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

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.