Skip to main content
Log in

Methylation-specific multiplex ligation-dependent probe amplification in meningiomas

  • Labaratory Investigation - Human/animal tissue
  • Published:
Journal of Neuro-Oncology Aims and scope Submit manuscript

Abstract

Genomic loss and promotor methylation contribute to inactivation of tumor suppressor genes (TSGs). Methylation-specific multiplex ligation-dependent probe amplification (MS-MLPA) is a relatively new method for simultaneous detection of both these alterations. Here, we apply MS-MLPA to a series of 15 meningiomas of different WHO grades. The two MS-MLPA probe sets used detect copy number changes in 55 unselected TSGs and promotor methylation in a subset of 36 of these genes. Our findings concerning genomic deletions are concordant with previously published studies using alternative techniques. The number of aberrations identified per tumor increased with histopathologically determined grading. The most frequent single event was deletion of the von Hippel-Lindau (VHL) gene in 12 of the 15 tumors. Moreover, VHL deletion status was associated with presence/absence of peritumoral edema. Methylation was rare, being observed in only four tumors and in each case restricted to a single gene. We conclude that a meningioma-specific MS-MLPA probe set would be a valuable tool for both research and diagnostic approaches in these tumors.

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.

Fig. 1
Fig. 2

Similar content being viewed by others

References

  1. Smith JS, Perry A, Borell TJ et al (2000) Alterations of chromosome arms 1p and 19q as predictors of survival in oligodendrogliomas, astrocytomas, and mixed oligoastrocytomas. J Clin Oncol 18:636–645

    PubMed  CAS  Google Scholar 

  2. Cairncross JG, Ueki K, Zlatescu MC et al (1998) Specific genetic predictors of chemotherapeutic response and survival in patients with anaplastic oligodendrogliomas. J Natl Cancer Inst 90:1473–1479. doi:10.1093/jnci/90.19.1473

    Article  PubMed  CAS  Google Scholar 

  3. Hegi ME, Diserens AC, Gorlia T et al (2005) MGMT gene silencing and benefit from temozolomide in glioblastoma. N Engl J Med 352:997–1003. doi:10.1056/NEJMoa043331

    Article  PubMed  CAS  Google Scholar 

  4. Ruttledge MH, Sarrazin J, Rangaratnam S et al (1994) Evidence for the complete inactivation of the NF2 gene in the majority of sporadic meningiomas. Nat Genet 6:180–184. doi:10.1038/ng0294-180

    Article  PubMed  CAS  Google Scholar 

  5. Schouten JP, McElgunn CJ, Waaijer R et al (2002) Relative quantification of 40 nucleic acid sequences by multiplex ligation-dependent probe amplification. Nucleic Acids Res 30:e57. doi:10.1093/nar/gnf056

    Article  PubMed  Google Scholar 

  6. Nowee ME, Snijders AM, Rockx DA et al (2007) DNA profiling of primary serous ovarian and fallopian tube carcinomas with array comparative genomic hybridization and multiplex ligation-dependent probe amplification. J Pathol 213:46–55. doi:10.1002/path.2217

    Article  PubMed  CAS  Google Scholar 

  7. Jeuken J, Cornelissen S, Boots-Sprenger S et al (2006) Multiplex ligation-dependent probe amplification: a diagnostic tool for simultaneous identification of different genetic markers in glial tumors. J Mol Diagn 8:433–443. doi:10.2353/jmoldx.2006.060012

    Article  PubMed  CAS  Google Scholar 

  8. Martinez-Glez V, Franco-Hernandez C, Lomas J et al (2007) Multiplex ligation-dependent probe amplification (MLPA) screening in meningioma. Cancer Genet Cytogenet 173:170–172. doi:10.1016/j.cancergencyto.2006.09.011

