Clinical Relevance and Interplay between miRNAs in Influencing Glioblastoma Multiforme Prognosis

Abstract

Glioblastoma multiforme (GBM) is usually treated with surgery followed by adjuvant partial radiotherapy combined with temozolomide (TMZ) chemotherapy. Recent studies demonstrated a better survival and good response to TMZ in methylguanine-DNA methyltransferase (MGMT)-methylated GBM cases. However, approximately 20% of patients with MGMT-unmethylated GBM display an unexpectedly favorable outcome. Therefore, additional mechanisms related to the TMZ response need to be investigated. As such, we decided to investigate the clinical relevance of six miRNAs involved in brain tumorigenesis (miR-181c, miR-181d, miR-21, miR-195, miR-196b, miR-648) as additional markers of response and survival in patients receiving TMZ for GBM. We evaluated miRNA expression and the interplay between miRNAs in 112 IDH wt GBMs by applying commercial assays. Then, we correlated the miRNA expression with patients' clinical outcomes. Upon bivariate analyses, we found a significant association between the expression levels of the miRNAs analyzed, but, more interestingly, the OS curves show that the combination of low miR-648 and miR-181c or miR-181d expressions is associated with a worse prognosis than cases with other low-expression miRNA pairs. To conclude, we found how specific miRNA pairs can influence survival in GBM cases treated with TMZ.

Keywords: clinical outcome; glioblastoma; miRNA pairs; miRNAs; overall survival; temozolomide.

Figure 1

Representation of the associations between miRNA expressions. Green boxes represent the pairs of miRNAs that are significantly associated; red boxes represent no statistically significant association. Up arrows represent the high expression of miRNAs (>3); down arrows represent the low expression of miRNAs (<0.333). The first arrow refers to the miRNA shown vertically, and the second to the miRNA shown horizontally.

Figure 2

OS curves obtained from the comparison of miRNA pair expression levels that were statistically significant against the group of all the other miRNA pairs analyzed in this study. Only statistically significant data are reported. (a) OS miR-181c (<0.333, low expression) + miR-648 (<0.333, low expression) versus low expression of all the other miRNA pairs (p = 0.01); (b) OS miR-181d (<0.333, low expression) + miR-648 (<0.333, low expression) versus low level of all the other miRNAs (p = 0.005).