Clinical Information

Adult World Health Organization (WHO) grade II and III astrocytomas, oligodendrogliomas and oligoastrocytomas, and secondary glioblastomas (GBM) have been shown to harbor IDH1 and IDH2 mutations.(1-5) These missense mutations most frequently involve the arginine amino acid at IDH1 position 132 (R132) and at IDH2 position 172 (R172). The most frequent IDH1 amino acid alteration accounting for over 90% mutations is R132H, in addition to R132C, R132S, R132G, R132L, and R132V.(1) For IDH2, R172K, R172G, R172M, and R172W mutations have also been reported.(4,5) IDH proteins are nicotinamide adenine dinucleotide phosphate (NADP)-dependent isocitrate dehydrogenases that catalyze the oxidative decarboxylation of isocitrate to produce alpha-ketoglutarate. IDH1 and IDH2 mutations appear to be an early event in the development of these tumors and impair the enzyme activity,(3-4) resulting in loss of the ability to catalyse conversion of isocitrate to alpha-ketoglutarate. However, the enzyme acquires a neomorphic activity and is able to catalyze the NADPH-reduction of alpha-ketoglutarate to R(-)-2-hydroxyglutarate (2HG). These mutations appear to have prognostic significance with increased overall survival(1,4) and have been found to be associated with a younger age among adult diffuse astrocytomas, WHO grade III astrocytomas,(4) and GBM patients.(1-3) Of note, IDH1 mutations are only rarely reported among pilocytic astrocytomas,(2-4) primary GBM,(1,2) supratentorial primitive neuroectodermal tumors,(2) and pleomorphic xanthoastrocytomas,(4) and are absent in pediatric diffuse astrocytomas, ependymomas, medulloblastomas, primitive neuroectodermal tumors, and dysembryoblastic tumors.(3,4)