    Article  PubMed  CAS  Google Scholar 

  9. Nygren AO, Ameziane N, Duarte HM et al (2005) Methylation-specific MLPA (MS-MLPA): simultaneous detection of CpG methylation and copy number changes of up to 40 sequences. Nucleic Acids Res 33:e128. doi:10.1093/nar/gni127

    Article  PubMed  Google Scholar 

  10. Berkhout M, Nagtegaal ID, Cornelissen SJ et al (2007) Chromosomal and methylation alterations in sporadic and familial adenomatous polyposis-related duodenal carcinomas. Mod Pathol 20:1253–1262. doi:10.1038/modpathol.3800952

    Article  PubMed  CAS  Google Scholar 

  11. Chen K, Sawhney R, Khan M et al (2007) Methylation of multiple genes as diagnostic and therapeutic markers in primary head and neck squamous cell carcinoma. Arch Otolaryngol Head Neck Surg 133:1131–1138. doi:10.1001/archotol.133.11.1131

    Article  PubMed  Google Scholar 

  12. Worsham MJ, Chen KM, Meduri V et al (2006) Epigenetic events of disease progression in head and neck squamous cell carcinoma. Arch Otolaryngol Head Neck Surg 132:668–677. doi:10.1001/archotol.132.6.668

    Article  PubMed  Google Scholar 

  13. Jeuken JW, Cornelissen SJ, Vriezen M et al (2007) MS-MLPA: an attractive alternative laboratory assay for robust, reliable, and semiquantitative detection of MGMT promoter hypermethylation in gliomas. Lab Invest J Tech Methods Pathol 87:1055–1065

    Article  CAS  Google Scholar 

  14. Louis DN, Ohgaki H, Wiestler OD et al (2007) The 2007 WHO classification of tumors of the central nervous system. Acta Neuropathol 114:97–109. doi:10.1007/s00401-007-0243-4

    Article  PubMed  Google Scholar 

  15. Teixeira MR (2002) Combined classical and molecular cytogenetic analysis of cancer. Eur J Cancer 38:1580–1584. doi:10.1016/S0959-8049(02)00117-X

    Article  PubMed  CAS  Google Scholar 

  16. Tomlinson IP, Lambros MB, Roylance RR (2002) Loss of heterozygosity analysis: practically and conceptually flawed? Genes Chromosomes Cancer 34:349–353. doi:10.1002/gcc.10085

    Article  PubMed  Google Scholar 

  17. van Dijk MC, Rombout PD, Boots-Sprenger SH et al (2005) Multiplex ligation-dependent probe amplification for the detection of chromosomal gains and losses in formalin-fixed tissue. Diagn Mol Pathol 14:9–16. doi:10.1097/01.pas.0000146701.98954.47

    Article  PubMed  Google Scholar 

  18. Simon M, Bostrom JP, Hartmann C (2007) Molecular genetics of meningiomas: from basic research to potential clinical applications. Neurosurgery 60:787–798. doi:10.1227/01.NEU.0000255421.78431.AE discussion 787–798

    Article  PubMed  Google Scholar 

  19. Weber RG, Bostrom J, Wolter M et al (1997) Analysis of genomic alterations in benign, atypical, and anaplastic meningiomas: toward a genetic model of meningioma progression. Proc Natl Acad Sci USA 94:14719–14724. doi:10.1073/pnas.94.26.14719

    Article  PubMed  CAS  Google Scholar 

  20. Bostrom J, Meyer-Puttlitz B, Wolter M et al (2001) Alterations of the tumor suppressor genes CDKN2A (p16(INK4a)), p14(ARF), CDKN2B (p15(INK4b)), and CDKN2C (p18(INK4c)) in atypical and anaplastic meningiomas. Am J Pathol 159:661–669

    PubMed  CAS  Google Scholar 

  21. Buschges R, Ichimura K, Weber RG et al (2002) Allelic gain and amplification on the long arm of chromosome 17 in anaplastic meningiomas. Brain Pathol 12:145–153

