|Year : 2022 | Volume
| Issue : 3 | Page : 87-89
Associations of O6-methylguanine-DNA methyltransferase promoter methylation status with age and 1p/19q codeletion status in isocitrate dehydrogenase mutation gliomas based on an Asian cohort: A narrative review
Xu Wang1, Mingzhi Han2
1 NorLux Neuro-Oncology Laboratory, University of Bergen, Bergen, Norway; Department of Neurosurgery, Qilu Hospital, Cheeloo College of Medicine, Institute of Brain and Brain-Inspired Science, Shandong University; Jinan Microecological Biomedicine Shandong Laboratory and Shandong Key Laboratory of Brain Function Remodeling, Jinan, Shandong Province, China
2 NorLux Neuro-Oncology Laboratory, University of Bergen, Bergen, Norway; Department of Neurosurgery, Qilu Hospital, Cheeloo College of Medicine, Institute of Brain and Brain-Inspired Science, Shandong University; Jinan Microecological Biomedicine Shandong Laboratory and Shandong Key Laboratory of Brain Function Remodeling; Medical Integration and Practice Center, Cheeloo College of Medicine, Shandong University, Jinan, Shandong Province, China
|Date of Submission||08-Sep-2022|
|Date of Decision||19-Sep-2022|
|Date of Acceptance||22-Sep-2022|
|Date of Web Publication||13-Oct-2022|
Dr. Mingzhi Han
Department of Neurosurgery, Qilu Hospital, Cheeloo College of Medicine, Institute of Brain and Brain-Inspired Science, Shandong University, Jinan, 250012, Shandong Province; University of Bergen, 5009 Bergen
Source of Support: None, Conflict of Interest: None
The expression of the DNA repair protein O6-methylguanine-DNA methyltransferase (MGMT) can lead to tumor cell resistance to alkylating agents. Glioblastomas with isocitrate dehydrogenase mutation (IDHmut) were reported to have significantly higher MGMT promoter methylation, which predicted improved outcomes after temozolomide treatment. However, the MGMT methylation status in IDHmut glioma remains controversial. To further explore the associations of MGMT promoter methylation status with other molecular features in IDHmut gliomas, in this work, we analyzed the relationship of MGMT promoter methylation status with 1p/19q codeletion status and age in IDHmut gliomas based on a large Asian (Chinese) cohort. We found that there was no significant difference in MGMT methylation status in IDHmut 1p/19q-codeleted oligodendrogliomas compared to IDHmut astrocytomas, in either primary or recurrent cases. Moreover, the MGMT methylation status was not associated with age. The difference compared to previous research which indicated the MGMT methylation status differed significantly among IDHmut glioma might be caused by differences between populations, indicating that routine assessment of MGMT methylation status in oligodendrogliomas may still be necessary.
Keywords: 1p/19q codeletion, age, glioma, isocitrate dehydrogenase mutation, O6-methylguanine-DNA methyltransferase promoter methylation, review
|How to cite this article:|
Wang X, Han M. Associations of O6-methylguanine-DNA methyltransferase promoter methylation status with age and 1p/19q codeletion status in isocitrate dehydrogenase mutation gliomas based on an Asian cohort: A narrative review. Glioma 2022;5:87-9
|How to cite this URL:|
Wang X, Han M. Associations of O6-methylguanine-DNA methyltransferase promoter methylation status with age and 1p/19q codeletion status in isocitrate dehydrogenase mutation gliomas based on an Asian cohort: A narrative review. Glioma [serial online] 2022 [cited 2023 Jun 9];5:87-9. Available from: http://www.jglioma.com/text.asp?2022/5/3/87/358554
| Introduction|| |
