Journal of Neuro-Oncology

, Volume 87, Issue 1, pp 63–70

Meningiomas exhibit loss of heterozygosity of the APC gene

  • Nives Pećina-Šlaus
  • Tamara Nikuševa Martić
  • Davor Tomas
  • Vili Beroš
  • Martina Zeljko
  • Hrvoje Čupić
lab. investigation-human/animal tissue


The molecular mechanisms and candidate genes involved in development of meningiomas still need investigation and elucidation. In the present study 33 meningiomas were analyzed regarding genetic changes of tumor suppressor gene Adenomatous polyposis coli (APC), a component of the wnt signaling. Gene instability was tested by polymerase chain reaction/loss of heterozygosity (LOH) using Restriction Fragment Length Polymorphism (RFLP) method. RFLP was performed by two genetic markers, Rsa I in APC’s exon 11 and Msp I in its exon 15. The results of our analysis showed altogether 15 samples with LOH of the APC gene out of 32 heterozygous patients (47%). Seven patients had LOHs at both exons, while four LOHs were exclusive for exon 11 and four for exon 15. The changes were distributed according to pathohistological grade as follows: 46% of meningothelial meningioma showed LOH; 33% of fibrous; 75% of mixed (transitional); 75% of angiomatous, and one LOH was found in a single case of psammomatous meningioma. None of the LOHs were found in atypical and anaplastic cases. Immunostaining showed that samples with LOHs were accompanied with the absence of APC protein expression or presence of mutant APC proteins (χ= 13.81, df = 2, < 0.001). We also showed that nuclear localization of β-catenin correlates to APC genetic changes (χ= 21.96, df = 2, < 0.0001). The results of this investigation suggest that genetic changes of APC gene play a role in meningioma formation.


Adenomatous polyposis coli gene (APC) Loss of heterozygosity Meningiomas Tumors of the CNS Wnt signaling pathway 


