Advertisement

Brain Tumor Pathology

, Volume 28, Issue 2, pp 127–135 | Cite as

O6-Methylguanine DNA methyltransferase expression in tumor cells predicts outcome of radiotherapy plus concomitant and adjuvant temozolomide therapy in patients with primary glioblastoma

  • Reiko Watanabe
  • Yoko Nakasu
  • Hiroshi Tashiro
  • Koichi Mitsuya
  • Ichiro Ito
  • Satoshi Nakasu
  • Takashi Nakajima
Original Article

Abstract

Expression of the O6-methylguanine-DNA methyltransferase (MGMT) gene has been shown to correlate with clinical outcomes in patients with glioblastoma multiforme treated with alkylating agents. We evaluated MGMT protein expression in 53 primary glioblastomas by the immunohistochemistry (IHC) and analyzed the correlation between results of immunostaining and patient outcomes. There were 28 MGMT-immunopositive and 25 negative glioblastomas. Patients with MGMT-immunonegative glioblastomas showed significantly longer progression-free survival (PFS) (P = 0.0032), but no statistically significant benefits on overall survival (OS) (P = 0.0825) were shown. In 41 glioblastomas treated with temozolomide (TMZ) therapy (MGMT-immunopositive: n = 22, negative: n = 19), both PFS and OS were significantly better in MGMT-immunonegative glioblastomas. (PFS: P = 0.0015, OS: P = 0.0384). We conclude that MGMT expression on immunohistochemistry (IHC) correlates with outcomes in patients with primary glioblastoma receiving TMZ and suggest the use of MGMT-IHC as a surrogate marker for predicting tumor chemosensitivity.

Keywords

Glioblastoma Immunohistochemistry MGMT Temozolomide 

Notes

Acknowledgments

We thank Mr. Piers Vigers for editorial assistance and advice on this work.

Conflict of interest

None declared.