O6-methylguanine-DNA methyltransferase (MGMT) promoter methylation predicts improved survival among glioma patients treated with temozolomide (TMZ). Although emerging data have suggested the importance of assessing MGMT methylation status and 1p/19q codeletion status in malignant glioma patients before starting treatment, the MGMT methylation status in glioma patients with isocitrate dehydrogenase mutation (IDHmut) is still controversial., Therefore, further investigations into the molecular correlation are warranted. Recently, Horbinski et al. reported that MGMT methylation is strongly associated with 1p/19q codeletion status in IDHmut gliomas in Northwestern Memorial Hospital (NMH) and the Cancer Genome Atlas More Details (TCGA) cohorts. The unmethylated MGMT rate was also significantly lower in IDHmut 1p/19q-codeleted oligodendroglioma (3.8% in NMH and 0.6% in TCGA) than IDHmut astrocytoma (17.5% in NMH and 11.7% in TCGA). Moreover, MGMT-unmethylated IDHmut astrocytomas tended to occur in younger patients compared to MGMT-methylated IDHmut astrocytomas (mean age = 32.5 years vs. 38.0 years in NMH and 32.6 years vs. 38.6 years in TCGA). Despite this interesting finding, there were a few limitations in the study, which raised concerns for us regarding interpreting and validating these results in broader clinical settings. First, the number of samples (NMH, n = 516; TCGA, n = 626) was relatively small, decreasing the power of the analysis. Second, the ethnicities in both cohorts were primarily limited to Caucasians. As the incidence and survival rates differ between ethnicities, the extension of the analyses to Asian populations (which have the highest incidence of glioma) would refine the discussion. Third, MGMT methylation status in primary glioma compared to recurrent glioma was not mentioned in the analysis.
To further assess MGMT methylation status in IDHmut glioma, we analyzed 926 Chinese cases with MGMT methylation status data from the Chinese Glioma Genome Atlas (CGGA). According to the 2021 WHO classification of tumors of glioma, IDH-mutant glioma was classified as astrocytoma or oligodendroglioma which carried 1p/19q codeletion. In line with the findings of Horbinski et al., unmethylated MGMT was more common in IDH wildtype (IDHwt) gliomas (around 60%) than IDHmut gliomas (>30%) [Figure 1]A. While in contrast, we found that 90/255 (35.3%) IDHmut astrocytomas lacked MGMT methylation, and this rate was similar in IDHmut 1p/19q-codeleted oligodendrogliomas (47/148, 31.8%) (P = 0.51 based on Fisher's exact test). Thus, there was no significant association between MGMT methylation and 1p/19q codeletion in Asian (Chinese) IDHmut glioma patients.
|Figure 1: MGMT promoter methylation status (measured through methylation bead chip analysis) in IDHmut gliomas in the CGGA. Data were summarized and analyzed from the CGGA database. Summary of MGMT promoter methylation status in 926 WHO Grade 2–4 gliomas (A) and 635 primary and 257 recurrent WHO Grade 2–4 gliomas (B). CGGA: Chinese Glioma Genome Atlas, IDHmut: Isocitrate dehydrogenase mutation, IDHwt: Isocitrate dehydrogenase wild type, MGMT: O6-methylguanine-DNA methyltransferase, WHO: World Health Organization|
Click here to view
Furthermore, we analyzed MGMT methylation in primary and recurrent gliomas separately. Regarding primary gliomas, 60/145 (41.4%) of IDHmut astrocytomas and 37/99 (37.4%) of IDHmut 1p/19q-codeleted oligodendrogliomas lacked MGMT methylation, with no significant association (P = 0.59) between MGMT methylation and 1p/19q codeletion. Regarding recurrent gliomas, 28/74 (29.8%) of IDHmut astrocytomas and 9/45 (20.0%) of IDHmut 1p/19q-codeleted oligodendrogliomas lacked MGMT methylation, with no significant association (P = 0.31) between MGMT methylation and 1p/19q codeletion [Figure 1]B.
