The comparison of clinical and biological characteristics between IDH1 and IDH2 mutations in gliomas

Abstract

Background: Mutations in isocitrate dehydrogenase 1 (IDH1) and isocitrate dehydrogenase 2 (IDH2) are frequent in low-grade gliomas and secondary glioblastomas (sGBM). Because they yield the same oncometabolite, D-2-hydroxyglutarate, they are often treated as equivalent and pooled. The objective of this study was to provide insight into the differences between IDH1 and IDH2 mutant gliomas.

Methods: To investigate the different clinical and molecular characterization between IDH1 mutant and IDH2 mutant gliomas, we studied 811 patients with IDH1 mutations, IDH2 mutations and IDH1/2 wild-type. In addition, whole-transcriptome sequencing and DNA methylation data were used to assess the distribution of genetic changes in IDH1 and IDH2 mutant gliomas in a Chinese population-based cohort.

Results: Among 811 gliomas in our cohort, 448 cases (55.2%) harbored an IDH1 mutation, 18 cases (2.2%) harbored an IDH2 mutation and 345 cases (42.6%) harbored an IDH1/2 wild-type. We found that IDH1 and IDH2 are mutually exclusive in gliomas, and IDH2 mutations are mutually exclusive with PTEN, P53 and ATRX mutations. Patients with IDH2 mutations had a higher frequency of 1p/19q co-deletion (p < 0.05) than IDH1 mutant patients. In addition, a Gene Set Enrichment Analysis (GSEA) showed that IDH2 mutant gliomas were associated with the oxidative phosphorylation gene set, and the four most representative biological processes for genes commonly altered by hypermethylation in IDH2 mutant gliomas were the regulation of cell proliferation, cell motion, cell migration and response to hypoxia. Patients with IDH2 mutant gliomas exhibited longer Overall survival (OS) (p < 0.05) and longer Progression-free survival (PFS) (p < 0.05) than patients with IDH1/2 wild-type gliomas. However, their OS and PFS did not differ from that of IDH1 mutant patients.

Conclusions: Our study revealed an intrinsic distinction between IDH1 and IDH2 mutant gliomas, and these mutations should be considered separately because their differences could have implications for the diagnosis and treatment of IDH1/2 mutant gliomas.

Keywords: DNA methylation analyzes; Glioma; IDH mutation; Whole transcriptome sequencing.

Fig. 1

Overview of clinical and molecular characterization of the cohort (n = 811). Each column represents a patient

Fig. 2

Gene Set Enrichment Analysis (GSEA) of overexpressed genes in glioma harboring IDH2 mutations. Each row represents a gene, and each column indicates a glioma with an IDH2 mutation, IDH1 mutation or IDH1/2 wild-type. Red indicates upregulated genes, and blue indicates downregulated genes. a Expression levels of genes annotated in IDH2 mutant gliomas compared to IDH1 mutant gliomas. b Expression levels of genes annotated in IDH2 mutant gliomas compared to IDH1/2 wild-type gliomas. c one representative plot of GSEA from a. d-e two representative plots of GSEA from (b)

Fig. 3

Clustering analysis of DNA methylation in IDH2 mutant gliomas. a The pattern of DNA methylation was associated with IDH2 mutant gliomas using a one-dimensional hierarchical clustering analysis. b Functional enrichment analysis of associated genes, indicating the functional roles of gene sets in different subgroups. Enrichment results for biological processes were obtained from the GO database. The orders of biological processes listed in the histogram are based on the number of targets annotated in the biological process (BP)

Fig. 4

The Kaplan–Meier estimates for Overall survival (OS) (a) and Progression-free survival (PFS) (b) indicates that IDH2 mutant gliomas associated with longer overall survival (p = 0.011) and longer progression-free survival (p = 0.011) than IDH1/2 wild-type gliomas. However, the OS and PFS did not significantly differ between IDH1 mutant and IDH2 mutant gliomas