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MGMT promoter hypermethylation and its associations with genetic alterations in a series of 350 brain tumors

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Abstract

MGMT (O 6-methylguanine-DNA methyltransferase) promoter hypermethylation is a helpful prognostic marker for chemotherapy of gliomas, although with some controversy for low-grade tumors. The objective of this study was to retrospectively investigate MGMT promoter hypermethylation status for a series of 350 human brain tumors, including 275 gliomas of different malignancy grade, 21 glioblastoma multiforme (GBM) cell lines, and 75 non-glial tumors. The analysis was performed by methylation-specific PCR and capillary electrophoresis. MGMT expression at the protein level was also evaluated by both immunohistochemistry (IHC) and western blotting analysis. Associations of MGMT hypermethylation with IDH1/IDH2 mutations, EGFR amplification, TP53 mutations, and 1p/19q co-deletion, and the prognostic significance of these, were investigated for the gliomas. MGMT promoter hypermethylation was identified in 37.8% of gliomas, but was not present in non-glial tumors, with the exception of one primitive neuroectodermal tumor (PNET). The frequency was similar for all the astrocytic gliomas, with no correlation with histological grade. Significantly higher values were obtained for oligodendrogliomas. MGMT promoter hypermethylation was significantly associated with IDH1/IDH2 mutations (P = 0.0207) in grade II–III tumors, whereas it had a borderline association with 1p deletion (P = 0.0538) in oligodendrogliomas. No other association was found. Significant correlation of MGMT hypermethylation with MGMT protein expression was identified by IHC in GBMs and oligodendrogliomas (P = 0.0001), but not by western blotting. A positive correlation between MGMT protein expression, as detected by either IHC or western blotting, was also observed. The latter was consistent with MGMT promoter hypermethylation status in GBM cell lines. In low-grade gliomas, MGMT hypermethylation, but not MGMT protein expression, was associated with a trend, only, toward better survival, in contrast with GBMs, for which it had favorable prognostic significance.

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Acknowledgments

This work was supported by a Grant from Compagnia di San Paolo, Turin. We are greatly indebted to Dr Bianca Pollo (Fondazione I.R.C.C.S. Istituto Neurologico C. Besta, Milan, Italy) for providing sGBMs.

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Authors and Affiliations

  1. Neuro-bio-oncology Center, Policlinico di Monza Foundation, Via Pietro Micca, 29–13100, Vercelli, Italy

    Marta Mellai, Oriana Monzeglio, Valentina Caldera, Laura Annovazzi & Davide Schiffer

  2. Department of Medical Sciences, University of Piemonte Orientale, Novara, Italy

    Angela Piazzi

  3. Department of Biomedical Sciences and Human Oncology, University of Turin, Turin, Italy

    Paola Cassoni

  4. Department of Clinical and Experimental Medicine, University of Piemonte Orientale, Novara, Italy

    Guido Valente

  5. Department of Neurology, Ospedale Regionale, Aosta, Italy

    Susanna Cordera

  6. Department of Neurology, Azienda Ospedaliera Santa Croce e Carle, Cuneo, Italy

    Cristina Mocellini

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  1. Marta Mellai
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  2. Oriana Monzeglio
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Correspondence to Davide Schiffer.

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Mellai, M., Monzeglio, O., Piazzi, A. et al. MGMT promoter hypermethylation and its associations with genetic alterations in a series of 350 brain tumors. J Neurooncol 107, 617–631 (2012). https://doi.org/10.1007/s11060-011-0787-y

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