Research in gliomas: diagnostic and prognostic value of the IDH1 codon 132 mutation and MGMT promoter methylation in gliomas
Maria Rosário Almeida, Olinda Rebelo, Herminio Tão
Gliomas are the most common primary brain tumors and their major representative forms are astrocytomas, oligodendrogliomas and ependymomas. Grade IV astrocytomas, usually referred as glioblastoma multiforme, is the most frequent and lethal type. Despite advances in therapeutic approaches, the prognosis of most patients is still extremely poor. Therefore, the identification of molecular markers to improve the clinical outcome of these patients represents an important challenge. This present study aimed to assess the frequency and the value of diagnostic and/or prognostic of two markers: (i) somatic mutations in isocitrate dehydrogensase 1 and 2 genes (IDH1 and IDH2) and (ii) the methylation of O6-methylguanine DNA methyltransferase gene (MGMT), in a series of Portuguese patients with gliomas. One hundred and twenty eight patients assisted in the University Hospital of Coimbra were enrolled. Of these, 103 patients with astrocitomas, 15 with oligodendrogliomas, 6 with mixed gliomas and 4 with ependymomas were screened for the presence of somatic mutations in IDH1 and IDH2 genes using directed sequencing. Hypermethylation of the promoter region of the MGMT gene was evaluated using Methylation-Specific Multiplex Ligation-dependent Probe Amplification (MS-MLPA) in 30 glioblastoma patients. We found seventeen patients with known missense mutations in codon 132 of the IDH1 gene, including Arg132His (most frequent), Arg132Ser and Arg132Leu. No mutations were found in IDH2 gene. Our data revealed that IDH1 mutations are frequent in secondary glioblastomas but rare in primary glioblastomas (100% vs 1%, p<0,0001).

This mutation seems to be associated with a more favorable prognosis. The MGMT promoter was methylated in 67% and unmethylated in 33% of glioblastoma patients. The patients who had the MGMT methylated and underwent chemotherapy/radiotherapy showed longer survival (p<0,001). In conclusion, our data suggested the importance of these markers evaluation, in a routine basis, due to their diagnostic and prognostic value.
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