Impact of MGMT methylation on overall survival in solid tumors: A systematic review and meta-analysis

O6-methylguanine-DNA methyltransferase (MGMT) serves a crucial role in DNA repair by removing alkyl lesions from the O6 position of guanine, maintaining genomic stability. Loss of MGMT expression, often due to promoter methylation, is linked to enhanced sensitivity to chemotherapy. While MGMT methylation has been observed in various cancers, its impact on overall survival (OS) in solid tumors remains uncertain. According to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines, studies were selected from PubMed that examined the impact of MGMT methylation on OS in adult patients with solid tumors. Data were extracted where methylation status was defined, and OS was reported through hazard ratios (HRs) and confidence intervals (CIs) from either univariate or multivariable analyses. R version 4.4.2 and the 'meta' package were employed for the meta-analysis, using both fixed-effects (Mantel-Haenszel method) and random-effects (DerSimonian-Laird method with Hartung-Knapp adjustment) models based on the I² statistic for heterogeneity. Subgroup analyses were performed by cancer type, and publication bias was assessed through funnel plot inspection and Egger's regression. A total of 21 studies involving 2,946 patients met the inclusion criteria. The fixed-effects model showed a significant association between MGMT promoter methylation and poorer OS (HR=1.27; 95% CI, 1.13-1.42; P<0.0001); however, notable heterogeneity (I²=64.7%) led to a non-significant result under the random-effects model (HR=1.26; 95% CI, 0.97-1.65; P=0.084). Subgroup analyses revealed that MGMT methylation was strongly associated with decreased survival in biliary tract (HR=2.31), cervical (HR=2.50) and duodenal cancers (HR=4.25), whereas melanoma exhibited improved survival (HR=0.32). Other cancer types, including colorectal, esophageal, head and neck, leiomyosarcoma, non-small cell lung cancer and pancreatic neuroendocrine tumors, demonstrated no notable relationship between MGMT methylation and OS. Sensitivity analyses confirmed the stability of these findings despite the inherent heterogeneity. In conclusion, MGMT promoter methylation may be a prognostic biomarker in select solid tumors; however, its impact on OS varies by cancer type. Further studies with standardized methylation assessment methods are warranted to clarify its prognostic and predictive utility, especially on OS.