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. 2017 Jan 3;8(1):191-202.
doi: 10.18632/oncotarget.13329.

IGFBP2 expression predicts IDH-mutant glioma patient survival

Lin Eric Huang  1   2 , Adam L Cohen  3 , Howard Colman  1 , Randy L Jensen  1   2 , Daniel W Fults  1   2 , William T Couldwell  1
Affiliations

IGFBP2 expression predicts IDH-mutant glioma patient survival

Lin Eric Huang et al. Oncotarget. .

Abstract

Mutations of the isocitrate dehydrogenase (IDH) 1 and 2 genes occur in ~80% of lower-grade (WHO grade II and grade III) gliomas. Mutant IDH produces (R)-2-hydroxyglutarate, which induces DNA hypermethylation and presumably drives tumorigenesis. Interestingly, IDH mutations are associated with improved survival in glioma patients, but the underlying mechanism for the difference in survival remains unclear. Through comparative analyses of 286 cases of IDH-wildtype and IDH-mutant lower-grade glioma from a TCGA data set, we report that IDH-mutant gliomas have increased expression of tumor-suppressor genes (NF1, PTEN, and PIK3R1) and decreased expression of oncogenes(AKT2, ARAF, ERBB2, FGFR3, and PDGFRB) and glioma progression genes (FOXM1, IGFBP2, and WWTR1) compared with IDH-wildtype gliomas. Furthermore, each of these genes is prognostic in overall gliomas; however, within the IDH-mutant group, none remains prognostic except IGFBP2 (encodinginsulin-like growth factor binding protein 2). Through validation in an independent cohort, we show that patients with low IGFBP2 expressiondisplay a clear advantage in overall and disease-free survival, whereas those with high IGFBP2 expressionhave worse median survival than IDH-wildtype patients. These observations hold true across different histological and molecular subtypes of lower-grade glioma. We propose therefore that an unexpected biological consequence of IDH mutations in glioma is to ameliorate patient survival by promoting tumor-suppressor signaling while inhibiting that of oncogenes, particularly IGFBP2.

Keywords: DNA hypermethylation; IDH; IGFBP2; glioma; prognosis.

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Conflict of interest statement

CONFLICTS OF INTEREST

The authors declare no conflicts of interest.

Figures

Figure 1
Figure 1. Increased NF1 and PTEN expression in IDH-mutant glioma correlates with overall survival of glioma patients
A. DNA methylation and mRNA (in z-scores) of tumor-suppressor genes are presented in box-and-whisker plots. Unpaired t-tests were performed to compare IDH-wildtype (IDH) and IDH-mutant (IDHm) gliomas. B. Overall survival with respect to mRNA levels of specified genes, superimposed with the survival curves of IDH-wildtype and IDH-mutant gliomas, is presented with p values in log-rank (Mantel-Cox) tests. Decreased (< 0 in z-scores) and increased (> 0 in z-scores) mRNA levels were used for comparison. **, p < 0.01; ****, p < 0.0001; ND, not done.
Figure 2
Figure 2. Comparative analysis of DNA methylation and gene expression between IDH-wildtype and IDH-mutant gliomas
A. Heat maps of mean DNA methylation values (left) and mean mRNA levels (right) of corresponding genes are presented with statistical significance marked between IDH and IDHm groups. B.-D. Protein abundance (in z-scores) of specified genes are presented in box-and-whisker plots. E. Phosphorylation of ERBB3 (p-ERBB3) at Y1289 and AKT (p-AKT) at S473 and T308 are presented in the same way as above. Unpaired t-tests were performed for comparison between IDH and IDHm groups. *, p < 0.05; ***, p < 0.001.
Figure 3
Figure 3. Evaluation of differentially expressed genes in the RTK-PI3K-AKT pathway with respect to glioma patient survival
A. and C. Overall survival with respect to mRNA levels of RTK genes A. and PI3K-AKT genes C. that were differentially expressed between IDH and IDHm groups. B. Overall survival with respect to ERBB3 abundance and ERBB3 and AKT phosphorylation. Decreased (< 0 in z-scores) and increased (> 0 in z-scores) protein abundance and phosphorylation were used for log-rank (Mantel-Cox) tests and presented with p values (unless not significant). The survival curves with statistical significance were compared with those of IDH-wildtype and IDH-mutant gliomas.
Figure 4
Figure 4. Comparative and survival analyses of glioma progression genes between IDH-wildtype and IDH-mutant gliomas
A. DNA methylation, mRNA (in z-scores), and protein abundance (in z-scores) of genes, as indicated, are presented in box-and-whisker plots. B. and C. Overall survival B. and disease-free survival C. with respect to the mRNA levels of specified genes were analyzed in log-rank (Mantel-Cox) tests and presented with p values (unless not significant). The survival curves with statistical significance were compared with those of IDH-wildtype and IDH-mutant gliomas.
Figure 5
Figure 5. IGFBP2 expression is a validated prognostic marker within IDH-mutant glioma
A. and B. Correlations of IGFBP2 mRNA levels with overall survival A. and disease-free survival B. of IDH-wildtype patients (in black) and IDH-mutant patients (in blue) were analyzed in log-rank (Mantel-Cox) tests. C.-E. The GSE16011 glioma data set was used for validation of IGFBP2 as a prognostic marker in gene expression between IDH1R132H-negative and IDH1R132H-positive gliomas C., and overall survival of all glioma patients D. and patients stratified based on IDH status E. with respect to IGFBP2 expression. IDH1R132H-negative is in black, and IDH1R132H-positive in blue.
Figure 6
Figure 6. IGFBP2 is prognostic across all histological types of glioma
A. A heat map depicts distinctive patterns of gene expression between IDH-wildtype and IDH-mutant gliomas (All) but a shared pattern among oligodendroglioma (ODG), oligoastrocytoma (OAC), and astrocytoma (AC) of the same IDH status. The listed genes were all associated with glioma patient survival. B. and C. IGFBP2 mRNA levels were compared between IDH and IDHm groups in each histological type B. and between tumor grades C.. D. Differential IGFBP2 expression correlated with distinct patterns of survival in all histological types in reference to their respective survival curves (in dotted lines). E. Within IDH-mutant gliomas, there was no statistical difference in mean IGFBP2 expression between subtypes with and without 1p/19q deletions, and between gliomas with and without mutations in CIC, FUBP1, and/or NOTCH1 and between those with and without mutations in TP53 and/or ATRX.
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