Abstract
BackgroundMutations 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.MethodsTo 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.ResultsAmong 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.ConclusionsOur 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.
Highlights
Mutations in isocitrate dehydrogenase 1 (IDH1) and isocitrate dehydrogenase 2 (IDH2) are frequent in low-grade gliomas and secondary glioblastomas
Mutations of IDH1 and IDH2 are mutually exclusive in gliomas, and biochemical investigations showed that IDH1 and IDH2 mutations differ in D-2-hydroxyglutarate (D-2HG) production in gliomas [10]
Clinical and molecular characterization of IDH2 mutations Among a total of 811 gliomas, IDH2 mutations were identified in 18 cases (2.2 %) (Table 1)
Summary
Mutations in isocitrate dehydrogenase 1 (IDH1) and isocitrate dehydrogenase 2 (IDH2) are frequent in low-grade gliomas and secondary glioblastomas (sGBM). Mutations in IDH1 and IDH2, which represent the most frequently mutated metabolic genes in human cancer, are implicated to be mutated in more than 50–80 % of low-grade gliomas and secondary glioblastomas (sGBM), 10 % of intrahepatic cholangiocarcinoma, 20 % of acute myeloid leukemia (AML), 56 % of chondrosarcomas, and over 10 % of melanoma cases [1,2,3,4,5]. IDH1 mutations are predominant in gliomas, chondrosarcoma, and cholangiocarcinoma, whereas IDH1 mutations and IDH2 mutations are common in AML Despite their different physiological characteristics, most genomic studies of the molecular landscapes in human cancer have frequently combined IDH1 mutations and IDH2 mutations as a single functional group
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