Secretory meningiomas are defined by combined KLF4 K409Q and TRAF7 mutations

Abstract

Meningiomas are among the most frequent intracranial tumors. The secretory variant of meningioma is characterized by glandular differentiation, formation of intracellular lumina and pseudopsammoma bodies, expression of a distinct pattern of cytokeratins and clinically by pronounced perifocal brain edema. Here we describe whole-exome sequencing analysis of DNA from 16 secretory meningiomas and corresponding constitutional tissues. All secretory meningiomas invariably harbored a mutation in both KLF4 and TRAF7. Validation in an independent cohort of 14 secretory meningiomas by Sanger sequencing or derived cleaved amplified polymorphic sequence (dCAPS) assay detected the same pattern, with KLF4 mutations observed in a total of 30/30 and TRAF7 mutations in 29/30 of these tumors. All KLF4 mutations were identical, affected codon 409 and resulted in a lysine to glutamine exchange (K409Q). KLF4 mutations were not found in 89 non-secretory meningiomas, 267 other intracranial tumors including gliomas, glioneuronal tumors, pituitary adenomas and metastases, 59 peripheral nerve sheath tumors and 52 pancreatic tumors. TRAF7 mutations were restricted to the WD40 domains. While KLF4 mutations were exclusively seen in secretory meningiomas, TRAF7 mutations were also observed in 7/89 (8 %) of non-secretory meningiomas. KLF4 and TRAF7 mutations were mutually exclusive with NF2 mutations. In conclusion, our findings suggest an essential contribution of combined KLF4 K409Q and TRAF7 mutations in the genesis of secretory meningioma and demonstrate a role for TRAF7 alterations in other non-NF2 meningiomas.

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

Fig. 1
Fig. 2
Fig. 3

References

  1. 1.

    Akaogi K, Nakajima Y, Ito I, Kawasaki S, Oie SH, Murayama A, Kimura K, Yanagisawa J (2009) KLF4 suppresses estrogen-dependent breast cancer growth by inhibiting the transcriptional activity of ERalpha. Oncogene 28:2894–2902

    PubMed  Article  CAS  Google Scholar 

  2. 2.

    Bouwmeester T, Bauch A, Ruffner H, Angrand PO, Bergamini G, Croughton K, Cruciat C, Eberhard D, Gagneur J, Ghidelli S, Hopf C, Huhse B, Mangano R, Michon AM, Schirle M, Schlegl J, Schwab M, Stein MA, Bauer A, Casari G, Drewes G, Gavin AC, Jackson DB, Joberty G, Neubauer G, Rick J, Kuster B, Superti-Furga G (2004) A physical and functional map of the human TNF-alpha/NF-kappa B signal transduction pathway. Nat Cell Biol 6:97–105

    PubMed  Article  CAS  Google Scholar 

  3. 3.

    Brastianos PK, Horowitz PM, Santagata S, Jones RT, McKenna A, Getz G, Ligon KL, Palescandolo E, Van Hummelen P, Ducar MD, Raza A, Sunkavalli A, Macconaill LE, Stemmer-Rachamimov AO, Louis DN, Hahn WC, Dunn IF, Beroukhim R (2013) Genomic sequencing of meningiomas identifies oncogenic SMO and AKT1 mutations. Nature genetics

  4. 4.

    Brembeck FH, Rustgi AK (2000) The tissue-dependent keratin 19 gene transcription is regulated by GKLF/KLF4 and Sp1. J biol chem 275:28230–28239

    PubMed  CAS  Google Scholar 

  5. 5.

    Buccoliero AM, Gheri CF, Castiglione F, Ammannati F, Gallina P, Taddei A, Garbini F, Rossi Degl’Innocenti D, Arganini L, Di Lorenzo N, Mennonna P, Taddei GL (2007) Merlin expression in secretory meningiomas: evidence of an NF2-independent pathogenesis? Immunohistochemical study. Appl Immunohistochem Mol Morphol 15:353–357

    PubMed  Article  Google Scholar 

  6. 6.

    Clark VE, Erson-Omay EZ, Serin A, Yin J, Cotney J, Ozduman K, Avsar T, Li J, Murray PB, Henegariu O, Yilmaz S, Gunel JM, Carrion-Grant G, Yilmaz B, Grady C, Tanrikulu B, Bakircioglu M, Kaymakcalan H, Caglayan AO, Sencar L, Ceyhun E, Atik AF, Bayri Y, Bai H, Kolb LE, Hebert R, Omay SB, Mishra-Gorur K, Choi M, Overton JD, Holland EC, Mane S, State MW, Bilguvar K, Baehring JM, Gutin PH, Piepmeier JM, Vortmeyer A, Brennan CW, Pamir MN, Kilic T, Lifton RP, Noonan JP, Yasuno K, Gunel M (2013) Genomic Analysis of Non-NF2 Meningiomas Reveals Mutations in TRAF7, KLF4, AKT1, and SMO. Science

  7. 7.

