Skip to main content
SpringerLink
Log in

DNA methylation of multiple promoter-associated CpG islands in meningiomas: relationship with the allelic status at 1p and 22q

  • Regular Paper
  • Published:
Acta Neuropathologica Aims and scope Submit manuscript

Abstract

The purpose of this research was to examine the DNA methylation profile of meningiomas. Accordingly, we examined the DNA methylation status of ten tumor-related genes (RB1, p16INK4a, p73, MGMT, ER, DAPK, TIMP-3, p14ARF, THBS1, and Caspase-8) in 98 meningiomas (68 grade I; 27 grade II; and 3 grade III samples) using methylation-specific PCR and sequencing. The most frequently methylated genes were THBS1 (30%), TIMP-3 (24%), p16INK4a (17%), MGMT (16%), p73 (15%), ER (15%), and p14ARF (13%), whereas methylation was relatively rare in the other genes (<10%). Methylation occurred in at least one gene in 77.5% of the cases and in three or more genes in 25.5%. Methylation was tumor specific since it was absent in the controls: two non-neoplastic meningeal samples and two non-neoplastic brain samples. The frequency of aberrant gene methylation in grade I versus grade II–III tumors showed some differences for TIMP-3, THBS1, MGMT, p16INK4a and p73; these differences reached statistical significance for TIMP-3: 18% in grade I versus 40% in grade II–III (P<0.02). Our previous loss of heterozygosity studies provided the allelic constitution at 1p and 22q for 60 of the 98 meningiomas included in this report. The level of aberrant promoter methylation increased in tumors (30 samples) displaying 1p loss (either isolated or as concurrent deletion at 1p/22q; P=0.014). These meningiomas primarily accumulated the epigenetic changes of THBS1 (14/30; 47%; P<0.005), TIMP-3 (12/30; 40%; P<0.05), p73 (10/30; 26%; P<0.02) and p14ARF/p16INK4a(7/30 each one; 23%; not significant). Our findings indicate that aberrant DNA methylation of promoter-associated CpG islands in meningiomas contributes to the development of these tumors.

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

Access this article

Log in via an institution

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. Alonso ME, Bello MJ, Gonzalez-Gomez P, Arjona D, Lomas J, Campos JM de, Isla A, Sarasa JL, Rey JA (2003) Aberrant promoter methylation of multiple genes in oligodendrogliomas and ependymomas. Cancer Genet Cytogenet 144:134–142

    Article  CAS  PubMed  Google Scholar 

  2. Alonso ME, Bello MJ, Gonzalez-Gomez P, Arjona D, Campos JM de, Gutierrez M, Rey JA (2004) Aberrant CpG island methylaiton of multiple genes in ependymal tumors. J Neurooncol 67:159–165

    Article  PubMed  Google Scholar 

  3. Amatya VJ, Takeshima Y, Inai K (2004) Methylation of p14(ARF) gene in meningiomas and its correlation to the p53 expression and mutation. Mod Pathol 17:705–710

    Google Scholar 

  4. Apte SS, Mattei M-G, Olsen BR (1994) Cloning of the cDNA encoding human tissue inhibitor of metalloproteinases-3 (TIMP-3) and mapping of the TIMP3 gene to chromosome 22. Genomics 19:86–90

    Article  CAS  PubMed  Google Scholar 

  5. Bachman KE, Herman JG, Corn PG, Merlo A, Costello JF, Cavenee WK, Baylin SB, Graff JR (1999) Methylation-associated silencing of the tissue inhibitor of Metalloproteinase-3 gene suggests a suppressor role in kidney, brain, and other human cancers. Cancer Res 59:798–802

    CAS  PubMed  Google Scholar 

  6. Baylin SB, Herman JG, Graff JR, Vertino PM, Issa JP (1998) Alterations in the DNA methylation: a fundamental aspect of neoplasia. Adv Cancer Res 72:141–196

