Mutations in IDH1, IDH2, and in the TERT promoter define clinically distinct subgroups of adult malignant gliomas

Abstract

// Patrick J. Killela 1,* , Christopher J. Pirozzi 1,* , Patrick Healy 2 , Zachary J. Reitman 1 , Eric Lipp 1 , B. Ahmed Rasheed 1 , Rui Yang 1 , Bill H. Diplas 1 , Zhaohui Wang 1 , Paula K. Greer 1 , Huishan Zhu 1 , Catherine Y. Wang 1 , Austin B. Carpenter 1 , Henry Friedman 1 , Allan H. Friedman 1 , Stephen T. Keir 1 , Jie He 3 , Yiping He 1 , Roger E. McLendon 1 , James E. Herndon II 2 , Hai Yan 1 and Darell D. Bigner 1 1 Department of Pathology, Duke University Medical Center, The Preston Robert Tisch Brain Tumor Center at Duke, and Pediatric Brain Tumor Foundation Institute at Duke, Durham, NC, USA 2 Department of Biostatistics and Bioinformatics, Duke University Medical Center, Durham, NC, USA 3 Department of Thoracic Surgery, Cancer Institute and Hospital Chinese Academy of Medical Sciences, Beijing, 100021, China * Denotes equal contribution Correspondence: Hai Yan, email: // Keywords : TERT promoter, IDH1, IDH2, Glioma Received : January 26, 2014 Accepted : January 28, 2014 Published : January 28, 2014 Abstract Frequent mutations in isocitrate dehydrogenase 1 and 2 ( IDH1 and IDH2 ) and the promoter of telomerase reverse transcriptase ( TERT ) represent two significant discoveries in glioma genomics. Understanding the degree to which these two mutations co-occur or occur exclusively of one another in glioma subtypes presents a unique opportunity to guide glioma classification and prognosis. We analyzed the relationship between overall survival (OS) and the presence of IDH1/2 and TERT promoter mutations in a panel of 473 adult gliomas. We hypothesized and show that genetic signatures capable of distinguishing among several types of gliomas could be established providing clinically relevant information that can serve as an adjunct to histopathological diagnosis. We found that mutations in the TERT promoter occurred in 74.2% of glioblastomas (GBM), but occurred in a minority of Grade II-III astrocytomas (18.2%). In contrast, IDH1/2 mutations were observed in 78.4% of Grade II-III astrocytomas, but were uncommon in primary GBM. In oligodendrogliomas, TERT promoter and IDH1/2 mutations co-occurred in 79% of cases. Patients whose Grade III-IV gliomas exhibit TERT promoter mutations alone predominately have primary GBMs associated with poor median OS (11.5 months). Patients whose Grade III-IV gliomas exhibit IDH1/2 mutations alone predominately have astrocytic morphologies and exhibit a median OS of 57 months while patients whose tumors exhibit both TERT promoter and IDH1/2 mutations predominately exhibit oligodendroglial morphologies and exhibit median OS of 125 months. Analyzing gliomas based on their genetic signatures allows for the stratification of these patients into distinct cohorts, with unique prognosis and survival.