Importantly, among all IDHmut astrocytomas in our study, MGMT methylation status was not associated with age (mean age = 38.8 years vs. 38.9 years for unmethylated vs. methylated cases, P = 0.96). This also differs from the finding of Horbinski et al. that MGMT-unmethylated IDHmut astrocytomas tended to occur in slightly younger patients.
| Retrieval Strategy|| |
The clinical information was collected from the CGGA website (http://cgga.org.cn/). The information of MGMT promoter methylation status, 1p/19q codeletion status, IDH mutation status, and age were collected from clinical data. After the integration of the sample in different sections (whole-exome sequencing data, mRNA sequencing data, mRNA microarray, DNA methylation microarray, and miRNA microarray), the repetitive samples or missing data were removed and then followed by data extraction of clinical information and analysis.
| Limitations|| |
The dataset was collected from the CGGA, while some latest clinical data regarding single-cell sequencing samples were not included in this study. Compared to the pyrosequencing assay to screen for MGMT promoter methylation status used in reference, the CGGA dataset used methylation bead chip analysis to detect methylation status. The differences in methods may lead to the risk of bias.
| Conclusions|| |
Taking our results together, MGMT methylation status was not significantly associated with 1p/19q codeletion status or age in IDHmut Chinese patients. The difference compared to previous research might be caused by differences in the populations involved; the detailed reasons need further exploration. While MGMT methylation has been established as a predictor of TMZ responsiveness in high-grade IDHmut glioma, the benefits of routine assessment of MGMT methylation status are still unclear for low-grade glioma. Although MGMT-methylated IDHmut astrocytomas were reported to have better progression-free survival than MGMT-unmethylated ones, higher levels of upfront MGMT methylation were associated with the development of hypermutation at recurrence in low-grade glioma. MGMT methylation status could be used to identify patients who may benefit from combination therapy in the upfront setting and thus minimize the risk of hypermutant recurrences. Considering the MGMT unmethylation rate in Chinese oligodendroglioma patients 31.76%; [Figure 1]A, routine assessment of MGMT methylation status in oligodendrogliomas may still be necessary.
Financial support and sponsorship
This work was supported by the Research Project of Jinan Microecological Biomedicine Shandong Laboratory (JNL-2022041C), Shandong Excellent Young Scientists Fund Program (2022HWYQ-035), Shandong Provincial Natural Science Foundation (ZR2021QH030), and the Qilu Young Scholar Program of Shandong University.
Conflicts of interest
There are no conflicts of interest.
| References|| |
Weller M, Stupp R, Hegi ME, van den Bent M, Tonn JC, Sanson M, et al
. Personalized care in Neuro-oncology coming of age: Why we need MGMT and 1p/19q testing for malignant glioma patients in clinical practice. Neuro Oncol 2012;14 Suppl 4:iv100-8.
Mulholland S, Pearson DM, Hamoudi RA, Malley DS, Smith CM, Weaver JM, et al
. MGMT CpG island is invariably methylated in adult astrocytic and oligodendroglial tumors with IDH1 or IDH2 mutations. Int J Cancer 2012;131:1104-13.
Horbinski C, McCortney K, Stupp R. MGMT promoter methylation is associated with patient age and 1p/19q status in IDH-mutant gliomas. Neuro Oncol 2021;23:858-60.
Ostrom QT, Cote DJ, Ascha M, Kruchko C, Barnholtz-Sloan JS. Adult glioma incidence and survival by race or ethnicity in the United States from 2000 to 2014. JAMA Oncol 2018;4:1254-62.
GBD 2016 Brain and Other CNS Cancer Collaborators. Global, regional, and national burden of brain and other CNS cancer, 1990-2016: A systematic analysis for the global burden of disease study 2016. Lancet Neurol 2019;18:376-93.
Zhao Z, Zhang KN, Wang Q, Li G, Zeng F, Zhang Y, et al
. Chinese glioma genome atlas (CGGA): A comprehensive resource with functional genomic data from Chinese glioma patients. Genomics Proteomics Bioinformatics 2021;19:1-12.
Louis DN, Perry A, Wesseling P, Brat DJ, Cree IA, Figarella-Branger D, et al
. The 2021 WHO classification of tumors of the central nervous system: A summary. Neuro Oncol 2021;23:1231-51.
Molenaar RJ, Verbaan D, Lamba S, Zanon C, Jeuken JW, Boots-Sprenger SH, et al
. The combination of IDH1 mutations and MGMT methylation status predicts survival in glioblastoma better than either IDH1 or MGMT alone. Neuro Oncol 2014;16:1263-73.