IDH1 and IDH2 mutations,immunohistochemistry and associations in a series of brain tumors

A total of 343 brain tumors were studied for IDH1 and IDH2 mutations by direct sequencing and for protein expression by immunohistochemistry with mIDH1^R132H antibody. Of these, 287 were gliomas (17 pilocytic astrocytomas, 13 grade II and 5 grade III astrocytomas, 167 primary (pGBMs) and 19 secondary (sGBMs) glioblastomas, 36 grade II and 26 grade III oligodendrogliomas and 4 grade II–III oligoastrocytomas). In gliomas, IDH1 mutations at codon R132 were identified in 22.3%, of which 93.7% were c.395G>A (p.R132H). Mutations were more frequent in oligodendrogliomas (53.2%) than in astrocytic tumors (22.8%) and in sGBMs (84.2%) upon pGBMs (1.8%). There was a statistically significant correlation between mIDH1^R132H antibody immunostaining and the relevant mutation c.395G>A (p.R132H) (P = 0.0001). No mutations were identified in non-glial tumors which were also negative to immunohistochemistry, with the exception of one PNET. A c.515G>T (p.R172M) mutation of the IDH2 gene was only identified in a grade II oligodendroglioma patient which was wild-type for IDH1. A direct correlation with MGMT promoter hypermethylation status and an inverse correlation with EGFR amplification was found, whereas the relationships with 1p/19q co-deletion and TP53 mutations only showed a trend toward correlation. In all gliomas, a positive correlation was found between IDH1 mutations and a young age (P = 0.0001). In contrast, a correlation with overall survival could only be obtained in low-grade gliomas. Immunohistochemistry appeared to be useful in differential diagnoses, especially toward non-tumor pathologic nervous tissue, and in recognizing infiltrating glioma cells. The mIDH1^R132H antibody positivity was complementary with Cyclin D1 expression.