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.
Highlights
Malignant gliomas are the most common primary brain tumors in adults [1], yet recurrent genetic changes that drive pathogenesis of World Health Organization (WHO) grade II and grade III gliomas remain to be identified [2, 3]
Further studies demonstrated the important role of insulin-like growth factor binding protein 2 (IGFBP2) in glioma progression [23, 24] and indicated that IGFBP2 expression was a poor prognostic marker in a mixed cohort ranging from grade II glioma to glioblastoma [31] as well as in glioblastoma alone [32]
Our analysis of 135 cases of The Cancer Genome Atlas (TCGA) glioblastoma data showed a 2-month statistical advantage in the median overall survival with low IGFBP2 mRNA levels. This advantage reduced by half and lost statistical significance when the only 7 isocitrate dehydrogenase (IDH)-mutant cases were subtracted from the analysis, further supporting an intimate relationship between IDH mutations and IGFBP2 in glioblastoma prognosis
Summary
Malignant gliomas are the most common primary brain tumors in adults [1], yet recurrent genetic changes that drive pathogenesis of WHO grade II and grade III gliomas (referred to collectively hereafter as lowergrade glioma, LGG) remain to be identified [2, 3]. Single somatic mutations of the isocitrate dehydrogenase 1 (IDH1) gene, predominantly R132H, occurred in ~80% of LGGs as well as in secondary glioblastomas [4, 5]. Mutant IDH1 inhibits histone demethylation and induces DNA hypermethylation in cell culture and animal model, thereby blocking cell differentiation [10,11,12]. Pharmacological targeting of mutant IDH1 or IDH2 induces tumor cell differentiation through reduction of (R)2-HG production [15, 16], the inhibitory effect on glioma growth remains less clear [16, 17], and there are www.impactjournals.com/oncotarget no appreciable changes in genome-wide DNA methylation [16]. Whether DNA methylationassociated gene expression is a cause of the survival advantage has yet to be explored
Sign-in/Register to view highlights & summary 
Published Version (
Free)
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call