Skip to main content
Log in

Different sized somatic NF1 locus rearrangements in neurofibromatosis 1-associated malignant peripheral nerve sheath tumors

  • Laboratory Investigation – Human/Animal Tissue
  • Published:
Journal of Neuro-Oncology Aims and scope Submit manuscript

Abstract

Neurofibromatosis type 1 (NF1) patients are at increased risk of developing both benign (neurofibromas) and malignant (malignant peripheral nerve sheath tumors, MPNST) tumors. Molecular data on tumor progression are scarce, and few studies have compared the NF1 locus copy number in these two tumor types. To further explore the role of such NF1 locus rearrangements in NF1 tumorigenesis, and the likely disruption to the associated genes, the NF1 gene region was analyzed in NF1-associated tumors. DNA from three MPNSTs and one neurofibroma, excised from three unrelated NF1 patients, were analyzed using an NF1 region customized array-based comparative genomic hybridization. The somatic NF1 inactivation mutational mechanisms associated with MPNSTs appear to be different from those in benign neurofibromas. Interestingly, the MPNST-associated deletion breakpoints did not involve the paralogous repetitive sequences that are involved in most germline NF1 deletions. The somatic smallest common region of deletion overlap, however, was restricted to approximately the same ~2.2-Mb interval that encompassed most of the genes deleted in NF1 recurrent constitutional deletions. A number of genes in addition to NF1 on 17q (centromere to 17q24.2) may be involved in MPNST development. A larger study is warranted to confirm these findings. As NF1 patients with such germline NF1 deletions do exhibit increased risk of developing MPNST, these present findings emphasize the likely role of at least some of these NF1 flanking genes in MPNST pathobiology.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

References

  1. Friedman JM (1999) Epidemiology of neurofibromatosis type 1. Am J Med Genet 89:1–6

    Article  PubMed  CAS  Google Scholar 

  2. Wallace MR, Marchuk DA, Andersen LB et al (1990) Type 1 neurofibromatosis gene: identification of a large transcript disrupted in three NF1. Science 249:181–186

    Article  PubMed  CAS  Google Scholar 

  3. Kluwe L, Siebert R, Gesk S, Friedrich RE, Tinschert S, Kehrer-Sawatzki H, Mautner VF (2004) Screening 500 unselected neurofibromatosis 1 patients for deletions of the NF1 gene. Hum Mutat 23:111–116

    Article  PubMed  CAS  Google Scholar 

  4. Ferner RE, Gutmann DH (2002) International consensus statement on malignant peripheral nerve sheath tumors in neurofibromatosis. Cancer Res 62:1573–1577

    PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  6. Brems H, Beert E, de Ravel T, Legius E (2009) Mechanisms in the pathogenesis of malignant tumors in neurofibromatosis type 1. Lancet Oncol 10:508–515

    Article  PubMed  CAS  Google Scholar 

  7. Upadhyaya M, Kluwe L, Spurlock G et al (2008) Germline and somatic NF1 gene mutation spectrum in NF1-associated malignant peripheral nerve sheath tumors (MPNSTs). Hum Mutat 29:74–82

    Article  PubMed  CAS  Google Scholar 

  8. Upadhyaya M, Spurlock G, Monem B et al (2008) Germline and somatic NF1 gene mutations in plexiform neurofibromas. Hum Mutat 29:E103–E111

    Article  PubMed  Google Scholar 

  9. Mantripragada KK, de Stahl TD, Patridge C et al (2009) Genome-wide high-resolution analysis of DNA copy number alterations in NF1-associated malignant peripheral nerve sheath tumors using 32 K BAC array. Genes Chromosomes Cancer 48:897–907

    Article  PubMed  CAS  Google Scholar 

  10. Stumpf D, Alksne J, Annegers J et al (1988) Neurofibromatosis conference statement. Arch Neurol 45:575–578

    Google Scholar 

  11. Spurlock G, Griffiths S, Uff J, Upadhyaya M (2007) Somatic alterations of the NF1 gene in an NF1 individual with multiple benign tumors (internal and external) and malignant tumor types. Fam Cancer 6:463–471

