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

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.

Fig 1. Distribution of TERT promoter and IDH1/2 mutations in a panel of 473 adult gliomas

Mutational analysis of 473 adult gliomas for TERT promoter and IDH1/2 mutations. Data are from 240 Grade IV GBM (A), 88 Grade II-III astrocytomas (B), 58 Grade II-III oligoastrocytomas (C), and, 87 Grade II-III oligodendrogliomas (D). Mutation status is indicated by color shading, with gray coloring indicating wild type sequence, red indicating mutations in the TERT promoter, and green indicating mutations in IDH1/2.

Fig 2. Overall Survival stratified by TERT promoter and IDH1/2 mutational status and histology within each tumor grade

Overall survival was represented by Kaplan Meier plots for individual WHO tumor grade: a) Grade II (n=103), b) Grade III (n=121), c) Grade IV (n=218). Only subgroups with at least 10 patients were included in the analyses. Tumors were represented by mutations status on the left (TERT promoter status / IDH1/2 status) and histology on the right (A represents Astrocytomas, O represents Oligodendrogliomas, and OA represents Oligoastrocytomas).

Fig 2. Overall Survival stratified by TERT promoter and IDH1/2 mutational status and histology within each tumor grade

Overall survival was represented by Kaplan Meier plots for individual WHO tumor grade: a) Grade II (n=103), b) Grade III (n=121), c) Grade IV (n=218). Only subgroups with at least 10 patients were included in the analyses. Tumors were represented by mutations status on the left (TERT promoter status / IDH1/2 status) and histology on the right (A represents Astrocytomas, O represents Oligodendrogliomas, and OA represents Oligoastrocytomas).

Fig 2. Overall Survival stratified by TERT promoter and IDH1/2 mutational status and histology within each tumor grade

Overall survival was represented by Kaplan Meier plots for individual WHO tumor grade: a) Grade II (n=103), b) Grade III (n=121), c) Grade IV (n=218). Only subgroups with at least 10 patients were included in the analyses. Tumors were represented by mutations status on the left (TERT promoter status / IDH1/2 status) and histology on the right (A represents Astrocytomas, O represents Oligodendrogliomas, and OA represents Oligoastrocytomas).

Fig 3. Overall Survival stratified by TERT promoter and IDH1/2 mutational status and histology among Grade III and IV patients

Overall survival was represented by Kaplan Meier plots stratified by a) histology (A represents Astrocytomas, O represents Oligodendrogliomas, OA represents Oligoastrocytomas, and GBM represents Glioblastoma) and b) TERT promoter / IDH1/2 mutation status for all Grade III and Grade IV gliomas analyzed in this study.