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Defining the cutoff value of MGMT gene promoter methylation and its predictive capacity in glioblastoma

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Abstract

Despite advances in the treatment of glioblastoma (GBM), median survival is 12–15 months. O6-methylguanine-DNA methyltransferase (MGMT) gene promoter methylation status is acknowledged as a predictive marker for temozolomide (TMZ) treatment. When MGMT promoter values fall into a “methylated” range, a better response to chemotherapy is expected. However, a cutoff that discriminates between “methylated” and “unmethylated” status has yet to be defined. We aimed to identify the best cutoff value and to find out whether variability in methylation profiles influences the predictive capacity of MGMT promoter methylation. Data from 105 GBM patients treated between 2008 and 2013 were analyzed. MGMT promoter methylation status was determined by analyzing 10 CpG islands by pyrosequencing. Patients were treated with radiotherapy followed by TMZ. MGMT promoter methylation status was classified into unmethylated 0–9 %, methylated 10–29 % and methylated 30–100 %. Statistical analysis showed that an assumed methylation cutoff of 9 % led to an overestimation of responders. All patients in the 10–29 % methylation group relapsed before the 18-month evaluation. Patients with a methylation status ≥30 % showed a median overall survival of 25.2 months compared to 15.2 months in all other patients, confirming this value as the best methylation cutoff. Despite wide variability among individual profiles, single CpG island analysis did not reveal any correlation between single CpG island methylation values and relapse or death. Specific CpG island methylation status did not influence the predictive value of MGMT. The predictive role of MGMT promoter methylation was maintained only with a cutoff value ≥30 %.

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Acknowledgments

Collaborating authors: Salvatore Roberto Bellia (Radiotherapy Unit) and Nada Riva (Department of Medical Oncology), IRCCS IRST, Meldola; Patrizia Cenni (Neuroradiology Unit) and Claudio Dazzi (Medical Oncology Unit), S. Maria delle Croci Hospital, Ravenna; Alessandro Gamboni (Medical Oncology Unit), Degli Infermi Hospital, Faenza; Roberto Montanari (Neuroradiology Unit), Umberto I Hospital, Lugo; Anna Maria Cremonini and Luigino Tosatto (Neurosurgery Unit), Franceschi Giancarlo (Neuroradiology Unit), Evandro Nigrisoli (Pathology Unit), and Maria Grazia Passarin (Neurology Unit), Bufalini Hospital, Cesena; Giuseppe Pasini (Department of Oncology) and Michele Sintini (Neuroradiology Unit), Infermi Hospital, Rimini; Antonio Polselli (Medical Oncology Unit) Cervesi Hospital, Cattolica; Italy. The authors thank Gráinne Tierney for editorial assistance.

Author contributions

Conception and design: Giovanni Brigliadori, Daniele Calistri, Marina Faedi and Dino Amadori. Provision of study materials or patients: Marina Faedi, Serenella Cerasoli, Elisabetta Melegari and Dino Amadori. Collection and assembly of data: Giovanni Brigliadori, Claudia Rengucci, Elisabetta Melegari and Serenella Cerasoli. Data analysis and interpretation: Giovanni Brigliadori, Flavia Foca, Monia Dall’Agata, Daniele Calistri. Manuscript writing: all authors. Final approval of manuscript: all authors.

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    Authors and Affiliations

    1. Biosciences Laboratory, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Via Maroncelli 40, 47014, Meldola, Italy

      Giovanni Brigliadori, Claudia Rengucci & Daniele Calistri

    2. Unit of Biostatistics and Clinical Trials, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola, Italy

      Flavia Foca & Monia Dall’Agata

    3. Department of Medical Oncology, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola, Italy

      Elisabetta Melegari, Dino Amadori & Marina Faedi

    4. Pathology Unit, Bufalini Hospital, Cesena, Italy

      Serenella Cerasoli

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    1. Giovanni Brigliadori
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    Correspondence to Giovanni Brigliadori.

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    Daniele Calistri and Marina Faedi equally contributed to the work.

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    Brigliadori, G., Foca, F., Dall’Agata, M. et al. Defining the cutoff value of MGMT gene promoter methylation and its predictive capacity in glioblastoma. J Neurooncol 128, 333–339 (2016). https://doi.org/10.1007/s11060-016-2116-y

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    • DOI: https://doi.org/10.1007/s11060-016-2116-y

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