Combined Therapy Sensitivity Index Based on a 13-Gene Signature Predicts Prognosis for IDH Wild-type and MGMT Promoter Unmethylated Glioblastoma Patients

Glioblastoma (GBM) is one of the lethal tumors with poor prognosis. However, prognostic prediction approaches need to be further explored. Therefore, we developed an evaluation system that could be used for prognostic prediction of GBM patients. Published mRNA expression datasets from The Cancer Genome Atlas (TCGA), Gene Expression Omnibus (GEO) and Chinese Glioma Genome Atlas (CGGA) were analyzed. Quantitative Realtime-PCR of signature genes and molecular aberrations of 178 Xiangya GBM patients were used for confirmation. Gene set enrichment analysis (GSEA) was performed for functional annotation. As a result, we established a 13-gene signature which named Combined Therapy Sensitivity Index (CTSI). Based on a cutoff point, we divided patients into high-risk group and low-risk group. Based on Kaplan-Meier analysis and multivariate Cox regression analysis, we found that patients in the high-risk group had a shorter overall survival time than patients in the low-risk group (p<0.001 in TCGA and CGGA datasets, p=0.047 in GSE4271 dataset, p=0.008 in Xiangya GBM cohort, HR: 1.65-3.42). By comparing the status of IDH mutation, TERT promoter mutation (TERTp-mut) and MGMT promoter methylation, CTSI was predictable in IDH wild-type (IDH-wt)/MGMT promoter unmethylated (MGMTp-unmeth) patients (p=0.037 in IDH-wt/TERTp-mut/MGMTp-unmeth subgroup, HR: 1.98; p=0.032 in IDH-wt/TERTp-wt/MGMTp-unmeth subgroup, HR: 2.09). Based on GESA, the Gene Ontology (GO) gene sets were enriched differently between CTSI high-risk and low-risk groups. Our results showed CTSI risk score can predict the prognosis of IDH-wt/MGMTp-unmeth GBM patients. Based on CTSI, combined with the status of IDH mutation, TERT promoter mutation and MGMT promoter methylation, a stepwise prognosis evaluation system which can provide precise prognosis prediction for GBM patients was established.