Combined MGMT Expression and MMR Deficiency Underlie Poor Outcomes of Temozolomide in IDH-Wildtype Grade 2 Gliomas

BackgroundIsocitrate dehydrogenase wildtype (IDHwt) histologic grade 2 adult diffuse gliomas represent a highly heterogeneous entity, and the effects of postoperative adjuvant temozolomide (TMZ) therapy, as well as the predictive value of chemotherapy-related biomarker O6-methylguanine-DNA methyltransferase promoter (MGMT-p) methylation, remain to be further investigated. MethodsA Discovery dataset, comprising 108 IDHwt histologic grade 2 gliomas obtained from three public resources, was constructed to investigate the impact of TMZ on patient survival. Furthermore, an independent Validation dataset, consisting of 123 IDHwt grade 2 gliomas, was created to validate the effect of TMZ on patient survival. Kaplan-Meier overall survival (OS) analyses and Cox proportional hazard models were used. ResultsMultivariable analysis in the validation dataset demonstrated that temozolomide (TMZ) chemotherapy was an adverse independent prognostic factor for survival in patients with histologic grade 2 IDH-wildtype (IDHwt) gliomas (HR = 2.19, P = 0.033). Subgroup analyses further revealed that the detrimental effect of TMZ was mainly confined to MGMT-p unmethylated tumors (Discovery cohort: TMZ vs noTMZ, median overall survival [OS]: 37.0 vs 130.0 months, log-rank P = 0.005, HR = 1.89; Validation cohort: TMZ vs noTMZ, median OS: 34.4 vs >120 months, log-rank P = 0.004, HR = 3.39). Moreover, in the validation cohort, TMZ therapy remained associated with significantly poorer survival in the NEC (Not Elsewhere Classified) subgroup (TMZ vs noTMZ, median OS: 73 vs >120 months, P = 0.017), while in molecular GBMs it did not reach statistical significance but still showed a trend toward worse survival (TMZ vs noTMZ, median OS: 20 vs 30 months, P = 0.37). By comparing multi-omics differences between patient groups, we observed that MMR-related genes were specifically downregulated in IDHwt grade 2 gliomas at both the single-cell and bulk transcriptomic levels. DiscussionThe therapeutic benefit of TMZ in IDHwt histologic grade 2 gliomas appears to be limited, with even a potential adverse impact on survival. Therefore, postoperative use of TMZ as a recommended chemotherapy should be approached with caution in these patients, particularly in cases with unmethylated MGMT-p, where alternative treatment strategies are warranted. High MGMT expression and specific downregulation of MMR-related genes may represent key factors underlying the limited efficacy of TMZ in IDHwt, MGMT-p unmethylation grade 2 gliomas. Level of evidenceIII.