Low MGMT digital expression is associated with a better outcome of IDH1 wildtype glioblastomas treated with temozolomide

Abstract

Introduction: Glioblastoma (GBM) is the deadliest primary brain tumor. The standard treatment consists of surgery, radiotherapy, and temozolomide (TMZ). TMZ response is heterogeneous, and MGMT promoter (MGMTp) methylation has been the major predictive biomarker. We aimed to describe the clinical and molecular data of GBMs treated with TMZ, compare MGMT methylation with MGMT expression, and further associate with patient's outcome.

Methods: We evaluate 112 FFPE adult GBM cases. IDH1 and ATRX expression was analyzed by immunohistochemistry, hotspot TERT promoter (TERTp) mutations were evaluated by Sanger or pyrosequencing, and MGMTp methylation was assessed by pyrosequencing and MGMT mRNA expression using the nCounter® Vantage 3D™ DNA damage and repair panel.

Results: Of the 112 GBMs, 96 were IDH1^WT, and 16 were IDH1^MUT. Positive ATRX expression was found in 91.6% (88/96) of IDH^WT and 43.7% (7/16) of IDH^MUT. TERTp mutations were detected in 70.4% (50/71) of IDH^WT. MGMTp methylation was found in 55.5% (35/63) of IDH^WT and 84.6% (11/13) of IDH^MUT, and as expected, MGMTp methylation was significantly associated with a better response to TMZ. MGMT expression was inversely correlated with MGMTp methylation levels (- 0.506, p < 0.0001), and MGMT low expression were significantly associated with better patient survival. It was also observed that integrating MGMTp methylation and expression, significantly improved the prognostication value.

Conclusions: MGMT mRNA levels evaluated by digital expression were associated with the outcome of TMZ-treated GBM patients. The combination of MGMT methylation and mRNA expression may provide a more accurate prediction of TMZ response in GBM patients.

Keywords: Biomarkers; Brazil; Glioblastoma; IDH; MGMT; Methylation; NanoString; Temozolomide.