    CAS  PubMed  Google Scholar 

  7. Bello MJ, Campos JM de, Kusak ME, Vaquero J, Sarasa JL, Pestaña A, Rey JA (1994) Allelic loss at 1p is associated with tumor progression of meningiomas. Genes Chromosomes Cancer 9:296–298

    CAS  PubMed  Google Scholar 

  8. Bello MJ, Campos JM de, Vaquero J, Kusak ME, Sarasa JL, Rey JA (2000) High-resolution analysis of chromosome arm 1p alterations in meningioma. Cancer Genet Cytogenet 120:30–36

    Article  CAS  PubMed  Google Scholar 

  9. Bello MJ, Alonso ME, Amiñoso C, Anselmo NP, Arjona D, Gonzalez-Gomez P, Lopez-Marin I, Campos JM de, Gutierrez M, Isla A, Kusak ME, Lassaletta L, Sarasa JL, Vaquero J, Casartelli C, Rey JA (2004) Hypermethylation of the DNA repair gene MGMT: association with TP53 G:C to A:T transitions in a series of 469 nervous system tumors. Mutation Res 554:23–32

    Article  CAS  Google Scholar 

  10. Boström J, Meyer-Puttlitz B, Wolter M, Blschke B, Weber RG, Lichter P, Ichimura K, Collins VP, Reifenberger G (2001) Alterations of the tumor suppressor genes CDKN2A (p16INK4a), p14ARF, CDKN2B (p15INK4b), and CDKN2C (p18INK4c) in atypical and anaplastic meningiomas. Am J Pathol 159:661–669

    PubMed  Google Scholar 

  11. Büschges R, Boström J, Wolter M, Blaschke B, Weber RG, Lichter P, Collins P, Reifenberger G (2001) Analysis of human meningiomas for aberrations of the MADH2, MADH4, APM-1 and DCC tumor suppressor genes on the long arm of chromosome 18. Int J Cancer 92:551–554

    Article  PubMed  Google Scholar 

  12. Cai DX, Banerjee R, Scheithauer BW, Lohse CM, Kleinschmidt-Demasters BK, Perry A (2001) Chromosome 1p and 14q FISH analysis in clinicopathologic subsets of meningioma: diagnostic and prognostic implications. J Neuropathol Exp Neurol 60:628–636

    Google Scholar 

  13. Corn PG, Kuerbitz SJ, Noesel MM van, Esteller M, Compitello N, Baylin SB, Herman JG (1999) Transcriptional silencing of the p73 gene in acute lymphoblastic leukemia and Burkitt’s lymphoma is associated with 5’ CpG island methylation. Cancer Res 59:3352–3356

    CAS  PubMed  Google Scholar 

  14. Costello JF, Plass C, Cavenee W (2000) Aberrant methylation of genes in low-grade astrocytomas. Brain Tumor Pathol 17:49–56

    CAS  PubMed  Google Scholar 

  15. Dong S-H, Pang JC-S, Poon W-S, Hu J, To K-F, Chang AR, Ng H-K (2001) Concurrent hypermethylation of multiple genes is associated with grade of oligodendroglial tumors. J Neuropathol Exp Neurol 60:808–816

    CAS  PubMed  Google Scholar 

  16. Esteller M, Toyota M, Sanchez-Cespedes M, Capella G, Peinado MA, Watkins DN, Issa J-PJ, Sidransky D, Baylin SB, Herman JG (2000) Inactivation of the DNA repair gene O6-methylguanine-DNA methyltransferase by promoter hypermethylation is associated with G to A mutations in K-ras in colorectal tumorigenesis. Cancer Res 60:2368–2371

    CAS  PubMed  Google Scholar 

  17. Esteller M, Corn PG, Baylin SB, Herman JG (2001) A gene hypermethylation profile of human cancer. Cancer Res 61:3225–3229

