(1) Background: Glioblastoma (GBM) is the most aggressive and common primary malignant brain tumor in adults, constituting 45.6% of tumors. We explored the impact of gene methylation of the O-6-Methylguanine-DNA Methyltransferase (MGMT) and the Transforming Growth Factor Beta (TGFB)gene complex using the TCGA dataset for GBM patients. (2) Methods: We implemented a multivariate Cox proportional hazards model to directly compare hazard ratios forTGFB1/2/3andMGMTmethylation in relation to OS, considering male versus female, age at diagnosis, and age interactions withTGFB2gene methylation and sex variables. Reactome analysis was performed to identify enriched pathways negatively correlated withTGFB2methylation. (3) Results: The GBM patients had high levels ofTGFB2gene methylation; this primarily benefited the young adult male patients, and multivariate analysis exhibited a significantly improved OS prognosis HR (95% CI range) = 0.04 (0.006–0.274);p= 0.001) relative to theTGFB1highMe(HR (95% CI range) = 0.657 (0.454–0.951);p= 0.026) andMGMThighMe(HR (95% CI range) = 0.667 (0.475–0.936);p= 0.019) groups of GBM patients. The Reactome pathways collectively represented T-cell activation, differentiation, effector functions, antigen presentation, and Toll-like receptor pathways. Gene level mRNA expression highlighted four positive prognostic genes upregulated in tumor tissues, and their expression was validated in independent single-cell RNA-seq experiments. These genes were highly expressed in macrophages (HIF1A, TRIM22, IRAK4, PARP9). In contrast, MALT1 mRNA expression was the only gene product with a negative prognostic impact on OS in GBM patients (HR (95% CI range) = 1.997 (1.1–3.625);p= 0.023). (4) Conclusions: Increased levelsof TGFB2gene methylation predict improved OS, especially in young adult male GBM patients, above that ofMGMTgene methylation, and should be considered during the administration of mRNA-based TGFB2 therapies.
（1）背景：胶质母细胞瘤（GBM）是成人中最具侵袭性且最常见的原发性恶性脑肿瘤，占所有脑肿瘤的45.6%。本研究利用TCGA数据库中GBM患者的数据，探讨了O-6-甲基鸟嘌呤-DNA甲基转移酶（MGMT）基因和转化生长因子β（TGFB）基因复合体甲基化对患者预后的影响。（2）方法：采用多变量Cox比例风险模型，直接比较TGFB1/2/3和MGMT甲基化与总生存期（OS）相关的风险比，同时纳入性别（男性与女性）、诊断年龄以及年龄与TGFB2基因甲基化及性别变量的交互作用。通过Reactome通路分析，识别与TGFB2甲基化呈负相关的富集通路。（3）结果：GBM患者中TGFB2基因甲基化水平较高，这主要对年轻成年男性患者有益。多变量分析显示，与TGFB1高甲基化组（风险比HR（95%置信区间CI）= 0.657（0.454–0.951）；p=0.026）和MGMT高甲基化组（HR（95% CI）= 0.667（0.475–0.936）；p=0.019）相比，TGFB2高甲基化组患者的OS预后显著改善（HR（95% CI）= 0.04（0.006–0.274）；p=0.001）。Reactome通路分析显示，这些通路共同涉及T细胞活化、分化、效应功能、抗原呈递以及Toll样受体通路。在基因水平上，mRNA表达分析突出了四种在肿瘤组织中上调且具有积极预后意义的基因，其表达在独立的单细胞RNA-seq实验中得到验证。这些基因在巨噬细胞中高表达（HIF1A、TRIM22、IRAK4、PARP9）。相比之下，MALT1 mRNA表达是唯一对GBM患者OS具有负面预后影响的基因产物（HR（95% CI）= 1.997（1.1–3.625）；p=0.023）。（4）结论：TGFB2基因甲基化水平升高预示着OS改善，尤其在年轻成年男性GBM患者中，其预测价值高于MGMT基因甲基化。在实施基于mRNA的TGFB2治疗时，应考虑这一因素。
Positive Prognostic Overall Survival Impacts of MethylatedTGFB2andMGMTin Adult Glioblastoma Patients
肿瘤(癌症)患者之家