Influence of Intratumor Heterogeneity on the Predictivity of MGMT Gene Promoter Methylation Status in Glioblastoma

Glioblastoma is the most aggressive tumor of the central nervous system. Prognosis is poor, even in the presence of a methylated state of MGMT gene promoter, which represents the biomarker with the highest prognostic/predictive value for the standard treatment of patients. Among patients with a methylated MGMT status, we identified an intermediate range of methylation above the standard 9% cut-off (gray zone) in which the predictive strength of the marker was lost. In an effort to improve the evaluation of the biomarker in clinical decision-making, we are carrying out a retrospective study, performing an in-depth analysis of samples used for diagnosis to understand how molecular heterogeneity, a hallmark of glioblastoma, impacts the evaluation of MGMT gene promoter methylation. Preliminary data from samples belonging to the "gray zone" tend to confirm the hypothesis of a mismatch between methylation values used for clinical decision-making and those included in our in-depth analysis. Confirmation of these data would help to better define the predictive power of MGMT promoter methylation status and greatly facilitate clinical decision-making.