    CAS  PubMed  Google Scholar 

  18. Esteller M, Risques R-A, Minoru T, Capella G, Moreno V, Peinado MA, Baylin SH, Herman JG (2001) Promoter hypermethylation of the DNA repair gen O6-methylguanine-DNA methyltransferase is associated with the presence of G:C to A:T transition mutations in p53 in human colorectal tumorigenesis. Cancer Res 61:4689–4692

    CAS  PubMed  Google Scholar 

  19. Gonzalez-Gomez P, Bello MJ, Alonso ME, Arjona D, Lomas J, Campos JM de, Isla A, Rey JA (2003) CpG island methylation status and mutation analysis of the RB1 gene essential promoter region and protein-binding pocket domain in nervous system tumours. Br J Cancer 88:109–114

    Article  CAS  PubMed  Google Scholar 

  20. Gonzalez-Gomez P, Bello MJ, Alonso ME, Lomas J, Arjona D, Campos JM de, Vaquero J, Isla A, Lassaletta L, Gutierrez M, Sarasa JL, Rey JA (2003) CpG island methylation in sporadic and neurofibromatosis type 2-associated schwannomas. Clin Cancer Res 9:5601–5606

    Google Scholar 

  21. Gonzalez-Gomez P, Bello MJ, Arjona D, Alonso ME, Lomas J, Campos JM de, Kusak ME, Gutierrez M, Sarasa JL, Rey JA (2003) Aberrant CpG island methylation in neurofibromas and neurofibrosarcomas. Oncol Rep 10:1519–1523

    CAS  PubMed  Google Scholar 

  22. Gonzalez-Gomez P, Bello MJ, Arjona D, Lomas J, Alonso ME, Campos JM de, Vaquero J, Isla A, Gutierrez M, Rey JA (2003) Promoter hypermethylation of multiple genes in astrocytic gliomas. Int J Oncol 22:601–608

    CAS  PubMed  Google Scholar 

  23. Gonzalez-Gomez P, Bello MJ, Lomas J, Alonso ME, Amiñoso C, Lopez-Marin I, Anselmo NP, Sarasa JL, Gutierrez M, Casartelli C, Rey JA (2003) Aberrant methylation of multiple genes in neuroblastic tumours: relationship with MYCN amplification and allelic status at 1p. Eur J Cancer 39:1478–1485

    Article  CAS  PubMed  Google Scholar 

  24. Herman JG, Graff JR, Myohannen S, Nelkin BD, Baylin BD (1996) Methylation-specific PCR: a novel PCR assay for methylaiton status of CpG islands. Proc Natl Acad Sci USA 93:9821–9826

    Article  CAS  PubMed  Google Scholar 

  25. Hong C, Bollen AW, Costello JF (2003) The contribution of genetic and epigenetic mechanisms to gene silencing in oligodendrogliomas. Cancer Res 63:7600–7605

    CAS  PubMed  Google Scholar 

  26. Horiguchi K, Tomizawa Y, Tosaka M, Ishiuchi S, Kurihara H, Mori M, Saito N (2003) Epigenetic inactivation of RASSF1A candidate tumor suppressor gene at 3p21.3 in brain tumors. Oncogene 22:7862–7865

    Article  CAS  PubMed  Google Scholar 

  27. Jiang SY, Jordan VC (1992) Growth regulation of estrogen receptor-negative breast cancer cells transfected with complementary DNAs for estrogen receptor. J Natl Cancer Inst 65:163–168

    Google Scholar 

  28. Kaghad M, Bonnet H, Yang A, Creancier L, Biscan JC, Valent A, Minty A, Chalon P, Lelias JM, Dumont X, Ferrara P, McKeon F, Caput D (1997) Monoallelically expressed gene related to p53 at 1p36, a region frequently deleted in neuroblastoma and other human cancer. Cell 90:809–819

    Article  CAS  PubMed  Google Scholar 

  29. Kamijo T, Weber JD, Zambetti G, Zindy F, Roussel MF, Sherr CJ (1998) Functional and physical interactions of the ARF tumor suppressor with p53 and Mdm2. Proc Natl Acad Sci USA 95:8292–8297

