Unveiling hierarchy and spatial distribution of O-methylguanine-DNA methyltransferase promoter methylation in World Health Organization grade 2-3 gliomas.

in Cancer science by Mingxiao Li, Jiang Liu, Jiancong Weng, Gehong Dong, Xuzhu Chen, Yong Cui, Xiaohui Ren, Shaoping Shen, Haihui Jiang, Xiaokang Zhang, Xuzhe Zhao, Ming Li, Xijie Wang, Hongxiang Ren, Qiang Li, Yulian Zhang, Quan Cheng, Yanbing Yu, Song Lin

TLDR

  • This study looked at how the way a protein called O-methylguanine-DNA methyltransferase (MGMTp) is methylated (or not methylated) affects the treatment and prognosis of different types of brain tumors called gliomas. The study found that the extent of resection (how much of the tumor is removed) is important for astrocytomas (a type of glioma with a specific genetic mutation) and oligodendrogliomas (another type of glioma with a different genetic mutation). The study also found that the way MGMTp is methylated can affect the response to chemotherapy (treatment with drugs) and the likelihood of the tumor invading other parts of the brain. The study's findings have important implications for clinical practice and future research in this field.

Abstract

This study investigated the role of O-methylguanine-DNA methyltransferase promoter (MGMTp) methylation hierarchy and heterogeneity in grade 2-3 gliomas, focusing on variations in chemotherapy benefits and resection dependency. A cohort of 668 newly diagnosed grade 2-3 gliomas, with comprehensive clinical, radiological, and molecular data, formed the basis of this analysis. The extent of resection was categorized into gross total resection (GTR ≥100%), subtotal resection (STR >90%), and partial resection (PR ≤90%). MGMTp methylation levels were examined using quantitative pyrosequencing. Our findings highlighted the critical role of GTR in improving the prognosis for astrocytomas (IDH1/2-mutant and 1p/19q non-codeleted), contrasting with its lesser significance for oligodendrogliomas (IDH1/2 mutation and 1p/19q codeletion). Oligodendrogliomas demonstrated the highest average MGMTp methylation levels (median: 28%), with a predominant percentage of methylated cases (average methylation levels >20%). Astrocytomas were more common in the low-methylated group (10%-20%), while IDH wild-type gliomas were mostly unmethylated (<10%). Spatial distribution analysis revealed a decrement in frontal lobe involvement from methylated, low-methylated to unmethylated cases (72.8%, 59.3%, and 47.8%, respectively). In contrast, low-methylated and unmethylated cases were more likely to invade the temporal-insular region (19.7%, 34.3%, and 40.4%, respectively). Astrocytomas with intermediate MGMTp methylation were notably associated with temporal-insular involvement, potentially indicating a moderate response to temozolomide and underscoring the importance of aggressive resection strategies. In conclusion, our study elucidates the complex interplay of MGMTp methylation hierarchy and heterogeneity among grade 2-3 gliomas, providing insights into why astrocytomas and IDH wild-type lower-grade glioma might derive less benefit from chemotherapy.

Overview

  • The study investigates the role of O-methylguanine-DNA methyltransferase promoter (MGMTp) methylation hierarchy and heterogeneity in grade 2-3 gliomas, focusing on variations in chemotherapy benefits and resection dependency. A cohort of 668 newly diagnosed grade 2-3 gliomas, with comprehensive clinical, radiological, and molecular data, formed the basis of this analysis. The extent of resection was categorized into gross total resection (GTR ≥100%), subtotal resection (STR >90%), and partial resection (PR ≤90%). MGMTp methylation levels were examined using quantitative pyrosequencing. The primary objective of the study is to understand the complex interplay of MGMTp methylation hierarchy and heterogeneity among grade 2-3 gliomas and its impact on chemotherapy benefits and resection dependency. The study aims to provide insights into why astrocytomas and IDH wild-type lower-grade glioma might derive less benefit from chemotherapy.

Comparative Analysis & Findings

  • The study compared the outcomes observed under different experimental conditions or interventions detailed in the study. The findings revealed that GTR significantly improved the prognosis for astrocytomas (IDH1/2-mutant and 1p/19q non-codeleted), contrasting with its lesser significance for oligodendrogliomas (IDH1/2 mutation and 1p/19q codeletion). Oligodendrogliomas demonstrated the highest average MGMTp methylation levels (median: 28%), with a predominant percentage of methylated cases (average methylation levels >20%). Astrocytomas were more common in the low-methylated group (10%-20%), while IDH wild-type gliomas were mostly unmethylated (<10%). Spatial distribution analysis revealed a decrement in frontal lobe involvement from methylated, low-methylated to unmethylated cases (72.8%, 59.3%, and 47.8%, respectively). In contrast, low-methylated and unmethylated cases were more likely to invade the temporal-insular region (19.7%, 34.3%, and 40.4%, respectively). Astrocytomas with intermediate MGMTp methylation were notably associated with temporal-insular involvement, potentially indicating a moderate response to temozolomide and underscoring the importance of aggressive resection strategies. The study found that MGMTp methylation hierarchy and heterogeneity play a critical role in determining chemotherapy benefits and resection dependency among grade 2-3 gliomas.

Implications and Future Directions

  • The study's findings highlight the importance of GTR in improving the prognosis for astrocytomas (IDH1/2-mutant and 1p/19q non-codeleted), contrasting with its lesser significance for oligodendrogliomas (IDH1/2 mutation and 1p/19q codeletion). The study also underscores the importance of aggressive resection strategies for astrocytomas with intermediate MGMTp methylation. Future research should focus on identifying novel therapeutic strategies for low-methylated and unmethylated cases, as well as exploring the role of MGMTp methylation in other types of gliomas. The study's findings have significant implications for clinical practice, highlighting the importance of considering MGMTp methylation status and resection extent when developing treatment plans for grade 2-3 gliomas.
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