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.
Highlights
Glioblastoma multiforme (GBM) is the most frequent and aggressive form of primary brain tumors in adults, with an annual incidence of 3.2 per 100,000 [1,2,3]
We evaluated miR expression in the TCGA-glioblastoma multiforme (GBM) cohort with regard to their prognostic value
We report the expression of miR-221 and miR-222 as important prognostic factors in both the TCGA training (n = 482) and HD validation cohort (n = 109)
Summary
Glioblastoma multiforme (GBM) is the most frequent and aggressive form of primary brain tumors in adults, with an annual incidence of 3.2 per 100,000 [1,2,3]. The therapy schema might be adapted in elderly patients [6,9,10,11,12]. O-6-methylguanine-DNA methyltransferase (MGMT) hypermethylation (increased efficacy of alkylating agents [13]) and IDH1/2 mutation (secondary GBM [8,14,15]) are the most important prognostic markers used in clinical routine [16,17,18]. Further molecular mechanisms underlying differences in therapy outcome as well as interindividual heterogeneity in response to radiochemotherapy are not yet well understood, despite efforts to classify tumors based on epigenetic alterations [19,20,21], and require further research aiming for a patient-tailored therapy adjustment
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