Prognostic role of mitochondrial pyruvate carrier in isocitrate dehydrogenase–mutant glioma

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OBJECTIVE

Gliomas are one of the most common types of primary brain tumors. Recent studies have supported the importance of key genetic alterations, including isocitrate dehydrogenase (IDH) mutations and 1p19q codeletion, in glioma prognosis. Mutant IDH produces 2-hydroxyglutarate from α-ketoglutarate, a key metabolite of the Krebs cycle. The mitochondrial pyruvate carrier (MPC) is composed of MPC1 and MPC2 subunits and is functionally essential for the Krebs cycle. The authors sought to explore the impact of MPC1 and MPC2 expression on patient prognosis.

METHODS

Genomic and clinical data in patients with lower-grade glioma (WHO grades II and III) from The Cancer Genome Atlas (TCGA) were evaluated using Kaplan-Meier analysis and hazards modeling. Validation was conducted with additional data sets, including glioblastoma.

RESULTS

A total of 286 patients with lower-grade glioma (mean age 42.7 ± 13.5 years, 55.6% males) included 54 cases of IDH–wild type (18.9%); 140 cases of IDH-mutant, 1p19q-intact (49.0%); and 85 cases of IDH-mutant, 1p19q-codeleted (29.7%) tumors. Kaplan-Meier analysis showed that an MPC1 z-score > 0 distinguished better survival, particularly in IDH-mutant (p < 0.01) but not IDH–wild type tumors. Conversely, an MPC2 z-score > 0 identified worsened survival, particularly in IDH-mutant (p < 0.01) but not IDH–wild type tumors. Consistently, neither MPC1 nor MPC2 was predictive in a glioblastoma data set containing 5% IDH-mutant cases. Within the IDH-stratified lower-grade glioma data set, MPC1 status distinguished improved survival in 1p19q-codeleted tumors (p < 0.05), whereas MPC2 expression delineated worsened survival in 1p19q-intact tumors (p < 0.01). A hazards model identified IDH and 1p19q status, age (p = 0.01, HR = 1.03), Karnofsky Performance Scale (KPS) score (p = 0.03, HR = 0.97), and MPC1 (p = 0.003, HR = 0.52) but not MPC2 (p = 0.38) as key variables affecting overall survival. Further validation confirmed MPC1 as an independent predictor of lower-grade glioma. A clinical risk score using IDH and 1p19q status, age, KPS score, and MPC1 and MPC2 z-scores defined 4 risk categories for lower-grade glioma; this score was validated using a secondary glioma data set.

CONCLUSIONS

These results support the importance of MPC, especially MPC1, in improving prognostication of IDH-mutant tumors. The generation of a risk score system directly translates this finding to clinical application; however, further research to improve the molecular understanding of the role of MPC in the metabologenomic regulation of gliomas is warranted.

ABBREVIATIONS FDR = false-discovery rate; KPS = Karnofsky Performance Scale; OS = overall survival; PFS = progression-free survival; TCGA = The Cancer Genome Atlas.

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Article Information

Correspondence L. Eric Huang: University of Utah, Salt Lake City, UT. neuropub@hsc.utah.edu.

INCLUDE WHEN CITING Published online March 16, 2018; DOI: 10.3171/2017.9.JNS172036.

Disclosures The authors report no conflict of interest concerning the materials or methods used in this study or the findings specified in this paper.

© AANS, except where prohibited by US copyright law.

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Figures

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    Comparative analysis of MPC1 and MPC2 mRNA levels with regard to IDH and 1p19q status. A: The mean MPC2 mRNA level was significantly greater in IDH–wild type glioma than in IDH-mutant glioma, as shown in scatterplot with mean ± SD. B: The mean MPC1 level was statistically greater in 1p19q-codeleted tumors than in 1p19q-intact tumors. C: The mean MPC2 level was statistically smaller in 1p19q-codeleted tumors than in IDH–wild type tumors. *p < 0.05; **p < 0.01; ***p < 0.001; ****p < 0.0001.

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    Comparison of MPC1 and MPC2 z-scores with OS. A: On scatterplot of MPC1 z-scores and OS along with IDH and 1p19q status, there was no significant correlation of MPC1 z-scores with OS for all patients (R = −0.5, p = 0.42). B: A scatterplot of MPC2 z-scores and OS indicated significant correlation for all patients (R = −0.1, p = 0.02). A wider spread of data is noted for MPC1 compared with MPC2. With MPC1 but not MPC2, IDH-mutant (mut), 1p19-intact patterns also cluster from IDH-mutant, 1p19q-codeleted (codel) patterns. Expression of MPC1 and MPC2 remains variable for IDH–wild type (wt) tumors. C: Comparison of MPC1 and MPC2 clustering for various IDH and 1p19q status in gliomas is shown. A significant correlation was seen between MPC1 and MPC2 expression for all patients (R = 0.1, p = 0.02). Figure is available in color online only.

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    Impact of MPC mRNA levels on survival in lower-grade gliomas. A: Evaluation of an MPC1 cutoff > 0 (thick line) showed better survival compared with MPC1 < 0 (thin line). B: An MPC1 cutoff > 0 also separated better survival in IDH-mutant (solid lines; top 2 survival curves) but not IDH–wild type (dashed lines; bottom 2 survival curves) tumors. C: A cutoff for MPC2 > 0 (thick line) showed a significant worsening of survival. D: For IDH-mutant tumors (solid lines; top 2 survival curves), an MPC2 cutoff > 0 showed worsened survival; however, this effect was not seen for IDH–wild type tumors (dashed lines; bottom 2 survival curves). *p < 0.05; **p < 0.01.

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    Association of survival effect of MPC with 1p19q status of IDH-mutant glioma. A and B: MPC1 expression separated survival of IDH-mutant glioma patients with 1p19q codeletion (A) but not those without (B); elevated MPC1 levels significantly improved survival only in 1p19q-codeleted tumors. C and D: Conversely, MPC2 expression differentiated survival in 1p19q-intact tumors (D) but not in 1p19q-codeleted tumors (C). These results support a prognostic role for MPC1 in oligodendrogliomas (1p19q-codeleted) and MPC2 in astrocytomas (1p19q-intact). *p < 0.05; **p < 0.01.

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    Distribution of MPC1 and MPC2 z-scores in molecular subtypes of lower-grade glioma. Waterfall graphs of MPC1 (left) and MPC2 (right) z-scores in IDH–wild type glioma (A), IDH-mutant, 1p19q-intact glioma (B), and IDH-mutant, 1p19q-codeleted glioma (C). Distribution percentages are indicated on the y-axis. Figure is available in color online only.

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    Kaplan-Meier survival analysis utilizing risk score for gliomas incorporating MPC status. Survival analysis was performed utilizing log-rank tests and a scoring system. A and B: Statistical correlation of the risk scores was observed with OS (A, p = 0.001) but not with PFS (B, p = 0.45). C: Predicted risk scores were validated on an independent lower-grade glioma data set (p = 0.0001). Figure is available in color online only.

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    Molecular pathway of MPC and IDH1/2. A molecular schematic of the glycolytic and Krebs cycle pathways depicts the potential interaction between MPC and IDH. The MPC1/2 complex mediates pyruvate transport through the inner mitochondrial membrane to provide α-ketoglutarate, which can ultimately serve as substrate for cytosolic conversion to 2-hydroxyglutarate (2-OG) by mutant IDH. Increased 2-hydroxyglutarate production results in a global hypermethylation phenotype in gliomas along with increased H3K9/H3K27 methylation and HIF-1 stabilization. GLUT = glucose transporter; MCT = monocarboxylic acid transporter. Figure is available in color online only.

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