Improved risk stratification in younger IDH wild-type glioblastoma patients by combining a 4-miRNA signature with MGMT promoter methylation status.
- Luxembourg Center of Neuropathology
The potential benefit of risk stratification using a 4-miRNA signature in combination with MGMT promoter methylation in IDH1/2 wild-type glioblastoma patients was assessed.Primary tumors from 102 patients with comparable treatment from the LMU Munich (n=37), the University Hospital Düsseldorf (n=33) and The Cancer Genome Atlas (TCGA, n=32) were included. Risk groups were built using expressions of hsa-let-7a-5p, hsa-let-7b-5p, hsa-miR-615-5p and hsa-miR-125a-5p to assess prognostic performance in overall survival (OS). MGMT promoter methylation and age were considered as cofactors. Integrated miRNA, DNA-Methylome and transcriptome analysis was used to explore the functional impact of signature miRNAs.The 4-miRNA signature defined high-risk (n=46, med. OS: 15.8 months) and low-risk patients (n=56, med. OS: 20.7 months; univariable Cox proportional hazard analysis: HR: 1.8, 95%-CI: 1.14-2.83, p=0.01). The multivariable Cox-PH-model including the 4-miRNA signature (p=0.161), MGMT promoter methylation (p<0.001) and age (p=0.034) significantly predicted OS (Log-rank-p < 0.0001). Likewise to clinical routine, analysis was performed for younger (≤60 years, n=50, med. OS: 20.2 months) and older patients (>60 years, n=52, med. OS: 15.8) separately. In younger patients, the 4-miRNA signature had prognostic value (HR: 1.92, 95%-CI 0.93-3.93, p=0.076). Particularly, younger, MGMT methylated, 4-miRNA signature low-risk patients (n=18, med. OS: 37.4 months) showed significantly improved survival, compared to other younger patients (n=32, OS 18.5 months; HR: 0.33, 95%-CI 0.15-0.71, p=0.003). Integrated data analysis revealed 4-miRNA signature-associated genes and pathways.The prognostic 4-miRNA signature in combination with MGMT promoter methylation improved risk stratification with potential for therapeutic sub-stratification especially of younger patients.