    Hartmann C, Sieberns J, Gelhaar C, Simon M, Paulus W, von Deimling A (2006) NF2 mutations in secretory and other rare variants of meningiomas. Brain Pathol 16:15–19

    PubMed  Article  CAS  Google Scholar 

  8. 8.

    Jones D, Jäger N, Kool M, Zichner T, Hutter B, Sultan M, Cho Y-J, Pugh T, Hovestadt V, Stütz A, Rausch T, Warnatz H-J, Ryzhova M, Bender S, Sturm D, Pleier S, Cin H, Pfaff E, Sieber L, Wittmann A, Remke M, Witt H, Hutter S, Tzaridis T, Weischenfeldt J, Raeder B, Avci M, Amstislavskiy V, Zapatka M, Weber U, Wang Q, Lasitschka B, Bartholomae C, Schmidt M, von Kalle C, Ast V, Lawerenz C, Eils J, Kabbe R, Benes V, van Sluis P, Koster J, Volckmann R, Shih D, Betts M, Russell R, Coco S, Tonini G, Schüller U, Hans V, Graf N, Kim Y-J, Monoranu C, Roggendorf W, Unterberg A, Herold-Mende C, Milde T, Kulozik A, von Deimling A, Witt O, Maass E, Rössler J, Ebinger M, Schuhmann M, Frühwald M, Hasselblatt M, Jabado N, Rutkowski S, von Bueren A, Williamson D, Clifford S, McCabe M, Collins V, Wolf S, Wiemann S, Lehrach H, Brors B, Scheurlen W, Felsberg J, Reifenberger G, Northcott P, Taylor M, Meyerson M, Pomeroy S, Yaspo M-L, Korbel J, Korshunov A, Eils R, Pfister S, Lichter P (2012) Dissecting the genomic complexity underlying medulloblastoma. Nature 488:100–105

    PubMed  Article  CAS  Google Scholar 

  9. 9.

    Korhonen K, Salminen T, Raitanen J, Auvinen A, Isola J, Haapasalo H (2006) Female predominance in meningiomas can not be explained by differences in progesterone, estrogen, or androgen receptor expression. J Neurooncol 80:1–7

    PubMed  Article  CAS  Google Scholar 

  10. 10.

    Li H (2011) Improving SNP discovery by base alignment quality. Bioinformatics 27:1157–1158

    PubMed  Article  CAS  Google Scholar 

  11. 11.

    Li H, Durbin R (2009) Fast and accurate short read alignment with Burrows-Wheeler transform. Bioinformatics 25:1754–1760

    PubMed  Article  CAS  Google Scholar 

  12. 12.

    Li H, Handsaker B, Wysoker A, Fennell T, Ruan J, Homer N, Marth G, Abecasis G, Durbin R (2009) The Sequence Alignment/Map format and SAMtools. Bioinformatics 25:2078–2079

    PubMed  Article  Google Scholar 

  13. 13.

    Louis D, Ohgaki H, Wiestler O, Cavenee W (2007) World Health Organization Classification of Tumours of the Central Nervous System. In: Bosman F, Jaffe E, Lakhani S, Ohgaki H (eds) World Health Organization Classification of Tumours, 4th edn. IARC, Lyon

    Google Scholar 

  14. 14.

    Luo A, Kong J, Hu G, Liew CC, Xiong M, Wang X, Ji J, Wang T, Zhi H, Wu M, Liu Z (2004) Discovery of Ca2+-relevant and differentiation-associated genes downregulated in esophageal squamous cell carcinoma using cDNA microarray. Oncogene 23:1291–1299

    PubMed  Article  CAS  Google Scholar 

  15. 15.

    McConnell BB, Yang VW (2010) Mammalian Kruppel-like factors in health and diseases. Physiol Rev 90:1337–1381

    PubMed  Article  CAS  Google Scholar 

  16. 16.

    Meyer J, Pusch S, Balss J, Capper D, Mueller W, Christians A, Hartmann C, von Deimling A (2010) PCR and Restriction Endonuclease based Detection of IDH1 Mutations. Brain Pathol 20:298–300

    PubMed  Article  CAS  Google Scholar 

  17. 17.

    Nakamura K, Oshima T, Morimoto T, Ikeda S, Yoshikawa H, Shiwa Y, Ishikawa S, Linak MC, Hirai A, Takahashi H, Altaf-Ul-Amin M, Ogasawara N, Kanaya S (2011) Sequence-specific error profile of Illumina sequencers. Nucleic Acids Res 39:e90

    PubMed  Article  CAS  Google Scholar 

  18. 18.

    Neff MM, Turk E, Kalishman M (2002) Web-based primer design for single nucleotide polymorphism analysis. Trends Genet 18:613–615

    PubMed  Article  CAS  Google Scholar 

  19. 19.

    Probst-Cousin S, Villagran-Lillo R, Lahl R, Bergmann M, Schmid KW, Gullotta F (1997) Secretory meningioma: clinical, histologic, and immunohistochemical findings in 31 cases. Cancer 79:2003–2015

    PubMed  Article  CAS  Google Scholar 

  20. 20.

