Abstract
Glioblastomas are among the most lethal cancers; however, recent advances in survival have increased the need for better prognostic markers. microRNAs (miRNAs) hold great prognostic potential being deregulated in glioblastomas and highly stable in stored tissue specimens. Moreover, miRNAs control multiple genes representing an additional level of gene regulation possibly more prognostically powerful than a single gene. The aim of the study was to identify a novel miRNA signature with the ability to separate patients into prognostic subgroups. Samples from 40 glioblastoma patients were included retrospectively; patients were comparable on all clinical aspects except overall survival enabling patients to be categorized as short-term or long-term survivors based on median survival. A miRNome screening was employed, and a prognostic profile was developed using leave-one-out cross-validation. We found that expression patterns of miRNAs; particularly the four miRNAs: hsa-miR-107_st, hsa-miR-548x_st, hsa-miR-3125_st and hsa-miR-331-3p_st could determine short- and long-term survival with a predicted accuracy of 78%. Heatmap dendrograms dichotomized glioblastomas into prognostic subgroups with a significant association to survival in univariate (HR 8.50; 95% CI 3.06–23.62; p<0.001) and multivariate analysis (HR 9.84; 95% CI 2.93–33.06; p<0.001). Similar tendency was seen in The Cancer Genome Atlas (TCGA) using a 2-miRNA signature of miR-107 and miR-331 (miR sum score), which were the only miRNAs available in TCGA. In TCGA, patients with O6-methylguanine-DNA-methyltransferase (MGMT) unmethylated tumors and low miR sum score had the shortest survival. Adjusting for age and MGMT status, low miR sum score was associated with a poorer prognosis (HR 0.66; 95% CI 0.45–0.97; p = 0.033). A Kyoto Encyclopedia of Genes and Genomes analysis predicted the identified miRNAs to regulate genes involved in cell cycle regulation and survival. In conclusion, the biology of miRNAs is complex, but the identified 4-miRNA expression pattern could comprise promising biomarkers in glioblastoma stratifying patients into short- and long-term survivors.
Highlights
Glioblastomas are the most common primary malignant brain tumors in adults
Patients diagnosed with glioblastoma have a poor prognosis, but improvements in overall survival have been made over the last decade [1, 2] increasing the necessity for better prognostic markers
Histology combined with new molecular techniques is the gold standard in glioma diagnostics [3]; as several molecular alterations have proved to be important as diagnostic and prognostic tools e.g. mutations in the isocitrate dehydrogenase 1/2 (IDH1/2) genes and the promoter of telomerase reverse transcriptase (TERT) as well as methylations of the O6-methylguanine-DNA-methyltransferase (MGMT) promoter [3, 4]
Summary
Glioblastomas are the most common primary malignant brain tumors in adults. Patients diagnosed with glioblastoma have a poor prognosis, but improvements in overall survival have been made over the last decade [1, 2] increasing the necessity for better prognostic markers. Glioblastoma patients with tumors of similar histological appearance and molecular pattern still show great differences in overall survival. Better separation of patients could help select candidates for more aggressive treatment and active rehabilitation. A group of non-coding RNAs called microRNAs (miRNAs) can base-pair to target messenger RNA (mRNA) causing translational repression or mRNA degradation based on the level of complementarity between strands. MiRNAs mainly inhibit mRNA translation under imperfect binding to miRNA-recognition elements (MRE) within the 3’-untranslated region (UTR) of target mRNAs [6, 7]
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