Isocitrate Dehydrogenase IDH1 and IDH2 Mutations in Human Cancer: Prognostic Implications for Gliomas

Abstract

Background: There are isolated reports of mutations in genes for isocitrate dehydrogenases (IDH1 and IDH2), but few have been examined in a large number of different malignancies. We aimed to analyze mutational prevalence of these genes in a large series of cancers and determine their significance in most mutated phenotype. Methods: We analyzed the frequencies of IDH1 and IDH2 mutations in 14,726 malignancies of 37 cancers. Furthermore, we examined these mutations in the most frequent cancer (gliomas, 923 cases) from a single cohort, and determined their clinical significance. Results: IDH1 mutations were present in 3% (473/14,726) of cancers. The highest frequencies were in oligodendrogliomas (91/102, 89%), anaplastic oligodendrogliomas (40/46, 87%), and diffuse astrocytomas (89/116, 77%). IDH2 mutation was detected in <1% (83/14,726) of cancers, but were present in 13% (6/46) of anaplastic oligodendrogliomas, 9% (9/102) of oligodendrogliomas, and in 5% (2/39) of cutaneous squamous cell carcinomas. Further analyses of 923 gliomas revealed 34 and 1% of IDH1 and IDH2 mutations, respectively. In up to 342 months of follow-up, IDH1 and IDH2 mutations were significantly linked with better overall (OS) (both p = 0.01) and progression-free survival (PFS) (p = 0.01; p = 0.004), respectively. Conclusion: IDH1 and IDH2 are often mutated in a tissue-specific manner, most commonly in gliomas. Mutation in both genes is linked to OS and PFS. Our findings suggest that these genes are promising therapeutic targets and strong prognostic biomarkers in gliomas.

Keywords: IDH1; IDH2; cancer; dehydrogenase; glioma; isocitrate; mutation.

FIGURE 1

Prevalence and prognostic significance of IDH1 mutations in gliomas (A) OncoPrint tab. The tab shows the IDH1 mutations identified in gliomas. The row indicates the IDH1 gene and each column show a tumor sample. The green squares plotted on the columns show non-synonymous somatic mutations. (B) Overall survival curve. Of 923 glioma cases, 2 patients were excluded from survival analysis due to overlap. The total number of patients included in the overall survival analysis = 921. Number of cases with IDH1 mutation = 312 (number of events = 64; median overall survival (months) = 207). Number of cases without IDH1 mutation = 609 (number of events = 280; median overall survival (months) = 25), p = 0.01. (C) Progression-free survival curve. The total number of patients included in the overall progression-free survival analysis = 622. Number of cases with IDH1 mutation = 302 (number of events = 116; median progression-free survival (months) = 100). Number of cases without IDH1 mutation = 320 (number of events = 262; median progression-free survival (months) = 9), p = 0.01. Diagrams (B,C) display the Kaplan–Meier plot of overall survival and progression-free survival of glioma patients in the absence or presence of the IDH1 mutations which is indicated in blue and red colour, respectively.

FIGURE 2

Prevalence and prognostic significance of IDH2 mutations in gliomas (A) OncoPrint tab. The tab shows the IDH2 mutations found in gliomas. The row indicates the IDH2 gene and each column shows a tumor sample. The green squares plotted on the columns show non-synonymous somatic mutations. (B) Overall survival curve. The total number of patients included in the overall survival analysis = 923. Number of cases with IDH2 mutation = 23 (number of events = 5; median overall survival (months) = 248). Number of cases without IDH2 mutation = 900 (number of events = 339; median overall survival (months) = 62), p = 0.01. (C) Progression-free survival curve. The total number of patients included in the overall progression-free survival analysis = 623. Number of cases with IDH2 mutation = 20 (number of events = 6; median progression-free survival (months) = 133). Number of cases without IDH1 mutation = 603 (number of events = 372; median progression-free survival (months) = 30), p = 0.004. Diagrams (B,C) display the Kaplan–Meier plot of overall survival and progression-free survival of glioma patients in the absence or presence of the IDH2 mutations which are indicated in blue and red colour, respectively.