多形性胶质母细胞瘤中MGMT甲基化及MGMT、P53、EGFR、MDM2和PTEN表达的预后意义

Prognostic significance of MGMT methylation and expression of MGMT, P53, EGFR, MDM2 and PTEN in glioblastoma multiforme.

作者信息

Limam Sarra, Missaoui Nabiha, Abdessayed Nihed, Mestiri Sarra, Selmi Boulbaba, Mokni Moncef, Yacoubi Mohamed Tahar

机构信息

Pathology department, Farhet Hached University Hospital, Sousse, Tunisia.

Pathology department, Farhet Hached University Hospital, Sousse, Tunisia, Research Unit UR14ES17, Faculty of medicine, University of Sousse, Tunisia, Faculty of sciences and techniques of Sidi Bouzid, University of Kairouan, Tunisia.

出版信息

Ann Biol Clin (Paris). 2019 Jun 1;77(3):307-317. doi: 10.1684/abc.2019.1448.

DOI:10.1684/abc.2019.1448

PMID:31131831

Abstract

The study investigated the pattern of MGMT promoter methylation and the expression of MGMT, P53, EGFR, MDM2 and PTEN proteins in glioblastomas multiforme (GBM) and evaluated their prognostic significance. We carried out a retrospective study of 80 GBM. Expression of MGMT as well as of P53, EGFR, MDM2 and PTEN was investigated by immunohistochemistry. MGMT promoter methylation was investigated by methylation specific-PCR of bisulfite-treated DNA. Twenty-five GBM exhibited MGMT expression. Methylation of MGMT promoter was detected in 35.1% of cases. No significant concordance was reported between MGMT promoter methylation and protein expression (κ=-0.047, p=0.11). MGMT promoter methylation was significantly associated only with PTEN expression (p=0.001): no other significant association was identified with clinical parameters as well as with expression of P53, EGFR and MDM2 (p >0.05). Tumor recurrence was significantly associated with unmethylated MGMT promoter (p=0.01) but not with MGMT expression (p=0.51). Recurrence-free survival (RFS) was significantly better among patients with methylated MGMT promoter (log rank, p <0.0001) and PTEN expression (log rank, p=0.025) but not with MGMT expression (log rank, p=0.308). As well, using univariate analysis, MGMT promoter methylation (p=0.001) and PTEN expression (p=0.044) were significantly associated with RFS. In multivariate analysis, only MGMT promoter methylation was significantly associated with RFS (p=0.003). Together, our findings support that MGMT protein expression doesn't reflect the MGMT promoter methylation status. Furthermore, MGMT promoter methylation remains a useful prognostic marker in Tunisian patients with GBM. PTEN expression could be a potential prognostic marker of this tumor.

摘要

该研究调查了多形性胶质母细胞瘤（GBM）中MGMT启动子甲基化模式以及MGMT、P53、EGFR、MDM2和PTEN蛋白的表达情况，并评估了它们的预后意义。我们对80例GBM进行了回顾性研究。通过免疫组织化学研究MGMT以及P53、EGFR、MDM2和PTEN的表达。通过对亚硫酸氢盐处理的DNA进行甲基化特异性PCR来研究MGMT启动子甲基化。25例GBM表现出MGMT表达。35.1%的病例检测到MGMT启动子甲基化。MGMT启动子甲基化与蛋白表达之间未报告有显著一致性（κ=-0.047，p=0.11）。MGMT启动子甲基化仅与PTEN表达显著相关（p=0.001）：未发现与临床参数以及P53、EGFR和MDM2表达有其他显著关联（p>0.05）。肿瘤复发与未甲基化的MGMT启动子显著相关（p=0.01），但与MGMT表达无关（p=0.51）。MGMT启动子甲基化（对数秩检验，p<0.0001）和PTEN表达（对数秩检验，p=0.025）的患者无复发生存期（RFS）明显更好，但与MGMT表达无关（对数秩检验，p=0.308）。同样，单因素分析显示，MGMT启动子甲基化（p=0.001）和PTEN表达（p=0.044）与RFS显著相关。多因素分析中，只有MGMT启动子甲基化与RFS显著相关（p=0.003）。总之，我们的研究结果支持MGMT蛋白表达不能反映MGMT启动子甲基化状态。此外，MGMT启动子甲基化仍是突尼斯GBM患者有用的预后标志物。PTEN表达可能是该肿瘤的潜在预后标志物。