miRNA-26a expression influences the therapy response to carmustine wafer implantation in patients with glioblastoma multiforme.

BACKGROUND: Glioblastoma multiforme is the most frequent malignant brain tumor in adults being marked with a very poor prognosis. Therapy concept implies concomitant radio-chemotherapy and facultative implantation of carmustine-eluted wafer. Current literature suggests microRNA 26a expression in glioblastoma to interact with alkylating chemotherapy. Subsequently, the aim of this study was to investigate the correlation of miRNA-26a expression and carmustine wafer implantation and its potential usefulness as a predictive marker for therapy response. METHODS: In total, 229 patients with glioblastoma multiforme were included into the final analysis. Of them, 80 cases were recruited from the Saarland University Medical Center for a retrospective matched-pair analysis stratified after therapy regime: One group (carmustine wafer group; n=40) received concomitant radio-chemotherapy with carmustine wafer implantation. The other group (control group; n=40) only received concomitant radio-chemotherapy. The results were confirmed by comparing them with an independent dataset of 149 patients from the TCGA database. All tumor specimens were evaluated for miRNA-26a expression, MGMT promoter methylation, and IDH1 R132H mutation status, and the results were correlated with the clinical data. RESULTS: Twenty-three patients in the carmustine wafer group showed low expression of miRNA-26a, while 17 patients showed a high expression. In the control group, 28 patients showed low expression, while 12 patients showed a high expression. The patients with high miRNA-26a expression in the carmustine wafer group were characterized by a significantly longer overall (hazard ratio [HR] 2.750 [95% CI 1.352-5.593]; p=0.004) and progression-free survival (HR 3.091 [95% CI 1.436-6.657]; p=0.003) than patients with low miRNA-26a expression. The 17 patients in the carmustine wafer group with high miRNA-26a expression showed a significantly longer progression-free survival (p=0.013) and overall survival (p=0.007) compared with the control group. There were no such correlations identified within the control group. TCGA datasets supported these findings. CONCLUSIONS: MiRNA-26a expression turned out to be a promising predictor of therapy response and clinical outcome in glioblastoma patients treated with carmustine wafer implantation. For evaluation of the role of miRNA-26a in a combined therapy setting, further studies are needed in order to translate general findings to the patient's individual situation.

The Influence of Distinct Regulatory miRNAs of the p15/p16/RB1/E2F Pathway on the Clinical Progression of Glioblastoma Multiforme.

OBJECTIVE: The microRNAs (miRNAs) -26a, -24, and -21 have been reported as regulators of the P15/P16/RB1/E2F pathway, which plays a major role in glioblastoma multiforme (GBM) progression. In the present study, their predictive marker for the progression of GBMs is evaluated and described. METHODS: The expression of miRNA-21, -24, and -26a was analyzed as fold change (FC) in tumor specimens of 104 patients with GBM and 8 specimen of non-neoplastic brain tissue as control group. The results were referred to the individual clinical data sets and evaluated statistically. RESULTS: The FC of miRNA-21, -24, and -26a was 1.51 ± 1.35, 0.75 ± 0.67, and 0.39 ± 0.24 in the tumor samples. Within the control group, FC of miRNA-21, -24, and -26a was 0.31 ± 0.51, 0.66 ± 0.33, and 0.18 ± 0.11, respectively. MiRNA-26a and -21 were significantly overexpressed in GBM samples compared with healthy brain tissue (miRNA-21: P < 0.001; miRNA-26a: P = 0.011). High expression ofmiRNA-24 trended for a prolonged overall survival (P = 0.07). Patients with high miRNA-26a expression showed a significantly prolonged progression-free survival (hazard ratio 0.21; 95% confidence interval 0.09-0.51], P < 0.001) and overall survival (hazard ratio 0.3; 95% confidence interval 0.136-0.682], P = 0.003). The effect of miRNA-26a was mediated via regulation of mRNA of RB1. There was a significant inverse correlation between mRNA-26a and mRNA expression of RB1. CONCLUSIONS: The expression levels of miRNA-26a and -24 turned out to be promising predictors of further clinical course in patients with GBM multiforme.