  1. 1.
    Groden J, Thliveris A, Samowitz W, Carlson M, Gelbert L, Albertsen H, Joslyn G, Stevens J, Spirio L, Robertson M (1991) Identification and characterization of the familial adenomatous polyposis coli gene. Cell 66:589–600PubMedCrossRefGoogle Scholar
  2. 2.
    Gordon MD, Nusse R (2006) Wnt signalling: multiple pathways, multiple receptors, and multiple transcription factors. J Biol Chem 281:22429–22433PubMedCrossRefGoogle Scholar
  3. 3.
    Peifer M, Polakis P (2000) Wnt signaling in oncogenesis and embriogenesis—a look outside the nucleus. Science 287:1606–1609PubMedCrossRefGoogle Scholar
  4. 4.
    Pecina-Slaus N, Gall-Troselj K, Slaus M, Radic K, Nikuseva-Martic T, Pavelic K (2004) Genetic changes of the E-cadherin and APC tumour suppressor genes in clear cell renal cell carcinoma. Pathology 36:145–151PubMedCrossRefGoogle Scholar
  5. 5.
    Koch A, Waha A, Tonn JC, Sorensen N, Berthold F, Wolter M, Reifenberger J, Hartmann W, Friedl W, Reifenberger G, Wiestler OD, Pietsch T (2001) Somatic mutations of WNT/wingless signaling pathway components in primitive neuroectodermal tumors. Int J Cancer 93:445–449PubMedCrossRefGoogle Scholar
  6. 6.
    Howng SL, Wu CH, Cheng TS, Sy WD, Lin PC, Wang C, Hong YR (2002) Differential expression of Wnt genes, beta-catenin and E-cadherin in human brain tumors. Cancer Lett 183:95–101PubMedCrossRefGoogle Scholar
  7. 7.
    Fogarty MP, Kessler JD, Wechsler-Reya RJ (2005) Morphing into Cancer: the role of developmental signaling pathways in brain tumor formation. J Neurobiol 64:458–475PubMedCrossRefGoogle Scholar
  8. 8.
    He TC, Sparks AB, Rago C, Hermeking H, Zawel L, da Costa LT, Morin PJ, Vogelstein B, Kinzler KW (1998) Identification of c-MYC as a target of the APC pathway. Science 281:1509–1512PubMedCrossRefGoogle Scholar
  9. 9.
    Kleihues P, Louis DN, Scheithauer BW, Rorke LB, Reifenberger G, Burger PC, Cavenee WK (2002) The WHO classification of tumors of the nervous system. J Neuropathol Exp Neurol 61:215–225PubMedGoogle Scholar
  10. 10.
    Riemenschneider MJ, Perry A, Reifenberger G (2006) Histological classification and molecular genetics of meningiomas. Lancet Neurol 5:1045–1054PubMedCrossRefGoogle Scholar
  11. 11.
    Fuller CE, Perry A (2005) Molecular diagnostics in central nervous system tumors. Adv Anat Pathol 12:180–194PubMedCrossRefGoogle Scholar
  12. 12.
    Weber RG, Bostrom J, Wolter M, Baudis M, Collins VP, Reifenberger G, Lichter P (1997) Analysis of genomic alterations in benign, atypical, and anaplastic meningiomas: toward a genetic model of meningioma progression. Proc Natl Acad Sci USA 94:14719–14724PubMedCrossRefGoogle Scholar
  13. 13.
    Hall AC, Lucas FR, Salinas PC (2000) Axonal remodeling and synaptic differentiation in the cerebellum is regulated by WNT-7a signaling. Cell 100:525–535PubMedCrossRefGoogle Scholar
  14. 14.
    Patapoutian A, Reichardt LF (2000) Roles of wnt proteins in neural development maintenance. Curr Opin Neurobiol 10:392–399PubMedCrossRefGoogle Scholar
  15. 15.
    Yu X, Malenka RC (2003) Beta-catenin is critical for dendritic morphogenesis. Nature Neurosci 6:1169–1177PubMedCrossRefGoogle Scholar
  16. 16.
    Lie DC, Colamarino SA, Song HJ, Desire L, Mira H, Consiglio A, Lein ES, Jessberger S, Lansford H, Dearie AR, Gage FH (2005) Wnt signalling regulates adult hippocampal neurogenesis. Nature 437:1370–1375PubMedCrossRefGoogle Scholar
  17. 17.
    Brakeman JS, Gu SH, Wang XB, Dolin G, Baraban JM (1999) Neuronal localization of the Adenomatous polyposis coli tumor suppressor protein. Neuroscience 91:661–672PubMedCrossRefGoogle Scholar
  18. 18.
    Mori T, Nagase H, Horii A, Miyoshi Y, Shimano T, Nakatsuru S, Nakatsuru S, Aoki T, Arakawa H, Yanagisawa A, Ushio Y (1994) Germ-line and somatic mutations of the APC gene in patients with Turcot syndrome and analysis of APC mutations in brain tumors. Genes Chromosomes Cancer 9:168–172PubMedCrossRefGoogle Scholar
  19. 19.
    Hamilton SR, Liu B, Parsons RE, Papadopoulos N, Jen J, Powell SM, Krush AJ, Berk T, Cohen Z, Tetu B (1995) The molecular basis of Turcot’s syndrome. N Engl J Med 332:839–840 PubMedCrossRefGoogle Scholar
  20. 20.
    Perry A, Gutmann DH, Reifenberger G (2004) Molecular pathogenesis of meningiomas. J Neuroonco l70:183–202CrossRefGoogle Scholar
  21. 21.
    Wrobel G, Roerig P, Kokocinski F, Neben K, Hahn M, Reifenberger G, Lichter P (2005) Microarray-based gene expression profiling of benign, atypical and anaplastic meningiomas identified novel genes associated with meningioma progression. Int J Cancer 114:249–256PubMedCrossRefGoogle Scholar
  22. 22.
    Pecina-Slaus N (2003) Tumor suppresor gene E-cadherin and its role in normal and malignant cells. Cancer Cell Int E3:17.
  23. 23.
    Schwechheimer K, Zhou L, Birchmeier W (1998) E-Cadherin in human brain tumours: loss of immunoreactivity in malignant meningiomas. Virchows Arch 432:163–167PubMedCrossRefGoogle Scholar
  24. 24.
    Utsuki S, Oka H, Sato Y, Kawano N, Tsuchiya B, Kobayashi I, Fujii K (2005) Invasive meningioma is associated with a low expression of E-cadherin and beta-catenin. Clin Neuropathol 24:8–12PubMedGoogle Scholar
  25. 25.
    Brunner EC, Romeike BF, Jung M, Comtesse N, Meese E (2006) Altered expression of beta-catenin/E-cadherin in meningiomas. Histopathology 49:178–187PubMedCrossRefGoogle Scholar
  26. 26.
    Lee JY, Finkelstein S, Hamilton RL, Rekha R, King JT Jr, Omalu B (2004) Loss of heterozygosity analysis of benign, atypical, and anaplastic meningiomas. Neurosurgery 55:1163–1173CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC. 2007

Authors and Affiliations

  • Nives Pećina-Šlaus
    • 1
    • 2
  • Tamara Nikuševa Martić
    • 1
    • 2
  • Davor Tomas
    • 3
  • Vili Beroš
    • 4
  • Martina Zeljko
    • 1
  • Hrvoje Čupić
    • 3
  1. 1.Laboratory of Neurooncology, Croatian Institute for Brain ResearchMedical School University of ZagrebZagrebCroatia
  2. 2.Department of BiologyMedical School University of ZagrebZagrebCroatia
  3. 3.Ljudevit Jurak Department of PathologyUniversity Hospital “Sisters of Charity”ZagrebCroatia
  4. 4.Department of NeurosurgeryUniversity Hospital “Sisters of Charity”ZagrebCroatia

Personalised recommendations