MGMT: Immunohistochemical Detection in High-Grade Astrocytomas
Eric S Lipp1,2, Patrick Healy3, Alan Austin4
1The Preston Robert Tisch Brain Tumor Center, Duke University Medical Center, Durham, NC, USA.
Journal of Neuropathology and Experimental Neurology
|December 1, 2018
Summary
This study investigated O6-methylguanine-DNA methyltransferase (MGMT) in glioma. Correcting MGMT scores for inflammatory cells improved prognostic accuracy, with cold spot analysis offering additional survival insights.
Area of Science:
- Neuro-oncology
- Cancer Biology
- Chemotherapy Resistance
Background:
- O6-methylguanine-DNA methyltransferase (MGMT) is a key mediator of therapeutic resistance to alkylating chemotherapy in gliomas.
- Accurate quantification of MGMT in tumor cells is crucial for predicting treatment response.
- Inflammatory and endothelial cells (IEC) can interfere with MGMT assessment in tumor biopsies.
Purpose of the Study:
- To develop and validate a method for improved MGMT discrimination in tumor cells versus IEC.
- To assess the prognostic impact of corrected MGMT scores and IEC infiltration on overall survival (OS) in glioma patients.
- To determine if identifying "cold spots" of low IEC infiltration enhances prognostic value.
Main Methods:
- Quantitative immunohistochemistry (IHC) for MGMT was performed on 982 glioblastomas (GBM) and 199 anaplastic astrocytomas.
- A CD45/HAM56/MGMT 2-color cocktail was used to differentiate tumor cells from IEC and correct MGMT quantification.
- MGMT promoter methylation (PM) was analyzed, and "cold spots" of minimal IEC infiltration were identified for targeted MGMT and IEC% assessment.
Main Results:
- Mean uncorrected and corrected MGMT percentages in GBM were 19.87% and 16.67%, respectively, with a mean IEC% of 18.65%.
- MGMT promoter methylation was present in 45.9% of GBM, and both uncorrected and corrected MGMT positivity correlated with PM.
- All three MGMT scores and cold spot IEC% were significantly correlated with OS in GBM, even after multivariate adjustment.
Conclusions:
- While correcting MGMT scores for IEC% did not significantly improve prognosis in this analysis, the IEC cold spot score provides valuable additional prognostic information.
- Accurate assessment of MGMT, considering inflammatory cell infiltration, is important for understanding glioma prognosis.
- This study highlights the utility of targeted analysis in specific tumor microenvironment regions for improved prognostic assessment.
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