    Article  CAS  PubMed  Google Scholar 

  30. Kang GH, Shim Y-H, Jung H-Y, Kim WH, Ro JY, Rhyu M-G (2001) CpG island methylation in premalignant stages of gastric carcinoma. Cancer Res 61:2847–2851

    CAS  PubMed  Google Scholar 

  31. Kino T, Takeshima H, Nakao M, Nishi T, Yamamoto K, Kimura T, Saito Y, Kochi M, Kuratsu J, Saya H, Ushio Y (2001) Identification of the cis-acting region in the NF2 gene promoter as a potential target for mutation and methylation-dependent silencing in schwannoma. Genes Cells 6:441–454

    Article  CAS  PubMed  Google Scholar 

  32. Lamszus K, Kluwe L, Matschke J, Meissner H, Laas R, Westphal M (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

    Article  CAS  PubMed  Google Scholar 

  33. Leone PE, Bello MJ, Campos JM de, Vaquero J, Sarasa JL, Pestaña A, Rey JA (1999) NF2 gene mutations and allelic status of 1p, 14q and 22q in sporadic meningiomas. Oncogene 18:2231–2239

    Article  CAS  PubMed  Google Scholar 

  34. Li Q, Ahuja N, Burger PC, Issa J-PJ (1999) Methylation and silencing of the thrombospondin-1 promoter in human cancer. Oncogene 18:3284–3289

    Article  CAS  PubMed  Google Scholar 

  35. Lindblom A, Ruttledge M, Collins VP, Nordenskjold M, Dumanski JP (1994) Chromosomal deletions in anaplastic meningiomas suggest multiple regions outside chromosome 22 as important in tumor progression. Int J Cancer 56:354–357

    CAS  PubMed  Google Scholar 

  36. Lomas J, Amiñoso C, Gonzalez-Gomez P, Alonso ME, Arjona D, Lopez-Marin I, Campos JM de, Isla A, Vaquero J, Gutierrez M, Sarasa JL, Bello MJ, Rey JA (2004) Methylation status of TP73 in meningiomas. Cancer Genet Cytogenet 148:148–151

    Article  CAS  PubMed  Google Scholar 

  37. Lopez-Gines C, Cerda-Nicolas M, Gil-Benso R, Callaghan R, Collado M, Roldan P, Llombart-Bosch A (2004) Association of loss of 1p and alterations of chromosome 14 in meningioma progression. Cancer Genet Cytogenet 148:123–128

    Article  CAS  PubMed  Google Scholar 

  38. Louis DN, Scheithauer BW, Budka H, Deimling A von, Kepes JJ (2000) Meningioma. In: Kleihues P, Cavenee WK (eds) Pathology and genetics. Tumours of the nervous system. World Health Organization classification of tumours. IARC Press, Lyon, pp 176–184

  39. Mihaila D, Gutierrez JA, Rosemblum ML, Newsham IF, Bogler O, Rempel SA (2003) Meningiomas: analysis of loss of heterozygosity on chromosome 10 in tumor progression and the delineation of four regions of chromosomal deletion in common with other cancers. Clin Cancer Res 9:4435–4442

    Google Scholar 

  40. Murakami M, Hashimoto N, Takahashi Y, Hosokawa Y, Inazawa J, Mineura K (2003) A consistent region of deletion on 1p36 in meningiomas: identification and relation to malignant progression. Cancer Genet Cytogenet 140:99–106

    Article  CAS  PubMed  Google Scholar 

  41. Nakamura M, Watanabe T, Yonekawa Y, Kleihues P, Ohgaki H (2001) Promoter methylation of the DNA repair gene MGMT in astrocytomas is frequently associated with G:C to A:T mutations of the TP53 tumor suppressor gene. Carcinogenesis 22:1715–1719

    Article  CAS  PubMed  Google Scholar 

  42. Nakamura M, Yonekawa Y, Kleihues P, Ohgaki H (2001) Promoter hypermethylation of the RB1 gene in glioblastomas. Lab Invest 81:77–82