    Article  PubMed  CAS  Google Scholar 

  12. Mantripragada KK, Thuresson AC, Piotrowski A 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

    Article  PubMed  CAS  Google Scholar 

  13. Upadhyaya M, Spurlock G, Majounie E et al (2006) The heterogeneous nature of germline mutations in NF1 patients with malignant peripheral serve sheath tumors (MPNSTs). Hum Mutat 27:716

    Article  PubMed  Google Scholar 

  14. Kresse SH, Skårn M, Ohnstad HO et al (2008) DNA copy number changes in high-grade malignant peripheral nerve sheath tumors by array CGH. Mol Cancer 7:48

    Article  PubMed  Google Scholar 

  15. 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 68:2094–2105

    Article  PubMed  CAS  Google Scholar 

  16. Kumar MS, Lu J, Mercer KL, Golub TR, Jacks T (2007) Impaired microRNA processing enhances cellular transformation and tumorigenesis. Nat Genet 39:673–677

    Article  PubMed  CAS  Google Scholar 

  17. De Raedt T, Brems H, Wolkenstein P et al (2003) Elevated risk for MPNST in NF1 microdeletion patients. Am J Hum Genet 72:1288–1292

    Article  PubMed  Google Scholar 

  18. 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

    Article  PubMed  CAS  Google Scholar 

  19. Douglas J, Cilliers D, Coleman K et al (2007) Mutations in RNF135, a gene within the NF1 microdeletion region, cause phenotypic abnormalities including overgrowth. Nat Genet 39:963–965

    Article  PubMed  CAS  Google Scholar 

  20. Sasaki Y, Oshima Y, Koyama R et al (2008) Identification of flotillin-2, a major protein on lipid rafts, as a novel target of p53 family members. Mol Cancer Res 6:395–406

    Article  PubMed  CAS  Google Scholar 

  21. Hata T, Ogawa T, Yokoyama TA, Fukushige S, Horii A, Furukawa T (2004) DSCP1, a novel TP53-inducible gene, is upregulated by strong genotoxic stresses and its overexpression inhibits tumor cell growth in vitro. Int J Oncol 24:513–520

    PubMed  CAS  Google Scholar 

  22. Hamimes S, Arakawa H, Stasiak AZ et al (2005) RDM1, a novel RNA recognition motif (RRM)-containing protein involved in the cell response to cisplatin in vertebrates. J Biol Chem 280:9225–9235

    Article  PubMed  CAS  Google Scholar 

  23. Thacker J (2005) The RAD51 gene family, genetic instability and cancer. Cancer Lett 219:125–135

    Article  PubMed  CAS  Google Scholar 

  24. Zou H, Hu L, Li J, Zhan S, Cao K (2006) Cloning and characterization of a novel small monomeric GTPase, RasL10B, with tumor suppressor potential. Biotechnol Lett 28:1901–1908

    Article  PubMed  CAS  Google Scholar 

  25. Mantripragada KK, Spurlock G, Kluwe L, Chuzhanova N, Ferner RE, Frayling IM, Dumanski JP, Guha A, Mautner V, Upadhyaya M (2008) 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

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

We are grateful to Cancer Research UK for their financial support. We thank Mrs. Stephens and Dr. Ferner for tumor samples.

Conflict of interest

The authors declare that they have no competing interests.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Eric Pasmant.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 1 (DOC 30 kb)

Supplementary material 2 (DOC 37 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Pasmant, E., Vidaud, D., Harrison, M. et al. Different sized somatic NF1 locus rearrangements in neurofibromatosis 1-associated malignant peripheral nerve sheath tumors. J Neurooncol 102, 341–346 (2011). https://doi.org/10.1007/s11060-010-0328-0

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11060-010-0328-0

Keywords

Navigation