    PubMed  CAS  Google Scholar 

  22. Perry A, Banerjee R, Lohse CM et al (2002) A role for chromosome 9p21 deletions in the malignant progression of meningiomas and the prognosis of anaplastic meningiomas. Brain Pathol 12:183–190

    PubMed  CAS  Google Scholar 

  23. Lamszus K, Kluwe L, Matschke J et al (1999) Allelic losses at 1p, 9q, 10q, 14q, and 22q in the progression of aggressive meningiomas and undifferentiated meningeal sarcomas. Cancer Genet Cytogenet 110:103–110. doi:10.1016/S0165-4608(98)00209-X

    Article  PubMed  CAS  Google Scholar 

  24. Cai DX, Banerjee R, Scheithauer BW et al (2001) Chromosome 1p and 14q FISH analysis in clinicopathologic subsets of meningioma: diagnostic and prognostic implications. J Neuropathol Exp Neurol 60:628–636

    PubMed  CAS  Google Scholar 

  25. Ozaki S, Nishizaki T, Ito H et al (1999) Comparative genomic hybridization analysis of genetic alterations associated with malignant progression of meningioma. J Neurooncol 41:167–174. doi:10.1023/A:1006086723607

    Article  PubMed  CAS  Google Scholar 

  26. Perry A, Gutmann DH, Reifenberger G (2004) Molecular pathogenesis of meningiomas. J Neurooncol 70:183–202. doi:10.1007/s11060-004-2749-0

    Article  PubMed  Google Scholar 

  27. Beetz C, Hartmann A, Kiehntopf M et al (2004) Rapid generation of detailed loss of heterozygosity profiles for routine diagnosis of gliomas. Clin Chem Lab Med 42:595–601. doi:10.1515/CCLM.2004.103

    Article  PubMed  CAS  Google Scholar 

  28. Arslantas A, Artan S, Oner U et al (2002) Comparative genomic hybridization analysis of genomic alterations in benign, atypical and anaplastic meningiomas. Acta Neurol Belg 102:53–62

    PubMed  Google Scholar 

  29. Lee JY, Finkelstein S, Hamilton RL et al (2004) Loss of heterozygosity analysis of benign, atypical, and anaplastic meningiomas. Neurosurgery 55:1163–1173. doi:10.1227/01.NEU.0000141081.07086.A0

    Article  PubMed  Google Scholar 

  30. Nakane Y, Natsume A, Wakabayashi T et al (2007) Malignant transformation-related genes in meningiomas: allelic loss on 1p36 and methylation status of p73 and RASSF1A. J Neurosurg 107:398–404. doi:10.3171/JNS-07/08/0398

    Article  PubMed  CAS  Google Scholar 

  31. Kim WY, Kaelin WG (2004) Role of VHL gene mutation in human cancer. J Clin Oncol 22:4991–5004. doi:10.1200/JCO.2004.05.061

    Article  PubMed  CAS  Google Scholar 

  32. Kaelin WG Jr (2004) The von Hippel-Lindau tumor suppressor gene and kidney cancer. Clin Cancer Res 10:6290S–6295S. doi:10.1158/1078-0432.CCR-sup-040025

    Article  PubMed  CAS  Google Scholar 

  33. Keen JC, Davidson NE (2003) The biology of breast carcinoma. Cancer 97:825–833. doi:10.1002/cncr.11126

    Article  PubMed  Google Scholar 

Download references

Acknowledgments

We thank the patients for participating and K. Stein for excellent technical assistance. The study was supported by a grant from the Interdisziplinäres Zentrum für Klinische Forschung (IZKF) Jena (TP 3.8 to T.D. and R.K.).

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Christian Beetz.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Ewald, C., Hofmann, T., Kuhn, S.A. et al. Methylation-specific multiplex ligation-dependent probe amplification in meningiomas. J Neurooncol 90, 267–273 (2008). https://doi.org/10.1007/s11060-008-9672-8

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11060-008-9672-8

Keywords

Navigation