References

  1. 1.
    Stupp R, Hegi ME, Mason WP et al (2009) Effects of radiotherapy with concomitant and adjuvant temozolomide versus radiotherapy alone on survival in gliobalstoma in a randomized phase III study: 5-year analysis of the EORTC-NCIC trial. Lancet Oncol 10:459–466PubMedCrossRefGoogle Scholar
  2. 2.
    Hegi ME, Diserens AC, Gorlia T et al (2005) MGMT gene silencing and benefit from temozolomide in glioblastoma. N Engl J Med 352:997–1003PubMedCrossRefGoogle Scholar
  3. 3.
    Everhard S, Tost J, Abdalaoui HE et al (2009) Identification of regions correlating MGMT promoter methylation and gene expression in bliobalstomas. Neuro Oncol 11:348–356PubMedCrossRefGoogle Scholar
  4. 4.
    Esteller M, Hamilton SR, Burger PC et al (1999) Inactivation of the DNA repair gene O6-methylguanine DNA methyltransferase by promoter hypermethylation is a common event in primary human neoplasia. Cancer Res 59:793–797PubMedGoogle Scholar
  5. 5.
    Möllemann M, Wolter M, Felsberg J et al (2005) Frequent promoter hypermethylation and low expression of the MGMT gene in oligodendroglioma tumors. Int J Cancer 113:379–385PubMedCrossRefGoogle Scholar
  6. 6.
    Brell M, Tortosa A, Verger E et al (2005) Prognostic significance of O6-methylguanine-DNA methyltransferase determined by promoter hypermethylation and immunohistochemical expression in anaplastic gliomas. Clin Cancer Res 11:5167–5174PubMedCrossRefGoogle Scholar
  7. 7.
    Maxwell JA, Johnson SP, Quinn JA et al (2006) Quantitative analysis of O6-alkylguanine-DNA alkyltransferase in malignant glioma. Mol Cancer Ther 5:2531–2539PubMedCrossRefGoogle Scholar
  8. 8.
    Jeuken JWM, Cornelissen SJB, 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 87:1055–1065PubMedCrossRefGoogle Scholar
  9. 9.
    Grasbon-Frodl EM, Kreth FW, Ruiter M et al (2007) Intratumoral homogeneity or MGMT promoter hypermethylation as demonstrated in serial stereotactic specimens from anaplastic astrocytomas and glioblastomas. Int J Cancer 121:2458–2464PubMedCrossRefGoogle Scholar
  10. 10.
    Capper D, Mittelbronn M, Meyermann R et al (2008) Pitfalls in the assessment of MGMT expression and in its correlation with survival in diffuse astrocytomas: proposal of a feasible immunohistochemical approach. Acta Neuropathol 115:249–259PubMedCrossRefGoogle Scholar
  11. 11.
    Riemenschneider M, Jeuken JWM, Wesseling P et al (2010) Molecular diagnostics of gliomas: state of the art. Acta Neuropathol 120:567–584PubMedCrossRefGoogle Scholar
  12. 12.
    Weller M, Stupp R, Reifenberger G et al (2010) MGMT promoter methylation in malignant gliomas: ready for personalized medicine? Nat Rev Neurol 6:39–51PubMedCrossRefGoogle Scholar
  13. 13.
    Ohgaki H, Kleihues P (2007) Genetic pathways to primary and secondary glioblastoma. Am J Pathol 170:1445–1453PubMedCrossRefGoogle Scholar
  14. 14.
    Macdonald DR, Cascino TL, Schold SC Jr et al (1990) Response criteria for phase II studies of supratentorial malignant glioma. J Clin Oncol 8:1277–1280PubMedGoogle Scholar
  15. 15.
    Nakasu S, Fukami T, Baba K et al (2004) Immunohistochemical study for O6-methylguanine-DNA methyltransferase in the non-neoplastic and neoplastic components of gliomas. J Neurooncol 70:333–340PubMedCrossRefGoogle Scholar
  16. 16.
    Gerson SL (2002) Clinical relevance of MGMT in the treatment of cancer. J Clin Oncol 20:2388–2399PubMedCrossRefGoogle Scholar
  17. 17.
    Watts GS, Pieper RO, Costello JF et al (1997) Methylation of discrete regions of the O6-methylguanine DNA methyltransferase (MGMT) CpG island is associated with heterochromatinization of the MGMT transcription start site and silencing of the gene. Mol Cell Biol 17:5612–5619PubMedGoogle Scholar
  18. 18.
    Hegi ME, Liu L, Herman JG et al (2008) Correlation of O6-methylguanine methyltransferase (MGMT) promoter methylation with clinical outcomes in glioblastoma and clinical strategies to modulate MGMT activity. J Clin Oncol 26:4189–4199PubMedCrossRefGoogle Scholar
  19. 19.
    Preusser M, Janzer RC, Felsberg J et al (2008) Anti-O6-methylguanine-methyltransferase (MGMT) immunohistochemistry in glioblastoma multiforme: observer variability and lack of association with patient survival impede its use as clinical biomarker. Brain Pathol 18:520–532PubMedGoogle Scholar
  20. 20.
    Chinot OL, Barrie M, Fuentes S et al (2007) Correlation between O6-methylguanine DNA methyltransferase and survival in inoperable newly diagnosed glioblastoma patients treated with neoadjuvant temozolomide. J Clin Oncol 25:1470–1475PubMedCrossRefGoogle Scholar
  21. 21.
    Spiegl-Kreinecker S, Pirker C, Filipits M et al (2010) O6-methylguanine-DNA methyltransferase protein expression in tumor cells predicts outcome of temozolomide therapy in glioblastoma patients. Neuro Oncol 12:28–36PubMedGoogle Scholar
  22. 22.
    Sasai K, Nodagashira M, Nishihara H et al (2008) Careful exclusion of non-neoplastic brain components is required for an appropriate evaluation of O6-methylguanine DNA methyltransferase status in glioma. Am J Surg Pathol 32:1220–1227PubMedCrossRefGoogle Scholar

Copyright information

© The Japan Society of Brain Tumor Pathology 2011

Authors and Affiliations

  • Reiko Watanabe
    • 1
  • Yoko Nakasu
    • 2
  • Hiroshi Tashiro
    • 1
  • Koichi Mitsuya
    • 2
  • Ichiro Ito
    • 1
  • Satoshi Nakasu
    • 3
  • Takashi Nakajima
    • 1
  1. 1.Division of Diagnostic PathologyShizuoka Cancer CenterShizuokaJapan
  2. 2.Division of NeurosurgeryShizuoka Cancer CenterShizuokaJapan
  3. 3.Division of Neuro-OncologyKusatsu General HospitalKusatsuJapan

Personalised recommendations