A novel nomogram based on DNA damage response-related gene expression in patients with O-6-methylguanine-DNA methyltransferase unmethylated glioblastoma receiving temozolomide chemotherapy: A population-based analysis

Background and Aim: Glioblastoma (GBM) is the most lethal primary brain tumor. Patients with unmethylated O-6-methylguanine-DNA methyltransferase (MGMT) promoter have higher MGMT expression, are less sensitive to temozolomide (TMZ), and are linked to poor prognosis. The aim of this study was to identify patients from this population with a better prognosis, explore the molecular mechanism, and provide a theoretical basis for the formulation of treatment strategies. Materials and Methods: Prognostic genes involved in the DNA damage response (DDR) pathway were screened, and the risk score of each GBM patient undergoing TMZ chemotherapy from The Cancer Genome Atlas (TCGA) and Chinese Glioma Genome Atlas (CGGA) database was calculated. A comprehensive prognostic nomogram model was constructed by combining the risk score and other clinical features. Results: Two DDR-related genes (replication factor C subunit 2 [RFC2] and methyl-CpG binding domain 4, DNA glycosylase [MBD4]) were identified as having a prognostic value in GBM patients with unmethylated MGMT promoter. Patients were classified into high- and low-risk groups using the risk score based on the expression of these two genes. The median overall survival of patients in the low-risk group was significantly longer than that recorded in the high-risk group in the TCGA cohort (15.95 vs. 11.90 months, respectively, P = 0.027) and CGGA cohort (25.90 vs. 11.87 months, respectively, P = 0.0082). The expression of those two genes was confirmed in tissue samples, and the risk scoring model showed that their prognostic value was independent of other clinical characteristics (P = 0.032), such as age. A final nomogram model was constructed, and its good performance was validated (concordance-index = 0.6656). Conclusions: A comprehensive prognostic model for patients with MGMT unmethylated GBM receiving TMZ chemotherapy was constructed using RFC2 and MBD4 gene expression, age, sex, and isocitrate dehydrogenase. The model showed good performance.