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- Title
'The Reports of My Death Are Greatly Exaggerated'—Evaluating the Effect of Necrosis on MGMT Promoter Methylation Testing in High-Grade Glioma.
- Authors
Satgunaseelan, Laveniya; Lee, Maggie; Iannuzzi, Sebastian; Hallal, Susannah; Deang, Kristine; Stanceski, Kristian; Wei, Heng; Mason, Sofia; Shivalingam, Brindha; Sim, Hao-Wen; Buckland, Michael E.; Alexander, Kimberley L.
- Abstract
Simple Summary: The MGMT gene is responsible for repairing DNA damage, including as a result of chemotherapy, and, therefore, antagonizes its effects. If the MGMT gene is 'silenced', there is defective DNA repair leading to increased chemotherapy-related tumor cell death. MGMT gene silencing can occur through a process called 'promoter methylation'. Specifically, the measurement of MGMT promoter methylation (MGMTp testing) has proven to be a robust way to predict which brain tumor patients will respond to chemotherapy. However, prior to treatment, brain tumors can already contain variably sized areas of dead tumor termed 'necrosis'. Necrosis has traditionally been assumed to reduce the reliability of MGMTp testing but has not been previously investigated. In this study, we demonstrate that necrosis has no material effect on the results of MGMTp testing, thus allowing for the inclusion of a broader range of brain tumor samples for future analysis. (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 (MGMTp) hypermethylation testing is currently unknown. Therefore, our study aims to evaluate the effect of varying degrees of necrosis on MGMTp 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. MGMTp status was determined by pyrosequencing. Comparisons of MGMTp status were made between the most viable and most necrotic blocks. (3) Results: 163 samples from 64 patients with HGGs were analyzed. MGMTp 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 MGMTp status was unaltered, irrespective of the degree of necrosis. (4) Conclusions: MGMTp 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 MGMTp status will increase our understanding of this predictive marker.
- Subjects
GLIOMAS; RESEARCH funding; NECROSIS; TUMOR markers; DNA methylation; SEQUENCE analysis
- Publication
Cancers, 2024, Vol 16, Issue 10, p1906
- ISSN
2072-6694
- Publication type
Article
- DOI
10.3390/cancers16101906