'The Reports of My Death Are Greatly Exaggerated'-Evaluating the Effect of Necrosis on MGMT Promoter Methylation Testing in High-Grade Glioma.

(1) Background: MGMT (O-6-methylguanine-DNA methyltransferase) promoter methylation remains an important predictive biomarker in high-grade gliomas (HGGs). The influence of necrosis on the fidelity of MGMT promoter ( MGMT p) hypermethylation testing is currently unknown. Therefore, our study aims to evaluate the effect of varying degrees of necrosis on MGMT p status, as determined by pyrosequencing, in a series of primary and recurrent HGGs; (2) Methods: Within each case, the most viable blocks (assigned as 'true' MGMTp status) and the most necrotic block were determined by histopathology review. MGMT p status was determined by pyrosequencing. Comparisons of MGMT p status were made between the most viable and most necrotic blocks. (3) Results: 163 samples from 64 patients with HGGs were analyzed. MGMT p status was maintained in 84.6% of primary and 78.3% of recurrent HGGs between the most viable and necrotic blocks. A threshold of ≥60% tumor cellularity was established at which MGMT p status was unaltered, irrespective of the degree of necrosis. (4) Conclusions: MGMT p methylation status, as determined by pyrosequencing, does not appear to be influenced by necrosis in the majority of cases at a cellularity of at least 60%. Further investigation into the role of intratumoral heterogeneity on MGMT p status will increase our understanding of this predictive marker.