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

Abstract

3146 Background: The protein O6-alkylguanine-DNA-alkyltransferase (AGT), encoded by the MGMT gene, plays a crucial role in DNA repair by singularly 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. Methods: According to PRISMA guidelines, we selected studies from PubMed that examined the impact of MGMT methylation on OS in adult patients with solid tumors. Data were extracted where MGMT methylation status was clearly defined, and OS was reported through hazard ratios (HR) from either uni- or multivariable analyses. We employed R version 4.4.2 and the ‘meta’ package for our meta-analysis, using both fixed-effects (Mantel-Haenszel method) and random-effects (DerSimonian and Laird’s method) models based on the I 2 statistic for heterogeneity. Subgroup analyses were conducted by cancer type, and publication bias was assessed through funnel plot inspection and Egger’s regression. Statistical significance was set at p < 0.05. Results: The meta-analysis included 23 studies, with a total of 3,410 participants across all studies. The studies included an array of cancers, the most common being colorectal (n = 7), then head and neck (n = 6), and lesser-represented groups like pancreatic neuroendocrine (n = 2) and others. The pooled analysis using a random-effects model demonstrated that MGMT methylation status was not significantly related with OS (HR of 1.1967; 95% CI: 0.9004 to 1.5904; p = 0.2040). Subgroup analysis revealed that the impact of MGMT methylation on survival varied significantly across different types of cancer. No significant association was yielded between MGMT methylation and OS for colorectal cancer (HR of 0.9496; 95% CI: 0.6252 to 1.4422), head and neck cancer (HR of 1.1520; 95% CI: 0.8223 to 1.6137), NSCLC (HR of 1.0479; 95% CI: 0.3343 to 3.2841) and pancreatic neuroendocrine cancer (HR of 1.5541; 95% CI: 0.6493 to 3.7195). Conversely, a significant association was yielded for less common cancers, including melanoma, biliary and cervical cancers. The funnel plot and Egger’s test for publication bias (t = -0.3999, p = 0.6933) suggested no significant asymmetry, indicating minimal publication bias within this meta-analysis. Conclusions: Our findings indicate that MGMT methylation does not universally predict OS across all solid tumors. The variability in survival impact across different cancer types suggests that the prognostic significance of MGMT methylation may be context-dependent, emphasizing the need for tumor-specific studies.