IDH gene testing in gliomas: rare and novel mutations in an australian cohort

Abstract

Isocitrate dehydrogenase (IDH) gene mutations are the earliest known molecular defects in the majority of low grade diffuse gliomas, and secondary glioblastomas. All reported mutations are heterozygous missense mutations which affect arginine residues in the substrate binding site of IDH1, or less commonly, IDH2. The IDH mutation status of a glioma is a strong predictor of tumour behaviour and patient outcome. Here we report our experience with IDH mutation testing of over 130 neurosurgical specimens. In this cohort the demographic and clinical characteristics of patients with IDH-mutant tumours are similar to those described from a variety of centres across the globe. Kaplan-Meier survival analyses showed significantly improved progression-free survival in IDH mutant astrocytomas compared to IDH wildtype astrocytomas. We also identified rare and novel IDH1 mutations: these include the first identified homozygous loss of wildtype IDH1 , an IDH1 (p.R100Q) mutation, and several instances of IDH1 (p.R132S) caused by a previously undescribed dinucleotide mutation. Our experience indicates that the spectrum of IDH1 defects in adult gliomas in Australia is more diverse than would be expected from the current literature, and that genetic screening should not be restricted to common IDH1 variants.