MicroRNA expression patterns in the malignant progression of gliomas and a 5-microRNA signature for prognosis

Abstract

MicroRNAs (miRNAs) are directly involved in the progression in various cancers. To date, no systematic researches have been performed on the expression pattern of miRNA during progression from low grade gliomas to anaplastic gliomas or secondary glioblastomas and those prognostic miRNAs in anaplastic gliomas and secondary glioblastomas. In the present study, high-throughput microarrays were used to measure miRNA expression levels in 116 samples in the different progression stages of glioma. We found that miRNA expression pattern totally altered when low grade gliomas progressed to anaplastic gliomas or secondary glioblastomas. However, anaplastic gliomas and secondary glioblastomas have similar expression pattern in miRNA level. Furthermore, we developed a five-miRNA signature (two protective miRNAs-miR-767-5p, miR-105; three risky miRNAs: miR-584, miR-296-5p and miR-196a) that could identify patients with a high risk of unfavorable outcome in anaplastic gliomas regardless of histology type. It should be highlighted that the five-miRNA signature can also identify patients who had a high risk of unfavorable outcome in secondary and TCGA Proneural glioblastomas, but not Neural, Classical and Mesenchymal glioblastomas. Taken together, our results demonstrate that miRNA expression patterns in the malignant progression of gliomas and a novel prognostic classifier, the five-miRNA signature, serve as a prognostic marker for patient risk stratification in anaplastic gliomas, Secondary and Proneural glioblastomas.

Figure 1. Differential expressed miRNAs among low grade, anaplastic gliomas and secondary glioblastomas (SAM: Fold change > 1.5, Q value < 1%)

Total 116 samples were ordered from low grade glioma to secondary glioblastomas, and differential expressed miRNAs were clustered. Arrows indicated genes that were discussed in the text.

Figure 2. Five miRNA risk-score analysis of anaplastic gliomas (n=44)

(A) The prognostic miRNA signature risk-score distribution. (B) Patients' survival status and time. (C) Color-gram of miRNA expression profiles of GBM patients; rows represent risky and protective miRNAs, and columns represent patients. The black dotted line represents the miRNA signature cutoff dividing patients into low-risk and high-risk groups.

Figure 3. The five-miRNA signature was tightly associated with prognosis in both Microarray cohort (n=44) and Validation cohort (n=134) independent of histology type

Histology types could stratify the anaplastic gliomas into different prognostic subpopulation although the P value is not enough small in both Microarray (A and F).and Validation cohort (K and P). The five-miRNA signature was could stratify the all anaplastic gliomas into two distinct prognostic subpopulation in both Microarray (B and G).and Validation cohort (L and Q). In each histological subtype of anaplastic gliomas (astrocytomas, oligodendrocytomas and oligoastrocytomas), the five-miRNA signature could also be taken as a stable method used for prognosis stratification in both Microarray (C, D, E, H, I and J) and Validation cohort (M, N, O, R, S and T).

Figure 4. The five-miRNA signature was tightly associated with prognosis in secondary glioblastomas

The five-miRNA signature was could stratify the all secondary glioblastomas into two distinct prognostic subpopulation in both Microarray (A and B).and Validation cohort (C and D).

Figure 5. The five-miRNA signature could predict the clinical outcome of TCGA Proneural glioblastomas

The five-miRNA signature was could stratify TCGA Proneural glioblastomas into two distinct prognostic subpopulation (A). However, the five-miRNA signature could not predict the clinical outcome in Neural, Classical and Mesenchymal glioblastomas (B, C and D).