al. (1998) Gross deletions of the neurofibromatosis type 1 (NF1) gene are predominantly of maternal origin and commonly associated with a learning disability, dysmorphic features and developmental delay. Hum. Genet. 102:591–7.CrossRefGoogle Scholar
  13. 13.
    Venturin M, et al. (2004) Mental retardation and cardiovascular malformations in NF1-microdeleted patients point to candidate genes in 17q11.2. J. Med. Genet. 41:35–41.CrossRefGoogle Scholar
  14. 14.
    Wu BL, Austin MA, Schneider GH, Boles RG, Korf BR. (1995) Deletion of the entire NF1 gene detected by the FISH: four deletion patients associated with severe manifestations. Am. J. Med. Genet. 59:528–35.CrossRefGoogle Scholar
  15. 15.
    Douglas J, et al. (2007) Mutations in RNF135, a gene within the NF1 microdeletion region, cause phenotypic abnormalities including overgrowth. Nat. Genet. 39:963–5.CrossRefGoogle Scholar
  16. 16.
    De Raedt, et al. (2003) Elevated risk for MPNST in NF1 microdeletion patients. Am. J. Hum. Genet. 72:1288–92.CrossRefGoogle Scholar
  17. 17.
    Kluwe L, Friedrich RE, Peiper M, Friedman J, Mautner VF. (2003) Constitutional NF1 mutations in neurofibromatosis 1 patients with malignant peripheral nerve sheath tumors. Hum. Mutat. 22:420.CrossRefGoogle Scholar
  18. 18.
    Wu R, et al. (1999) Germline mutations in NF1 patients with malignancies. Genes Chromosomes Cancer 26:376–80.CrossRefGoogle Scholar
  19. 19.
    Pasmant E, et al. (2010) NF1 microdeletions in neurofibromatosis type 1: from genotype to phenotype. Hum. Mutat. 31:E1506–18.CrossRefGoogle Scholar
  20. 20.
    Piddubnyak V, et al. (2007) Positive regulation of apoptosis by HCA66, a new Apaf-1 interacting protein, and its putative role in the physiopathology of NF1 microdeletion syndrome patients. Cell Death Differ. 14:1222–33.CrossRefGoogle Scholar
  21. 21.
    Avellana-Adalid V, et al. (1998) In vitro and in vivo behaviour of NDF-expanded monkey Schwann cells. Eur. J. Neurosci. 10:291–300.CrossRefGoogle Scholar
  22. 22.
    Glasow A, et al. (2001) Expression of leptin (Ob) and leptin receptor (Ob-R) in human fibroblasts: regulation of leptin secretion by insulin. J. Clin. Endocrinol. Metab. 86:4472–9.CrossRefGoogle Scholar
  23. 23.
    Royer B, et al. (2001) Autocrine regulation of cord blood-derived human mast cell activation by IL-10. J. Allergy Clin. Immunol. 108:80–6.CrossRefGoogle Scholar
  24. 24.
    Bieche I, et al. (2001) Identification of CGA as a novel estrogen receptor-responsive gene in breast cancer: an outstanding candidate marker to predict the response to endocrine therapy. Cancer Res. 61:1652–8.PubMedGoogle Scholar
  25. 25.
    Bieche I, et al. (1999) Real-time reverse transcription-PCR assay for future management of ERBB2-based clinical applications. Clin. Chem. 45:1148–56.PubMedGoogle Scholar
  26. 26.
    Mann H, Whitney D. (1947) On a test of whether one of two random variables is stochastically larger than the other. Annals of Mathematical Statistics 18:50–60.CrossRefGoogle Scholar
  27. 27.
    Levy P, et al. (2004) Molecular profiles of neurofibromatosis type 1-associated plexiform neurofibromas: identification of a gene expression signature of poor prognosis. Clin. Cancer Res. 10:3763–71.CrossRefGoogle Scholar
  28. 28.
    Levy P, et al. (2004) Molecular profiling of malignant peripheral nerve sheath tumors associated with neurofibromatosis type 1, based on large-scale real-time RT-PCR. Mol. Cancer 3:20.CrossRefGoogle Scholar
  29. 29.
    Wang KC, et al. (2002) Oligodendrocyte-myelin glycoprotein is a Nogo receptor ligand that inhibits neurite outgrowth. Nature 417:941–4.CrossRefGoogle Scholar
  30. 30.
    Habib AA, Gulcher JR, Högnason T, Zheng L, Stefánsson K. (1998) The OMG gene, a second growth suppressor within the NF1 gene. Oncogene 16:1525–31.CrossRefGoogle Scholar
  31. 31.
    Lee TI, et al. (2006) Control of developmental regulators by Polycomb in human embryonic stem cells. Cell. 125:301–13.CrossRefGoogle Scholar
  32. 32.
    Sparmann A, van Lohuizen M. (2006) Polycomb silencers control cell fate, development and cancer. Nat Rev Cancer 6:846–56.CrossRefGoogle Scholar
  33. 33.
    Kirmizis A, Bartley SM, Farnham PJ. (2003) Identification of the polycomb group protein SUZ12 as a potential molecular target for human cancer therapy. Mol. Cancer Ther. 2:113–21.PubMedGoogle Scholar
  34. 34.
    Reynolds PA, et al. (2006) Tumor suppressor P16INK4A regulates polycomb-mediated DNA hypermethylation in human mammary epithelial cells. J. Biol. Chem. 281:24790–802.CrossRefGoogle Scholar
  35. 35.
    Li H, et al. (2007) Effects of rearrangement and allelic exclusion of JJAZ1/SUZ12 on cell proliferation and survival. Proc. Natl. Acad. Sci. U. S. A. 104:20001–6.CrossRefGoogle Scholar
  36. 36.
    Bartelt-Kirbach B, Wuepping M, Dodrimont-Lattke M, Kaufmann D. (2009) Expression analysis of genes lying in the NF1 microdeletion interval points to four candidate modifiers for neurofibroma formation. Neurogenetics 10:79–85.CrossRefGoogle Scholar
  37. 37.
    Hanck T, Stricker R, Sedehizade F, Reiser G. (2004) Identification of gene structure and subcellular localization of human centaurin alpha 2, and p42IP4, a family of two highly homologous, Ins 1,3,4,5-P4-/PtdIns 3,4,5-P3-binding, adapter proteins. J. Neurochem. 88:326–36.CrossRefGoogle Scholar
  38. 38.
    Randazzo PA, Hirsch DS. (2004) Arf GAPs multifunctional proteins that regulate membrane traffic and actin remodelling. Cell. Signal. 16:401–13.CrossRefGoogle Scholar
  39. 39.
    Hayashi H, et al. (2006) Centaurin-alpha1 is a phosphatidylinositol 3-kinase-dependent activator of ERK1/2 mitogen-activated protein kinases. J. Biol. Chem. 281:1332–7.CrossRefGoogle Scholar
  40. 40.
    Venkateswarlu K, Brandom KG, Yun H. (2007) PI-3-kinase-dependent membrane recruitment of centaurin-alpha2 is essential for its effect on ARF6-mediated actin cytoskeleton reorganisation. J. Cell. Sci. 120:792–801.CrossRefGoogle Scholar

