There have been robust efforts to decipher the molecular biomarkers of glioma and their prognostic significance as well as apply these findings to clinical practice, particularly in choosing appropriate candidates for initial chemotherapy [30, 33–38]. TERT promoter mutation and MGMT methylation status are among the most important markers. MGMT promoter methylation is one of the few treatment-relevant markers, encoding an enzyme that removes mutagenic methylating lesions from the O6 guanine position. Methylation of the MGMT promoter leads to low expression of MGMT and inactivation of the repair protein, rendering tumor cells more sensitive to effects of alkylating agents [39]. Consequently, MGMT methylation is considered a favorable prognosis marker associated with longer survival outcomes [40].
Additionally, mutation in the TERT promoter has shown to have prognostic value across a range of tumors [4, 33, 37, 41–45]. Mutations in this promoter region maintain telomere length and tumor cell survival [46, 47]. Interestingly, high TERT activity occurs in 90% of human cancers [47], including gliomas (70%) [48].
Our study demonstrated that TERT promoter mutations showed contradicting effects in MGMT-meth and MGMT-unmeth gliomas. In MGMT-meth gliomas, TERT promoter mutation was correlated with a favorable survival outcome. In contrast, in MGMT-unmeth gliomas, TERT promoter mutation was regarded as an indicator of poor prognosis. From our results, the OS of gliomas can be further stratified into four distinct survival subgroups with ascending survival time as follow: TERT-mut/MGMT-unmeth < < TERT-wt/MGMT-unmeth < < TERT-wt/MGMT-meth < < TERT-mut/MGMT-meth which is consistent with previous reports [16, 26]. This risk stratification will help clinicians better predict patient survival and tailor treatment decisions accordingly. However, the underlying mechanism on how MGMT promoter methylation modulates TERT promoter mutation has not been well elucidated. In one recent study, the TERT-mut/MGMT-unmeth GBM was associated with worse magnetic resonant imaging (MRI) characteristics such as low apparent diffusion coefficient values, obvious edema, obvious necrosis, unobvious non-contrast enhancing tumor, deep white matter invasion, and a high Ki-67 labeling rather than other groups.[49] On the other hand, it is interesting to note that TERT promoter mutation is an independent prognostic marker in other cancers (e.g., melanoma, thyroid cancer, urothelial carcinoma) and is not influenced by other mutations such as RAS or BRAF mutations [44, 45, 50–52]. In gliomas, the prognostic impact of TERT promoter mutation has been known to be modulated by IDH mutations [13]. Therefore, the principal concept of these modulations in glioma warrants further mechanistic investigation. In contrast to TERT promoter mutation, the prognostic impact of MGMT methylation was not dependent on other confounding factors including the status of TERT promoter mutation, emphasizing the important role of MGMT methylation as an independent prognostic marker in gliomas.
While the positive prognosis role of MGMT methylation in patients treated with TMZ has been observed in many studies [9, 36, 53–56], there were still conflicting results regarding the prognostic value of this genetic marker in GBM patients [34, 57]. It raises the question that there might be other factors affecting the responsiveness to TMZ besides MGMT methylation status. Our results led us to the observation that TERT promoter mutation was associated with the MGMT methylation benefit in GBM patients treated by TMZ whereas, in the TERT-wt group, MGMT methylation was not associated with improved OS in these patients. As a result, it is crucial to test for TERT promoter mutation and MGMT methylation in GBM patients who are eligible for TMZ chemotherapy.
The biological mechanism of interaction between TERT promoter mutation and MGMT methylation that may influence sensitivity to TMZ treatment of gliomas has not yet clearly defined. We believe that the efficacy of TMZ depends on both telomerase hyperactivity and muted MGMT gene expression. Based on our results, we assumed that MGMT promoter methylation might increase sensitivity to TMZ, mainly in the context of TERT promoter mutation. MGMT encodes an enzyme that removes alkylating lesions added by TMZ from the O6 guanine position. Methylation of MGMT promoter leads to low expression of MGMT and silence of repair protein, which makes tumor cells more sensitive to effects of TMZ [58]. Consequently, MGMT methylated status is considered a favorable prognostic marker associated with longer survival outcomes [8, 59–61]. Our immune system’s response to tumor may be in play as well. TMZ may improve tumor antigen presentation to T lymphocytes in a process known as cross-priming [62]. The facilitation of cell division by the TERT promoter mutation may lead cancerous cells to divide more quickly, divide, the more cell death and tumor lysis occur, which might increase releasing of tumor antigen. As a result, patients harboring TERT promoter mutation and MGMT methylation might show survival benefit with TMZ. Further investigation is required to understand clearly how these two genetic markers influence treatment response. In the unmethylated MGMT subgroup, TMZ’s cytotoxic alkylating effect is counteracted by the DNA repair enzyme. Other studies have also shown no significant survival benefit of TMZ chemotherapy in MGMT unmethylated patients [8, 60, 63].
Acknowledging minimal heterogeneity, we believe that our meta-analysis provides robust and useful directionality regarding the potential interaction between TERT and MGMT in glioma patients. However, we acknowledge that our meta-analysis is mainly based on retrospective studies which can lead to unavoidable selection biases. Moreover, our results were calculated from both individual and aggregate level data. While we attempted to minimize the differences in demographic and therapeutic data among the included studies by adjusting for various covariates, it should be noted that there might still be some discrepancies among different datasets such as molecular profiling of other genetic markers, tumor locations, and salvage therapies throughout the treatment of patients.