Prognostic Value of microRNA-221/2 and 17-92 Families in Primary Glioblastoma Patients Treated with Postoperative Radiotherapy

Abstract

MicroRNAs (miRs) are non-coding master regulators of transcriptome that could act as tumor suppressors (TSs) or oncogenes (oncomiRs). We aimed to systematically investigate the relevance of miRs as prognostic biomarkers in primary glioblastoma multiforme (GBM) treated with postoperative radio(chemo)therapy (PORT). For hypothesis generation, tumor miR expression by Agilent 8x15K human microRNA microarrays and survival data from 482 GBM patients of The Cancer Genome Atlas (TCGA cohort) were analyzed using Cox-PH models. Expression of candidate miRs with prognostic relevance (miR-221/222; miR-17-5p, miR-18a, miR-19b) was validated by qRT-PCR using Taqman technology on an independent validation cohort of GBM patients (n = 109) treated at Heidelberg University Hospital (HD cohort). In TCGA, 50 miRs showed significant association with survival. Among the top ranked prognostic miRs were members of the two miR families miR-221/222 and miR-17-92. Loss of miR-221/222 was correlated with improved prognosis in both cohorts (TCGA, HD) and was an independent prognostic marker in a multivariate analysis considering demographic characteristics (age, sex, Karnofsky performance index (KPI)), molecular markers (O-6-methylguanine-DNA methyltransferase (MGMT) methylation, IDH mutation status) and PORT as co-variables. The prognostic value of miR-17-92 family members was ambiguous and in part contradictory by direct comparison of the two cohorts, thus warranting further validation in larger prospective trials.

Unlocking the potential ofmiR-19bin the regulation of temozolomide response in glioblastoma patients via targeting PPP2R5E, a subunit of the protein phosphatase 2A complex

“…It is also significantly up-regulated in glioma tissues and positively correlates with the glioma grade (26). MiR-19b expression is associated with an unfavorable prognosis of GBM patients (27,28), a finding also confirmed in our study (Fig. 1C).…”

Systematic characterization and biological functions of non‐coding RNAs in glioblastoma

“…High expression of miR‐1258 , miR‐935 and miR‐128‐3p was associated with better overall survival (OS) in patients with GBM, 23 , 24 , 25 while low miR‐542‐3p and miR‐221/222 clusters expression was associated with better OS in patients with GBM. 26 , 27 Previous studies evaluated the effect of cell‐free circulating RNA on patients with GBM. Nadaradjane et al 28 found that miR‐370‐3p could be treated in patients with GBM by enhancing temozolomide sensitivity, while it could not be used as a cell‐free circulating biomarker and was not associated with patient OS.…”

“…The average survival time of patients with glioma is 12–15 months, the 5‐year survival rate is <5%, and the survival and prognosis of patients with GBM are worse 22 ; thus, it is important to evaluate the patient's prognosis. High expression of miR‐1258 , miR‐935 and miR‐128‐3p was associated with better overall survival (OS) in patients with GBM, 23–25 while low miR‐542‐3p and miR‐221/222 clusters expression was associated with better OS in patients with GBM 26,27 . Previous studies evaluated the effect of cell‐free circulating RNA on patients with GBM.…”

Uncovering Spatiotemporal Heterogeneity of High-Grade Gliomas: From Disease Biology to Therapeutic Implications

“…Targeting DNA repair mechanisms with PARP inhibitors, and mutant IDH enzyme and gene fusions with appropriate inhibitors holds potential for treating GBM patients with such genetic alterations (171,172,(174)(175)(176). Identification of several markers relevant to GBM diagnostics using liquid biopsies with NGS for circulating free DNA and/or circulating tumor cells could be used in molecular diagnosis of cytological specimens and potential administration of innovative precision therapy (177,178).…”