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

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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.

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References

  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 10:459–466

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  3. Everhard S, Tost J, Abdalaoui HE et al (2009) Identification of regions correlating MGMT promoter methylation and gene expression in bliobalstomas. Neuro Oncol 11:348–356

    Article  PubMed  CAS  Google Scholar 

  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 59:793–797

    PubMed  CAS  Google Scholar 

  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 113:379–385

    Article  PubMed  Google Scholar 

  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 11:5167–5174

    Article  PubMed  CAS  Google Scholar 

  7. Maxwell JA, Johnson SP, Quinn JA et al (2006) Quantitative analysis of O6-alkylguanine-DNA alkyltransferase in malignant glioma. Mol Cancer Ther 5:2531–2539

    Article  PubMed  CAS  Google Scholar 

  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 87:1055–1065

    Article  PubMed  CAS  Google Scholar 

  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 121:2458–2464

    Article  PubMed  CAS  Google Scholar 

  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 115:249–259

    Article  PubMed  CAS  Google Scholar 

  11. Riemenschneider M, Jeuken JWM, Wesseling P et al (2010) Molecular diagnostics of gliomas: state of the art. Acta Neuropathol 120:567–584

    Article  PubMed  CAS  Google Scholar 

  12. Weller M, Stupp R, Reifenberger G et al (2010) MGMT promoter methylation in malignant gliomas: ready for personalized medicine? Nat Rev Neurol 6:39–51

    Article  PubMed  CAS  Google Scholar 

  13. Ohgaki H, Kleihues P (2007) Genetic pathways to primary and secondary glioblastoma. Am J Pathol 170:1445–1453

    Article  PubMed  CAS  Google Scholar 

  14. Macdonald DR, Cascino TL, Schold SC Jr et al (1990) Response criteria for phase II studies of supratentorial malignant glioma. J Clin Oncol 8:1277–1280

    PubMed  CAS  Google Scholar 

  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 70:333–340

    Article  PubMed  Google Scholar 

  16. Gerson SL (2002) Clinical relevance of MGMT in the treatment of cancer. J Clin Oncol 20:2388–2399

    Article  PubMed  CAS  Google Scholar 

  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 17:5612–5619

    PubMed  CAS  Google Scholar 

  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 26:4189–4199

    Article  PubMed  CAS  Google Scholar 

  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 18:520–532

    PubMed  CAS  Google Scholar 

  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 25:1470–1475

    Article  PubMed  CAS  Google Scholar 

  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 12:28–36

    PubMed  CAS  Google Scholar 

  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 32:1220–1227

    Article  PubMed  Google Scholar 

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Acknowledgments

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

Conflict of interest

None declared.

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Authors and Affiliations

  1. Division of Diagnostic Pathology, Shizuoka Cancer Center, 1007 Shimonagakubo, Nagaizumi, Sunto, Shizuoka, 411-8777, Japan

    Reiko Watanabe, Hiroshi Tashiro, Ichiro Ito & Takashi Nakajima

  2. Division of Neurosurgery, Shizuoka Cancer Center, Nagaizumi, Shizuoka, Japan

    Yoko Nakasu & Koichi Mitsuya

  3. Division of Neuro-Oncology, Kusatsu General Hospital, Yabase, Kusatsu, Shiga, Japan

    Satoshi Nakasu

Authors
  1. Reiko Watanabe
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  2. Yoko Nakasu
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  3. Hiroshi Tashiro
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  4. Koichi Mitsuya
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  5. Ichiro Ito
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  6. Satoshi Nakasu
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  7. Takashi Nakajima
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Corresponding author

Correspondence to Reiko Watanabe.

Additional information

Parts of this research were presented at the Japan Society of Brain Tumor Pathology Annual Meeting (21–22 May 2010, Osaka, Japan) and the Japan Neurosurgical Society Annual Meeting (27–29 October 2010, Fukuoka, Japan).

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Watanabe, R., Nakasu, Y., Tashiro, H. et al. O6-Methylguanine DNA methyltransferase expression in tumor cells predicts outcome of radiotherapy plus concomitant and adjuvant temozolomide therapy in patients with primary glioblastoma. Brain Tumor Pathol 28, 127–135 (2011). https://doi.org/10.1007/s10014-011-0022-8

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  • DOI: https://doi.org/10.1007/s10014-011-0022-8

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