    CAS  PubMed  Google Scholar 

  43. Natarajan AT, Vermeulen S, Darroudi F, Valentine MB, Brent TP, Mitra S, Tano K (1992) Chromosomal localization of human O(6)-methylguanine-DNA methyltransferase (MGMT) gene by in situ hybridization. Mutagenesis 7:83–85

    CAS  PubMed  Google Scholar 

  44. Pegg AE (1990) Mammalian O6-alkylguanine-DNA alkyltransferase regulation and importance in response to alkylating carcinogenic and therapeutic agents. Cancer Res 50:6119–6129

    CAS  PubMed  Google Scholar 

  45. Powe DG, Brough JL, Carter GI, Bailey EM, Stetler-Stevenson WG, Turner DR, Hewitt RE (1997) TIMP-3 mRNA expression is regionally increased in moderately and poorly differentiated colorectal adenocarcinoma. Br J Cancer 75:1678–1683

    CAS  PubMed  Google Scholar 

  46. Rempel SA, Schwechheimer K, Davis RL, Cavenee WK, Rosemblum, ML (1993) Loss of heterozygosity for loci on chromosme 10 is associated with morphologically malignant meningioma progression. Cancer Res 53:2386–2392

    CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  48. Simon M, Deimling A von, Larson JJ, Wellenreuther R, Kaskel P, Waha A, Warnick RE, Tew JM, Menon AG (1995) Allelic losses on chromosome 14, 10, and 1 in atypical and malignant meningiomas. A genetic model of meningioma progression. Cancer Res 55:4696–4701

    CAS  PubMed  Google Scholar 

  49. Simpson DJ, Hibberts NA, McNicol AM, Clayton RN, Farrell WE (2000) Loss of pRB expression in pituitary adenomas is associated with methylation of the RB1 CpG island. Cancer Res 60:1211–1216

    CAS  PubMed  Google Scholar 

  50. Sherr CJ (1996) Cancer cell cycles. Science 274:1672–1677

    Article  CAS  PubMed  Google Scholar 

  51. Teitz T, Wei T, Valentine MB, Vanin EF, Grenet J, Valentine VA, Behm FG, Look AT, Lahti JM, Kidd VJ (2000) Caspase 8 is deleted or silenced preferentially in childhood neuroblastoams with amplification of MYCN. Nat Med 6:529–535

    Article  CAS  PubMed  Google Scholar 

  52. Tse JY, Ng HK, Lo KW, Lam PY, Ng EK, Poon WS, Huang DP (1998) Analysis of cell cycle regulators: p16INK4A, pRb, and CDK4 in low- and high-grade meningiomas. Hum Pathol 29:1200–1207

    Article  CAS  PubMed  Google Scholar 

  53. Uhlmann K, Rohde K, Zeller C, Szymas J, Vogel S, Marczinek K, Thiel G, Nürnberg P, Laird PW (2003) Distinct methylaiton profiles of glioma subtypes. Int J Cancer 106:52–59

    Article  CAS  PubMed  Google Scholar 

  54. Watanabe T, Nakamura M, Yonekawa Y, Kleihues P, Ohgaki H (2001) Promoter hypermethylation and homozygous deletion of the p14ARF and p16INK4a genes in oligodendrogliomas. Acta Neuropathol 101:185–189

    CAS  PubMed  Google Scholar 

  55. Weber RG, Boström J, Wolter M, Baudis M, Collins VP, Reifenberger G, Lichter P (1997) Analysis of geneomic alterations in benign, atypical, and anaplastic meningiomas. Toward a genetic model of meningioma progression. Proc Natl Acad Sci USA 94:14719–14724

    Article  CAS  PubMed  Google Scholar 

  56. Wolter M, Reifenberger J, Blaschke B, Ichimura K, Schmidt EE, Collins VP, Reifenberger G (2001) Oligodendroglial tumors frequently demonstrate hypermethylation of the CDKN2A (MTS1, p16INK4a), p14ARF, and CDKN2B (MTS2, p15INK4b) tumor suppressor genes. J Neuropathol Exp Neurol 60:1170–1180