    Regelsberger J, Hagel C, Emami P, Ries T, Heese O, Westphal M (2009) Secretory meningiomas: a benign subgroup causing life-threatening complications. Neuro Oncol 11:819–824

    PubMed  Article  Google Scholar 

  21. 21.

    Rowland BD, Peeper DS (2006) KLF4, p21 and context-dependent opposing forces in cancer. Nat Rev Cancer 6:11–23

    PubMed  Article  CAS  Google Scholar 

  22. 22.

    Ruttledge MH, Sarrazin J, Rangaratnam S, Phelan CM, Twist E, Merel P, Delattre O, Thomas G, Nordenskjöld M, Collins VP, Dumanski JP, Rouleau GA (1994) Evidence for the complete inactivation on the NF2 gene in the majority of sporadic meningiomas. Nat Genet 6:180–184

    PubMed  Article  CAS  Google Scholar 

  23. 23.

    Saifudeen Z, Dipp S, Fan H, El-Dahr SS (2005) Combinatorial control of the bradykinin B2 receptor promoter by p53, CREB, KLF-4, and CBP: implications for terminal nephron differentiation. Am J Physiol Ren Physiol 288:F899–F909

    Article  CAS  Google Scholar 

  24. 24.

    Schuetz A, Nana D, Rose C, Zocher G, Milanovic M, Koenigsmann J, Blasig R, Heinemann U, Carstanjen D (2011) The structure of the Klf4 DNA-binding domain links to self-renewal and macrophage differentiation. Cell Mol Life Sci 68:3121–3131

    PubMed  Article  CAS  Google Scholar 

  25. 25.

    Stover JF, Dohse NK, Unterberg AW (2000) Significant reduction in brain swelling by administration of nonpeptide kinin B2 receptor antagonist LF 16–0687Ms after controlled cortical impact injury in rats. J Neurosurg 92:853–859

    PubMed  Article  CAS  Google Scholar 

  26. 26.

    Takahashi K, Yamanaka S (2006) Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell 126:663–676

    PubMed  Article  CAS  Google Scholar 

  27. 27.

    Wang K, Li M, Hakonarson H (2010) ANNOVAR: functional annotation of genetic variants from high-throughput sequencing data. Nucleic Acids Res 38:e164

    PubMed  Article  Google Scholar 

  28. 28.

    Wellenreuther R, Kraus J, Lenartz D, Menon AG, Schramm J, Louis DN, Ramesh V, Gusella JF, Wiestler OD, von Deimling A (1995) Analysis of the neurofibromatosis 2 gene reveals molecular variants of meningioma. Am J Pathol 146:827–832

    PubMed  CAS  Google Scholar 

  29. 29.

    Wu J, Jiao Y, Dal Molin M, Maitra A, de Wilde RF, Wood LD, Eshleman JR, Goggins MG, Wolfgang CL, Canto MI, Schulick RD, Edil BH, Choti MA, Adsay V, Klimstra DS, Offerhaus GJ, Klein AP, Kopelovich L, Carter H, Karchin R, Allen PJ, Schmidt CM, Naito Y, Diaz LA Jr, Kinzler KW, Papadopoulos N, Hruban RH, Vogelstein B (2011) Whole-exome sequencing of neoplastic cysts of the pancreas reveals recurrent mutations in components of ubiquitin-dependent pathways. Proc Natl Acad Sci USA 108:21188–21193

    PubMed  Article  CAS  Google Scholar 

  30. 30.

    Zotti T, Uva A, Ferravante A, Vessichelli M, Scudiero I, Ceccarelli M, Vito P, Stilo R (2011) TRAF7 protein promotes Lys-29-linked polyubiquitination of IkappaB kinase (IKKgamma)/NF-kappaB essential modulator (NEMO) and p65/RelA protein and represses NF-kappaB activation. J Biol Chem 286:22924–22933

    PubMed  Article  CAS  Google Scholar 

  31. 31.

    Zotti T, Vito P, Stilo R (2012) The seventh ring: exploring TRAF7 functions. J Cell Physiol 227:1280–1284

    PubMed  Article  CAS  Google Scholar 

Download references

Acknowledgments

We wish to thank Tanja Göck, Kerstin Lindenberg and Diana Rieker for skillful technical assistance. We thank GATC Biotech AG for sequencing services.

Author information

Affiliations

Authors

Corresponding author

Correspondence to Andreas von Deimling.

Additional information

Note added in proof During the process of submitting this manuscript, a study published by Clark et al. reported the presence of TRAF7, KLF4, AKT1 and SMO mutations in Non-NF2 meningiomas [6].

Electronic supplementary material

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Reuss, D.E., Piro, R.M., Jones, D.T.W. et al. Secretory meningiomas are defined by combined KLF4 K409Q and TRAF7 mutations. Acta Neuropathol 125, 351–358 (2013). https://doi.org/10.1007/s00401-013-1093-x

Download citation

Keywords

  • Meningioma
  • Secretory
  • KLF4
  • TRAF7
  • NF2
  • Krüppel-like factor 4