Isocitrate Dehydrogenase 1 Codon 132 Mutation Is an Important Prognostic Biomarker in Gliomas

TLDR

The study sequenced IDH1 codon 132 in 404 glioma patients (100 grade 2, 121 grade 3, 183 grade 4) and correlated the 155 detected mutations—131 Arg132His—with histology, genomic profile, MGMT promoter methylation, and clinical outcome. IDH1 codon 132 mutation is inversely correlated with glioma grade, associated with 1p19q codeletion and MGMT methylation, mutually exclusive with EGFR amplification and chromosome 10 loss, and independently predicts improved survival across grades 2–4.

Abstract

Unexpected mutations affecting the isocitrate dehydrogenase (IDH1) gene at codon 132 have been found in 12% of glioblastomas.IDH1 codon 132 sequencing was performed in a series of 404 patients with glioma (100 grade 2, 121 grade 3, and 183 grade 4 gliomas) and correlated with histology, genomic profile, methylguanyl methyltransferase (MGMT) promoter methylation status, and outcome.A total of 155 codon 132 mutations were found, of which 131 were Arg132His (88.5%). The IDH1 mutation was inversely correlated with grade, affecting 77% of grade 2, 55% of grade 3, and 6% of grade 4 gliomas (P < 10(-15)). The IDH1 mutation was tightly associated with a 1p19q codeleted genotype (P < 10(-14)) and an MGMT methylated status (P < .001) but mutually exclusive with EGFR amplification (P < 10(-15)) and loss of chromosome 10 (P < 10(-15)). The presence (v absence) of IDH1 mutation was associated with a better outcome in grade 2 (150.9 v 60.1 months, respectively; P = .01), grade 3 (81.1 v 19.4 months, respectively; P < .001), and grade 4 gliomas (27.4 v 14 months, respectively; P < .01). After adjustment for grade, age, MGMT status, genomic profile, and treatment, multivariate analysis confirmed that IDH1 mutation was an independent favorable prognostic marker (hazard ratio = 0.297; 95% CI, 0.157 to 0.564, P = .00021).This study indicates that IDH1 codon 132 mutation is closely linked to the genomic profile of the tumor and constitutes an important prognostic marker in grade 2 to 4 gliomas.