title: IGFBP2 expression predicts IDH-mutant glioma patient survival.
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.
authors.affiliation: Department of Neurosurgery, Clinical Neurosciences Center, Salt Lake City, Utah, USA.|Department of Oncological Sciences, Huntsman Cancer Institute, Salt Lake City, Utah, USA.
authors.forename: Lin Eric
authors.initials: LE
authors.lastname: Huang
authors.affiliation: Division of Oncology, Huntsman Cancer Institute, Salt Lake City, Utah, USA.
authors.forename: Adam L
authors.initials: AL
authors.lastname: Cohen
authors.affiliation: Department of Neurosurgery, Clinical Neurosciences Center, Salt Lake City, Utah, USA.
authors.forename: Howard
authors.initials: H
authors.lastname: Colman
authors.affiliation: Department of Neurosurgery, Clinical Neurosciences Center, Salt Lake City, Utah, USA.|Department of Oncological Sciences, Huntsman Cancer Institute, Salt Lake City, Utah, USA.
authors.forename: Randy L
authors.initials: RL
authors.lastname: Jensen
authors.affiliation: Department of Neurosurgery, Clinical Neurosciences Center, Salt Lake City, Utah, USA.|Department of Oncological Sciences, Huntsman Cancer Institute, Salt Lake City, Utah, USA.
authors.forename: Daniel W
authors.initials: DW
authors.lastname: Fults
authors.affiliation: Department of Neurosurgery, Clinical Neurosciences Center, Salt Lake City, Utah, USA.
authors.forename: William T
authors.initials: WT
authors.lastname: Couldwell
mesh_terms: D001932:Brain Neoplasms; D019175:DNA Methylation; D030561:Databases, Nucleic Acid; D018450:Disease Progression; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D005910:Glioma / Q000235:genetics* / Q000378:metabolism / Q000401:mortality* / Q000473:pathology; D006801:Humans; D018971:Insulin-Like Growth Factor Binding Protein 2 / Q000235:genetics*; D007521:Isocitrate Dehydrogenase / Q000235:genetics*; D053208:Kaplan-Meier Estimate; D009154:Mutation; D060787:Neoplasm Grading; D009367:Neoplasm Staging; D025542:Neurofibromin 1 / Q000235:genetics; D051059:PTEN Phosphohydrolase / Q000235:genetics; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D011379:Prognosis; D016016:Proportional Hazards Models; D051057:Proto-Oncogene Proteins c-akt; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D018971:Insulin-Like Growth Factor Binding Protein 2; D025542:Neurofibromin 1; D007521:Isocitrate Dehydrogenase; D019869:Phosphatidylinositol 3-Kinases; D020794:Receptor Protein-Tyrosine Kinases; D051057:Proto-Oncogene Proteins c-akt; D051059:PTEN Phosphohydrolase
keywords: DNA hypermethylation; IDH; IGFBP2; glioma; prognosis