Introduction: Sex differences in glioblastoma (GBM) have been observed in incidence, genetic and epigenetic alterations, and immune response. These differences have extended to the methylation of the MGMT promoter, which critically impacts temozolomide resistance. However, the association between sex, MGMT methylation, and survival is poorly understood, which this study sought to evaluate.Methods: A retrospective cohort study was conducted and reported following STROBE guidelines, based on adults with newly diagnosed GBM who received their first surgical intervention at Cleveland Clinic (Ohio, USA) between 2012 and 2018. Kaplan–Meier and multivariable Cox proportional hazards models were used to analyze the association between sex and MGMT promoter methylation status on overall survival (OS). MGMT was defined as methylated if the mean of CpG 1-5 ≥ 12. Propensity score matching was performed on a subset of patients to evaluate the effect of individual CpG site methylation.Results: A total of 464 patients had documented MGMT methylation status with a mean age of 63.4 (range 19–93) years. A total of 170 (36.6%) were female, and 133 (28.7%) received gross total resection as a first intervention. A total of 42.5% were MGMT methylated, with females more often having MGMT methylation than males (52.1% vs. 37.4%,p= 0.004). In univariable analysis, OS was significantly longer for MGMT promoter methylated than un-methylated groups for females (2 yr: 36.8% vs. 11.1%; median: 18.7 vs. 9.5 months;p= 0.001) but not for males (2 yr: 24.3% vs. 12.2%; median: 12.4 vs. 11.3 months;p= 0.22,pfor MGMT–sex interaction = 0.02). In multivariable analysis, MGMT un-methylated versus methylated promoter females (2.07; 95% CI, 1.45–2.95;p< 0.0001) and males (1.51; 95% CI, 1.14–2.00;p= 0.004) had worse OS. Within the MGMT promoter methylated group, males had significantly worse OS than females (1.42; 95% CI: 1.01–1.99;p= 0.04). Amongst patients with data on MGMT CpG promoter site methylation values (n= 304), the median (IQR) of CpG mean methylation was 3.0% (2.0, 30.5). Females had greater mean CpG methylation than males (11.0 vs. 3.0,p< 0.002) and higher per-site CpG methylation with a significant difference at CPG 1, 2, and 4 (p< 0.008). After propensity score matching, females maintained a significant survival benefit (18.7 vs. 10.0 months,p= 0.004) compared to males (13.0 vs. 13.6 months,p= 0.76), and the pattern of difference was significant (P for CpG–sex interaction = 0.03).Conclusions: In this study, females had higher mean and individual CpG site methylation and received a greater PFS and OS benefit by MGMT methylation that was not seen in males despite equal degrees of CpG methylation.
引言：胶质母细胞瘤（GBM）在发病率、遗传与表观遗传改变以及免疫反应方面存在性别差异。这些差异进一步延伸至MGMT启动子的甲基化状态，该状态对替莫唑胺耐药性具有关键影响。然而，目前对性别、MGMT甲基化与生存率之间的关联认识不足，本研究旨在对此进行评估。 方法：本研究基于2012年至2018年间在克利夫兰诊所（美国俄亥俄州）接受首次手术干预的新诊断GBM成人患者，开展了一项回顾性队列研究并遵循STROBE指南进行报告。采用Kaplan-Meier法和多变量Cox比例风险模型分析性别与MGMT启动子甲基化状态对总生存期（OS）的关联。若CpG 1-5的平均甲基化水平≥12%，则定义为MGMT甲基化。对部分患者进行倾向评分匹配，以评估单个CpG位点甲基化的影响。 结果：共有464例患者具有记录的MGMT甲基化状态，平均年龄63.4岁（范围19-93岁）。其中女性170例（36.6%），133例（28.7%）首次干预时接受大体全切术。42.5%的患者存在MGMT甲基化，女性MGMT甲基化比例显著高于男性（52.1% vs. 37.4%，p=0.004）。单变量分析显示，在女性患者中，MGMT启动子甲基化组的总生存期显著长于非甲基化组（2年生存率：36.8% vs. 11.1%；中位生存期：18.7 vs. 9.5个月；p=0.001），而男性患者中未观察到显著差异（2年生存率：24.3% vs. 12.2%；中位生存期：12.4 vs. 11.3个月；p=0.22，MGMT-性别交互作用p=0.02）。多变量分析显示，与非甲基化MGMT启动子相比，甲基化状态在女性（HR=2.07；95% CI：1.45-2.95；p<0.0001）和男性（HR=1.51；95% CI：1.14-2.00；p=0.004）中均与更差的总生存期相关。在MGMT启动子甲基化组内，男性总生存期显著差于女性（HR=1.42；95% CI：1.01-1.99；p=0.04）。在具有MGMT CpG启动子位点甲基化数值数据的患者中（n=304），CpG平均甲基化水平的中位数（IQR）为3.0%（2.0，30.5）。女性平均CpG甲基化水平高于男性（11.0% vs. 3.0%，p<0.002），且各CpG位点甲基化程度更高，其中CpG 1、2和4位点存在显著差异（p<0.008）。倾向评分匹配后，女性仍保持显著的生存获益（中位生存期：18.7 vs. 10.0个月，p=0.004），而男性无显著差异（13.0 vs. 13.6个月，p=0.76），且差异模式具有统计学意义（CpG-性别交互作用p=0.03）。 结论：本研究发现，女性患者具有更高的平均及单个CpG位点甲基化水平，且从MGMT甲基化中获得的无进展生存期和总生存期获益显著高于男性，即使在CpG甲基化程度相同的情况下，男性也未观察到同等程度的生存获益。
MGMT Methylation and Differential Survival Impact by Sex in Glioblastoma
肿瘤(癌症)患者之家