基于跨平台整合微阵列法研究多基因联合评估胶质母细胞瘤病人预后的作用

O6-methylguanine-DNA methyltransferase (MGMT) promoter methylation status play an important role in the treatment and prognostic evaluation of the guidance gliomablastoma patients (GBMs). However, there have inadequacies in the clinical application. MGMT promoter methylation in the GBMs application of temozolomide combined with radiotherapy treatment prognosis are still differences; MGMT promoter methylation status of existence of the conversion phenomena in the primary and recurrent tumors. In the preliminary research, we cross-platform integrate 355 cases of GBM microarray datasets in TCGA database, combined with the DNA copy number, DNA methylation status and mRNA expression of candidate genes screening assessment of prognosis and the impact of MGMT promoter methylation state conversion; The proposed further in frozen and paraffin-embedded specimens to validate the candidate gene, multi-gene combined with the prognostic evaluation model developed and validated; the promoter methylation status of conversion affect the prognosis of GBMs, to research the mechanism of MGMT promoter methylation state conversion and chemotherapy resistance in tumor cell lines. This study reveals the molecular mechanism of GBM progress, GBMs individual treatment have important theoretical and practical significance.

O6-甲基鸟嘌呤-DNA-甲基转移酶（MGMT）启动子甲基化状态在指导胶质瘤母细胞瘤病人（GBMs）治疗和预后评估中发挥重要作用。但临床应用尚存不足，MGMT启动子发生甲基化的GBMs应用替莫唑胺联合放疗的预后仍有差异；在GBMs的初发和复发肿瘤中MGMT启动子甲基化状态存在转换现象。本课题组前期研究中应用生物信息学技术对TCGA数据库中355例GBM微阵列数据进行跨平台整合分析，结合DNA拷贝数，DNA甲基化状态，mRNA表达筛选评估预后的候选基因，并且发现MGMT启动子甲基化状态转换和GBMs预后相关；拟进一步在冰冻、石蜡标本验证候选基因，建立并验证多基因联合的预后评估模型；研究启动子甲基化状态转换对GBMs预后的影响，应用肿瘤细胞株研究MGMT启动子甲基化状态转换和化疗抵抗的机制。本研究对揭示GBM进展的分子机制、实现GBMs个体化治疗具有重要的理论和现实意义。

胶质瘤是最常见的中枢神经系统原发肿瘤，其中多形性胶质瘤母细胞瘤（Glioblastoma multiforme, GBM）属于WHO IV级，恶性程度高，病人预后差，中位生存期少于15个月。替莫唑胺（Temozolomide, TMZ）联合放疗(Radiotherapy, RT)已经成为临床常规的胶质瘤术后治疗方案。但是病人对于辅助治疗的敏感性不同，预后差别大。研究影响肿瘤病人对放化疗敏感性及预后相关基因，对病人进行个性化治疗，提高我国多形性胶质母细胞瘤治疗水平具有重要临床意义。目前，仅根据MGMT启动子甲基化状态指导GBM患者治疗和进行预后评估是非常困难的。在本项目中，我们通过整合TCGA数据库中GBM的微阵列数据，对MGMT病人甲基化程度进行分类研究，筛选辅助评估预后基因，并建立评估模型，应用临床样本进行验证。同时筛选与MGMT甲基化状态转换相关的调控基因，研究潜在调控基因的作用机制，对于进一步深入研究MGMT在TMZ耐药中的作用机制具有重要的理论和应用价值。