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. 2013 Oct 18;8(10):e77769.
doi: 10.1371/journal.pone.0077769. eCollection 2013.

Glioma IL13Rα2 is associated with mesenchymal signature gene expression and poor patient prognosis

Christine E Brown  1 , Charles D Warden, Renate Starr, Xutao Deng, Behnam Badie, Yate-Ching Yuan, Stephen J Forman, Michael E Barish
Affiliations

Glioma IL13Rα2 is associated with mesenchymal signature gene expression and poor patient prognosis

Christine E Brown et al. PLoS One. .

Erratum in

Abstract

A major challenge for successful immunotherapy against glioma is the identification and characterization of validated targets. We have taken a bioinformatics approach towards understanding the biological context of IL-13 receptor α2 (IL13Rα2) expression in brain tumors, and its functional significance for patient survival. Querying multiple gene expression databases, we show that IL13Rα2 expression increases with glioma malignancy grade, and expression for high-grade tumors is bimodal, with approximately 58% of WHO grade IV gliomas over-expressing this receptor. By several measures, IL13Rα2 expression in patient samples and low-passage primary glioma lines most consistently correlates with the expression of signature genes defining mesenchymal subclass tumors and negatively correlates with proneural signature genes as defined by two studies. Positive associations were also noted with proliferative signature genes, whereas no consistent associations were found with either classical or neural signature genes. Probing the potential functional consequences of this mesenchymal association through IPA analysis suggests that IL13Rα2 expression is associated with activation of proinflammatory and immune pathways characteristic of mesenchymal subclass tumors. In addition, survival analyses indicate that IL13Rα2 over-expression is associated with poor patient prognosis, a single gene correlation ranking IL13Rα2 in the top ~1% of total gene expression probes with regard to survival association with WHO IV gliomas. This study better defines the functional consequences of IL13Rα2 expression by demonstrating association with mesenchymal signature gene expression and poor patient prognosis. It thus highlights the utility of IL13Rα2 as a therapeutic target, and helps define patient populations most likely to respond to immunotherapy in present and future clinical trials.

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Conflict of interest statement

Competing Interests: The authors have declared that no competing interests exist.

Figures

Figure 2
Figure 2. IL13Rα2 expression is associated with mesenchymal signature gene expression in gliomas.
(A, B) Principal Component Analysis (PCA) plots of signature genes with respect to IL13Rα2 for glioma subclasses defined by (A) Verhaak et al. [5] (proneural (PN), neural (NL), classical (CL) and mesenchymal (MES)) and (B) Phillips et al. [6] (proneural (PN), proliferative (PROLIF) and mesenchymal (MES). Each point represents the position of one signature gene. (C, D) Silhouette plots of Pearson correlation coefficients for all significant correlations (FDR < 0.05) between IL13Rα2 and probes for genes defining glioma subtypes as defined by (C) Verhaak et al. [5], and (D) Phillips et al. [6] . Correlations are sorted based upon GBM subtype and then ordered by increasing correlation coefficient values. (E-F) Scatter plots for IL13Rα2 expression versus the average expression of (E) TCGA mesenchymal (MES), proneural (PN), classical (CL) and neural (NL) genes, and (F) the average expression of Phillips mesenchymal (MES), proliferative (PROLIF), and proneural (PN) genes). Linear regression of IL13Rα2 expression as a function of gene expression is shown by the orange lines. Number of signature genes (n) used to calculate average signature gene expression is reported for each plot (Methods and Datasets S3 and S4 in File S2).
Figure 1
Figure 1. Expression of glioma IL13Rα2 with respect to tumor grade and histological sub-type.
(A) Comparison of IL13Rα2 gene expression levels (robust multichip average, RMA) versus glioma tumor grade (WHO grades I-IV) from a combined data set of 429 patient samples [20,24]. The level of IL13Rα2 expression is 3.5-fold higher for WHO grade IV patients as compared to all other patients (2-way ANOVA with linear contrast, p=1.5 x 10-9). Shown are box plots marking median (bar), 25th and 75th percentiles (box), and 10th and 90th percentiles (error bars). (B) Comparison of IL13Rα2 gene expression levels for 184 samples [20,24] segregated based on glioma WHO grade II (orange circles) and grade III (green circles), and histological sub-types: astrocytoma, oligoastrocytoma and oligodenroglioma. No significant difference in IL13Rα2 expression levels were observed for the three patient cohorts (p=0.83, 2-way ANOVA). Box plots define percentiles as in (A). (C ) Biomodal distributions of IL13Rα2 for GBM (WHO IV) as defined by eight gene-array studies [5,6,19-25] (black line). Reported for each study is the frequency of tumors over-expressing IL13Rα2 estimated using a non-linear least squares regression (red line) .
Figure 3
Figure 3. IL13Rα2 expression is associated with mesenchymal gene expression in low-passage primary glioma cell lines.
Flow cytometry analyses of (A) IL13Rα2-negative glioma cell lines (PBT003-4, PBT008, PBT009, PBT022), and (B) IL13Rα2-positive glioma cell lines (PBT015, PBT017-4, PBT030, PBT036, and U251T) for expression of the proneural marker CD133 and mesenchymal markers CD44 and CD54/ICAM-1 (grey histograms). Solid lines show isotype and secondary control antibodies. (C) Comparison of mean fluorescence intensity (MFI) of IL13Rα2-negative and IL13Rα2-positive glioma cell lines shown in panels A and B. (D-E) Distribution plots of Affymetrix gene array expression analyses of (D) IL13Rα2-negative and (E) IL13Rα2-positive glioma cell lines for mesenchymal, classical, neural and proneural signature gene expression. (F) Correlation of mesenchymal (MES) versus proneural (PN) average gene expression with RMA normalized IL13Rα2 expression in glioma cell lines.
Figure 4
Figure 4. Over-expression of IL13Rα2 is associated with decreased patient survival.
(A) Kaplan-Meier survival plot for patients with GBM segregated based on ‘high’ versus ‘low’ IL13Rα2 expression as determined using non-linear least-squares regression (Table S1 in File S1). Kaplan-Meier plots for the same patient cohort evaluated in panel (A) are segregated based on (B) mesenchymal signature gene expression or (C) proneural signature gene expression, with ’high‘ and ’low‘ expression determined by median expression level.
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