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Molecular Bases of Gliomagenesis and Gene Sequencing-Based Study of the 06-Methylguanine-DNA-Methyltransferase Promoter Methylation: Prognostic and Therapeutic Implications

Giuseppe Raudino*, Giuseppe Umana, Federica Raudino, Valentina Lacognata, Rosario Iemmolo, Gaspare Francesco Montemagno, Gianluca Scalia, Sebastiano Cavallaro

Epigenetic mutations of some peculiar genic functions play a crucial role in gliomagenesis. One of the most important in neurooncological pharmaco-epigenetics is represented by the MGMT promoter methylation.

We evaluated the MGMT gene promoter methylation status by real-time PCR and sequencing of the entire promoter. The samples from 25 patients, men and women with an average age of 55 years, with intracranial tumors, were consecutively evaluated. By subsequent and definitive histological typing, the patient distribution showed 11 patients with GBM, 3 with HGG, 3 with LGG and 8 with brain metastases.

Analyzing the MGMT gene promoter methylation status of a non-homogeneous series of 25 consecutive patients, 5 patients had High-Grade Glioma (HGG) with unmethylated MGMT gene promoter and 4 patients had glioblastoma with almost complete MGMT gene promoter methylation, higher than the cut-off value of 80%, indicated as a possible threshold for highly positive response to temozolomide. The remaining patients (including those with metastatic disease) presented partial methylation, which does not indicate, at the current moment, any peculiar prognostic and therapeutic indications.

The present study has confirmed the validity of this method, both in terms of sensitivity and specificity, for the evaluation of MGMT gene promoter methylation status, based on the amplification of specific DNA methylation and not on real-time PCR and sequencing of the en-tire MGMT gene promoter sequence. These data certainly open a new scenario up in oncology, which now combines with the study of the tumor epigenomics.