Oncotarget

Research Papers:

IGFBP2 expression predicts IDH-mutant glioma patient survival

Lin Eric Huang _, Adam L. Cohen, Howard Colman, Randy L. Jensen, Daniel W. Fults and William T. Couldwell

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Oncotarget. 2017; 8:191-202. https://doi.org/10.18632/oncotarget.13329

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Abstract

Lin Eric Huang1,2, Adam L. Cohen3, Howard Colman1, Randy L. Jensen1,2, Daniel W. Fults1,2 and William T. Couldwell1

1 Department of Neurosurgery, Clinical Neurosciences Center, Salt Lake City, Utah, USA

2 Department of Oncological Sciences, Huntsman Cancer Institute, Salt Lake City, Utah, USA

3 Division of Oncology, Huntsman Cancer Institute, Salt Lake City, Utah, USA

Correspondence to:

Lin Eric Huang, email:

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

Received: October 20, 2016 Accepted: October 25, 2016 Published: November 12, 2016

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.


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