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Weak MGMT gene promoter methylation confers a clinically significant survival benefit in patients with newly diagnosed glioblastoma: a retrospective cohort study

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Abstract

Introduction

Quantitative methylation specific PCR (qMSP) is a frequently used technique to assess MGMT gene promoter methylation in glioblastoma patients. The optimal technical cut-off value to distinguish methylated from unmethylated samples is nevertheless still undetermined. In literature, a “grey zone” of diagnostic uncertainty has been described.

Methods

We performed a retrospective analysis of newly diagnosed glioblastoma patients treated according to the Stupp protocol. Epidemiological data were gathered from the individual patient files. MGMT gene promoter methylation status was determined on stored tumour samples using qMSP. A strong, weak or absent promoter methylation was determined based on Cq values (quantification value) of the MGMT and ACTB primers as well as a positive control sample.

Results

In total, 181 patient files were reviewed and included for statistical analysis. MGMT promoter hypermethylation was detected in 38.7% of glioblastoma patients. The median overall survival of unmethylated and strongly methylated patients was 10.1 months and 19.7 months respectively. Furthermore, 11% of the total patient cohort had a weak MGMT gene promoter methylation. The median OS in this subgroup was 15.4 months, significantly better compared to the unmethylated cohort (P < 0.001). Multivariate Cox regression analysis showed weak MGMT promoter methylation as an independent prognostic parameter for overall survival.

Conclusion

Glioblastoma patients with weak promoter methylation show a statistically significant longer overall survival when compared to clearly unmethylated patients. Patients with grey zone qMSP test results should receive additional molecular analysis in future to further direct individual therapy strategies.

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Funding

This work was supported by grants from Ghent University Hospital, Centre for Oncology, from the “Stichting Luka Hemelaere” and “Fonds Arne Lannoy AKA Zorro.”

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Author notes

  1. H. Pinson and G. Hallaert have contributed equally to this article.

Authors and Affiliations

  1. Department of Neurosurgery, Ghent University Hospital, C. Heymanslaan 10, 9000, Ghent, Belgium

    H. Pinson, G. Hallaert, D. Van Roost & J. P. Kalala

  2. Center for Medical Genetics, Ghent University Hospital, Ghent, Belgium

    J. Van der Meulen

  3. Department of Pathology, AZ Delta, Roeselare, Belgium

    F. Dedeurwaerdere

  4. Department of Neurosurgery, AZ Delta, Roeselare, Belgium

    D. Vanhauwaert

  5. Department of Pathology, Ghent University Hospital, Ghent, Belgium

    C. Van den Broecke & J. Van Dorpe

  6. Department of Pathology, AZ St. Lucas Gent, Ghent, Belgium

    C. Van den Broecke

  7. Department of Radiation Oncology, Ghent University Hospital, Ghent, Belgium

    T. Boterberg

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  1. H. Pinson
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Pinson, H., Hallaert, G., Van der Meulen, J. et al. Weak MGMT gene promoter methylation confers a clinically significant survival benefit in patients with newly diagnosed glioblastoma: a retrospective cohort study. J Neurooncol 146, 55–62 (2020). https://doi.org/10.1007/s11060-019-03334-5

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  • DOI: https://doi.org/10.1007/s11060-019-03334-5

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