Singh Alka, Singh Anurag, Agrawal Sarita, Jaiswal Awadhesh, Jaiswal Sushila
Department of Pathology, Sanjay Gandhi Post Graduate Institute of Medical Sciences Lucknow, India.
Department of Medical Genetics, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow, India.
Discoveries (Craiova). 2023 Sep 26;11(3):e175. doi: 10.15190/d.2023.14. eCollection 2023 Jul-Sep.
Glioblastoma is the most aggressive and commonest primary malignant brain tumour. Current standard of care includes surgery, radiation, and alkylating agent chemotherapy. Despite multimodal treatment, the survival of glioblastoma patients is dismal. Loss of O6-methylguanine-DNA-methyltransferase(MGMT) protein expression due to promoter methylation reduces glioma cell DNA repair activity and resistance to alkylating agents. Thus, in world health organization (WHO) grade 4 diffuse glioma patients treated with an alkylating agent, methylated MGMT promoter is currently being considered a clinically relevant prognostic as well as predictive biomarker. Our aim was to assess the frequency of MGMT promoter methylation in WHO grade 4 diffuse glioma patients and study their prognostic role and clinicopathological correlations. A two-year prospective cohort research was conducted on 89 WHO grade 4 diffuse glioma patients. The clinical and demographic data were retrieved from our hospital information system. MGMT methylation was assessed using methylation specific polymerase chain reaction. Data was analysed using SPSS-24 software. We studied 89 cases of WHO grade 4 diffuse glioma, of which 38.2% showed methylation of MGMT promoter. There was no significant difference in age, sex, location of tumor and clinical presentation between the methylated and unmethylated groups. A statistically significant association of methylated MGMT promoter was observed with isocitrate dehydrogenase-1 (IDH1) protein expression (p = 0.050) and alpha-thalassemia/mental retardation syndrome X-linked (ATRX) loss (p = 0.003). No significant association was noted with p53 overexpression (p = 0.492) and Ki-67 index (p = 0.698). The median overall survival in these patients receiving standard radiotherapy and concomitant temozolomide chemotherapy showed a trend towards better survival in group with methylated MGMT promoter (p < 0.001). Our study suggests that methylation of MGMT promoter is more frequent in the subset of grade 4 diffuse gliomas that significantly exhibit IDH1 immunopositivity and loss of ATRX expression. Also, patients who receive radiation therapy and simultaneous temozolomide chemotherapy have a considerably better prognosis and treatment outcome, if the promoter region of MGMT is methylated.
胶质母细胞瘤是最具侵袭性且最常见的原发性恶性脑肿瘤。当前的标准治疗方案包括手术、放疗和烷化剂化疗。尽管采用了多模式治疗，但胶质母细胞瘤患者的生存率仍不容乐观。由于启动子甲基化导致的O6-甲基鸟嘌呤-DNA甲基转移酶（MGMT）蛋白表达缺失会降低胶质瘤细胞的DNA修复活性以及对烷化剂的抗性。因此，在接受烷化剂治疗的世界卫生组织（WHO）4级弥漫性胶质瘤患者中，甲基化的MGMT启动子目前被视为一种具有临床相关性的预后及预测生物标志物。我们的目的是评估WHO 4级弥漫性胶质瘤患者中MGMT启动子甲基化的频率，并研究其预后作用及临床病理相关性。对来自我们医院信息系统的89例WHO 4级弥漫性胶质瘤患者进行了为期两年的前瞻性队列研究。使用甲基化特异性聚合酶链反应评估MGMT甲基化情况。采用SPSS-24软件对数据进行分析。我们研究了89例WHO 4级弥漫性胶质瘤病例，其中38.2%显示MGMT启动子甲基化。甲基化组与未甲基化组在年龄、性别、肿瘤位置和临床表现方面无显著差异。观察到甲基化的MGMT启动子与异柠檬酸脱氢酶-1（IDH1）蛋白表达（p = 0.050）和X连锁的α地中海贫血/智力发育迟缓综合征（ATRX）缺失（p = 0.003）存在统计学显著关联。未发现与p53过表达（p = 0.492）和Ki-67指数（p = 0.698）有显著关联。在接受标准放疗和同步替莫唑胺化疗的这些患者中，MGMT启动子甲基化组的总生存期中位数显示出更好的生存趋势（p < 0.001）。我们的研究表明，MGMT启动子甲基化在显著表现出IDH1免疫阳性和ATRX表达缺失的4级弥漫性胶质瘤亚组中更为常见。此外，如果MGMT的启动子区域发生甲基化，接受放疗和同步替莫唑胺化疗的患者预后和治疗效果会明显更好。