    CAS  PubMed  Google Scholar 

  57. Xing EP, Nie Y, Song Y, Yang G-Y, Cai YC, Wang LD, Yang CS (1999) Mechanisms of inactivation of p14ARF, p15INK4b, and p16INK4a genes in human esophageal squamous cell carcinoma. Clin Cancer Res 5:2704–2713

    Google Scholar 

  58. Yin D, Xie D, Hofmann W-K, Miller CW, Black KL, Koeffler HP (2002) Methylation, expression, and mutation analysis of the cell cycle control genes in human brain tumors. Oncogene 21:8372–8378

    Article  CAS  PubMed  Google Scholar 

  59. Yin D, Xie D, Hofmann W-K, Zhang W, Asotra K, Wong R, Black KL, Koeffler HP (2003) DNA repair gene O6-methylguanine-DNA methyltransferase: promoter hypermethylation associated with decreased expression and G:C to A:T mutations of p53 in brain tumors. Mol Carcinogenesis 36:23–31

    Article  CAS  Google Scholar 

  60. Zöchbauer-Müller S, Fong KM, Virmani AK, Geradts J, Gazdar AF, Minna JD (2001) Aberrant promoter methylation of multiple genes in non-small cell lung cancers. Cancer Res 61:249–255

    PubMed  Google Scholar 

Download references

Acknowledgements

This work was supported by grants 02/0669 and 03/0235 from FIS, Ministerio de Sanidad, and grant 08.1/0040/2003.1 from Consejeria de Educacion, Comunidad de Madrid, and grant from Fundación Mapfre Medicina. M. E. Alonso is supported by a predoctoral fellowship from Consejeria de Educacion, Comunidad de Madrid. We are indebted to Daniel Callejo (Servicio de Bioestadística, Hospital La Paz) for statistical advice.

Author information

Authors and Affiliations

  1. Department of C. Experimental, Laboratorio Oncogenetica Molecular, Hospital Universitario La Paz, Paseo Castellana 261, 28046, Madrid, Spain

    M. Josefa Bello, Cinthia Amiñoso, Isabel Lopez-Marin, Dolores Arjona, Pilar Gonzalez-Gomez, M. Eva Alonso, Jesus Lomas & Juan A. Rey

  2. Department of Neurosurgery, Hospital del Rio Hortega, 47010, Valladolid, Spain

    Jose M. de Campos & M. Elena Kusak

  3. Department of Neurosurgery, Clinica Puerta de Hierro, 28035, Madrid, Spain

    Jesus Vaquero

  4. Department of Neurosurgery, Hospital Universitario La Paz, 28046, Madrid, Spain

    Alberto Isla

  5. Department of Pathology, Hospital Universitario La Paz, 28046, Madrid, Spain

    Manuel Gutierrez

  6. Department of Pathology, Fundacion Jimenez Diaz, 28040, Madrid, Spain

    Jose L. Sarasa

Authors
  1. M. Josefa Bello
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Cinthia Amiñoso
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Isabel Lopez-Marin
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Dolores Arjona
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Pilar Gonzalez-Gomez
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. M. Eva Alonso
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Jesus Lomas
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Jose M. de Campos
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. M. Elena Kusak
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Jesus Vaquero
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Alberto Isla
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Manuel Gutierrez
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Jose L. Sarasa
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Juan A. Rey
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Juan A. Rey.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Bello, M.J., Amiñoso, C., Lopez-Marin, I. et al. DNA methylation of multiple promoter-associated CpG islands in meningiomas: relationship with the allelic status at 1p and 22q. Acta Neuropathol 108, 413–421 (2004). https://doi.org/10.1007/s00401-004-0911-6

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00401-004-0911-6

Keywords

Search

Navigation