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. 2016 Nov 8;7(45):74031-74042.
doi: 10.18632/oncotarget.12188.

Classifying lower grade glioma cases according to whole genome gene expression

Baoshi Chen  1 , Tingyu Liang  1   2 , Pei Yang  1   2   3 , Haoyuan Wang  4 , Yanwei Liu  1   2   3 , Fan Yang  1   2 , Gan You  1   2   3
Affiliations

Classifying lower grade glioma cases according to whole genome gene expression

Baoshi Chen et al. Oncotarget. .

Abstract

Objective: To identify a gene-based signature as a novel prognostic model in lower grade gliomas.

Results: A gene signature developed from HOXA7, SLC2A4RG and MN1 could segregate patients into low and high risk score groups with different overall survival (OS), and was validated in TCGA RNA-seq and GSE16011 mRNA array datasets. Receiver operating characteristic (ROC) was performed to show that the three-gene signature was more sensitive and specific than histology, grade, age, IDH1 mutation and 1p/19q co-deletion. Gene Set Enrichment Analysis (GSEA) and GO analysis showed high-risk samples were associated with tumor associated macrophages (TAMs) and highly invasive phenotypes. Moreover, HOXA7-siRNA inhibited migration and invasion in vitro, and downregulated MMP9 at the protein level in U251 glioma cells.

Methods: A cohort of 164 glioma specimens from the Chinese Glioma Genome Atlas (CGGA) array database were assessed as the training group. TCGA RNA-seq and GSE16011 mRNA array datasets were used for validation. Regression analyses and linear risk score assessment were performed for the identification of the three-gene signature comprising HOXA7, SLC2A4RG and MN1.

Co nclusions: We established a three-gene signature for lower grade gliomas, which could independently predict overall survival (OS) of lower grade glioma patients with higher sensitivity and specificity compared with other clinical characteristics. These findings indicate that the three-gene signature is a new prognostic model that could provide improved OS prediction and accurate therapies for lower grade glioma patients.

Keywords: gene signature; lower grade glioma; prognosis; risk score.

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Conflict of interest statement

CONFLICTS OF INTEREST

None for all authors.

Figures

Figure 1
Figure 1. Heat map of differentially expressed genes in short (<1year) and long (>5year) survival groups
Red, High expression; Green, Low expression.
Figure 2
Figure 2. Ability of the three-gene signature to predict overall survival in the training and validation sets
L, Low-risk group; H, High-risk group. A. CGGA mRNA array data (p<0.0001); B. TCGA RNA-seq data (p<0.0001); C. GSE16011 mRNA array data (p<0.0001).
Figure 3
Figure 3. ROC analysis in assessing sensitivity and specificity for two-year survival prediction by the three-gene signature, histology, grade, age, IDH mut, and 1p/19q co-deletion in CGGA mRNA array and TCGA RNA-seq sets (largest validation set)
Figure 4
Figure 4. Functional annotation of risk groups
A. Top five enriched pathways in the high-risk group, analysed by gene set enrichment analysis of CGGA data. B. Three representative plots of GSEA from A. C. GO analysis revealed significant associations of genes with increased expression in the high-risk group with eight main pathways. D. Genes encoding CD163, CD68, IL10, IL6, MMP2, and MMP9 are expressed at higher levels in the high-risk group.
Figure 5
Figure 5. HOXA7 knockdown inhibits glioma cell migration and invasion in vitro
A. RT-qPCR analysis showed that HOXA7-siRNA downregulated HOXA7 expression in U251 glioma cells. B. Western blot analysis showed the biological effects of HOXA7-siRNA. Downregulation of HOXA7 inhibited protein expression of MMP9, a well-known migration and invasion marker. C. HOXA7-siRNA inhibited U251 cell migration and invasion capacities (p<0.01). Representative images and accompanying statistical plots are shown.
Figure 6
Figure 6. Procedure for selecting the 3 genes (HOXA7, SLC2A4RG and MN1) through whole genome mRNA profiling
See this image and copyright information in PMC

References

    1. Gao KM, Chen XC, Zhang JX, Wang Y, Yan W, You YP. A pseudogene-signature in glioma predicts survival. Journal of experimental & clinical cancer research. 2015;34:23. - PMC - PubMed
    1. Wang Y, Wang X, Zhang J, Sun G, Luo H, Kang C, Pu P, Jiang T, Liu N, You Y. MicroRNAs involved in the EGFR/PTEN/AKT pathway in gliomas. Journal of neuro-oncology. 2012;106:217–224. - PubMed
    1. Yang P, You G, Zhang W, Wang Y, Wang Y, Yao K, Jiang T. Correlation of preoperative seizures with clinicopathological factors and prognosis in anaplastic gliomas: a report of 198 patients from China. Seizure. 2014;23:844–851. - PubMed
    1. Chan AK, Yao Y, Zhang Z, Shi Z, Chen L, Chung NY, Liu JS, Li KK, Chan DT, Poon WS, Wang Y, Zhou L, Ng HK. Combination genetic signature stratifies lower-grade gliomas better than histological grade. Oncotarget. 2015;6:20885–20901. doi: 10.18632/oncotarget.4928. - DOI - PMC - PubMed
    1. Jiang T, Mao Y, Ma W, Mao Q, You Y, Yang X, Jiang C, Kang C, Li X, Chen L, Qiu X, Wang W, Li W, Yao Y, Li S, Li S, et al. CGCG clinical practice guidelines for the management of adult diffuse gliomas. Cancer letters. 2016;375:263–273. - PubMed