关键词: 胶质瘤, O6-甲基鸟嘌呤DNA甲基转移酶, 双/三基因联合分析, 预后, 替莫唑胺

Abstract:

Background and purpose: Glioma is a common malignant tumor of central nervous system with poor prognosis. Postoperative concurrent chemoradiotherapy with temozolomide (TMZ) is the main treatment for glioma. The methylation status of the O6-methylguanine-DNA methyltransferase (MGMT) promoter can predict the sensitivity of glioma patients to TMZ treatment, however its relationship with clinical pathology and how to better predict treatment and prognosis still need further research. The purpose of this study was to analyze the status of MGMT promoter methylation (MGMTmet) in gliomas and its correlation with clinical pathological features and other common molecular abnormalities, and to explore the value of combined analysis of MGMTmet and other molecular abnormalities in predicting the prognosis of glioma and the efficacy of TMZ treatment. Methods: We retrospectively collected clinical and pathological data from 205 glioma patients diagnosed by the Department of Pathology, Fudan University Shanghai Cancer Center from July 2019 to September 2022. Real-time fluorescence quantitative polymerase chain reaction (RTFQ-PCR) was used to detect MGMTmet status. Sanger sequencing was used to detect the mutation of isocitrate dehydrogenase 1 and 2 (IDH1/2) and telomerase reverse transcriptase (TERT) genes. Fluorescence in situ hybridization (FISH) was used to detect the deletion of the short arm of chromosome 1 and the long arm of chromosome 19 (1p19q). Results: Among 205 patients, the incidence of MGMTmet was higher in female patients than in male patients. Compared to glioblastoma (47.3%), astrocytoma (74.1%) and oligodendroglioma (100.0%) were more prone to methylation of the MGMT gene promoter (P<0.05). In MGMTmet group, IDH1 mutation rate and 1p19q co-deletion rate were significantly increased, and methylation of MGMT promoter was correlated with IDH1 mutation and 1p19q co-deletion (P<0.05). Patients with MGMTmet, age less than 55 years, oligodendroglioma, and World Health Organization (WHO) grade 1-3 all showed longer overall survival (OS), and the difference is statistically significant (P<0.05). Compared with individual influencing factors, dual/triple gene combination analysis (MGMTmet/IDH1 mutation or MGMTmet/1p19q co-deletion or MGMTmet/IDH1 mutation/1p19q co-deletion) had better effect for predicting the patient prognosis (P<0.05), with the latter two being independent prognostic factors. Among TMZ treated patients, MGMTmet (MGMTmet/TMZ+) patients had a better prognosis than other groups. If the patients had combined IDH1 mutations, the prognosis of the patients was further improved (P<0.05). Conclusion: MGMTmet is more common in women and patients with oligodendroglioma. It is positively correlated with IDH1 mutation and 1p19q co-deletion. Patients with MGMTmet are associated with better TMZ treatment efficacy and prognosis, and MGMTmet combined with IDH mutations and 1p19q co-deletion analysis have better TMZ treatment efficacy and prognostic implications.

Key words: Glioma, O6 methylguanine DNA methyltransferase, Double/triple gene conjoint analysis, Prognosis, Temozolomide