An Integrative Analysis of O6-Methylguanine-DNA Methyltransferase (MGMT) Methylation and the Single-Nucleotide Polymorphism (SNP) rs1625649 Reveals Distinct Survival Patterns in Glioblastoma: A Retrospective Study

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Background O6-methylguanine-DNA methyltransferase (MGMT) promoter methylation is an established predictive and prognostic biomarker in glioblastoma (GBM). However, the influence of MGMT promoter single-nucleotide polymorphisms (SNPs), particularly rs1625649, on gene expression and patient outcomes remains unclear. This study evaluated the prognostic impact of MGMT methylation and SNP rs1625649 in GBM patients. Methods This retrospective analytical study included 66 histologically confirmed GBM patients (IDH1 R132H-negative), treated at a tertiary care center from 2018 to 2022. MGMT methylation was assessed using methylation-specific PCR, and SNP rs1625649 genotyping was performed by PCR-restriction fragment length polymorphism (PCR-RFLP). Survival analyses were conducted using Kaplan-Meier and Cox proportional hazards models. Key clinical variables, including age, Karnofsky performance status (KPS), extent of resection, and treatment data, were analyzed. Results MGMT promoter methylation was present in 56.1% of cases and was significantly associated with longer overall survival (OS: 86.4 days (≈2.9 months) vs. 35.0 days (≈1.2 months); p < 0.001). The SNP rs1625649 AA genotype was observed in 15.2% of patients and was associated with prolonged OS (130.8 days) compared to CA (64.2 days) and CC (47.0 days) (p = 0.002). Among methylated cases, the AA genotype conferred superior survival (160.7 days; p = 0.009). Multivariate Cox analysis confirmed MGMT methylation (HR = 0.46; p = 0.005) and the rs1625649 AA genotype (HR = 0.41; p = 0.040) as independent prognostic factors. Conclusion MGMT promoter methylation and the SNP rs1625649 AA genotype are independently associated with improved survival in GBM. These findings highlight the potential prognostic utility of incorporating MGMT SNP genotyping alongside methylation status in clinical practice. Further large-scale studies are warranted to validate these results.

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