Copyright information

© The Feinstein Institute for Medical Research 2011

Authors and Affiliations

  • Eric Pasmant
    • 1
    • 2
  • Julien Masliah-Planchon
    • 1
    • 2
  • Pascale Lévy
    • 1
  • Ingrid Laurendeau
    • 1
  • Nicolas Ortonne
    • 3
  • Béatrice Parfait
    • 1
    • 2
  • Laurence Valeyrie-Allanore
    • 4
  • Karen Leroy
    • 5
  • Pierre Wolkenstein
    • 4
  • Michel Vidaud
    • 1
    • 2
  • Dominique Vidaud
    • 1
    • 2
  • Ivan Bièche
    • 1
    • 2
    • 6
  1. 1.UMR745 INSERMUniversité Paris Descartes, Faculté des Sciences Pharmaceutiques et BiologiquesParisFrance
  2. 2.Service de Biochimie et de Génétique MoléculaireHôpital BeaujonClichyFrance
  3. 3.Département de Pathologie, Hôpital Henri Mondor-AP-HPUniversité Paris 12CréteilFrance
  4. 4.Service de Dermatologie, Hôpital Henri Mondor-AP-HPUniversité Paris 12CréteilFrance
  5. 5.Platform of Biological Resources, Hôpital Henri Mondor-AP-HPUniversité Paris 12CréteilFrance
  6. 6.INSERM U735Centre René HugueninSaint-CloudFrance

Personalised recommendations