Clinical and Molecular Features of Patients with Gliomas Harboring Idh1 Non-Canonical Mutations: A Systematic Review and Meta-Analysis.

Abstract

Purpose The canonical isocitrate dehydrogenase 1 R132 mutation (IDH1 R132) is the most frequent mutation among IDH mutated gliomas. Non-canonical IDH1 mutations or IDH2 mutations are unusual and their clinical and biological role is still unclear.Methods We performed a systematic review and meta-analysis aimed to assess the clinical role of IDH non-canonical mutations. ResultsOverall, we selected 13 of 3513 studies reporting data of 4007 patients with a diagnosis of grade 2 and grade 3 including 3091 patients with a molecularly proven IDH1 or IDH2 mutation. Patients with non-canonical IDH1 mutations were younger and presented a higher DNA methylation level as compared to those with canonical IDH1 R132H alteration. The overall incidence of non-canonical IDH1 mutations was 7.9% (95% CI 5.4 – 10.7%) in patients with IDH mutated gliomas. There was no statistical difference in terms of incidence between patients with grade 2 or grade 3 glioma. Patients with non-canonical IDH mutations had a lower rate of 1p19q codeletion (risk difference: 31%, 95% CI 23 -38%) and presented a significantly prolonged survival (pooled-HR 0.47, 95% CI, 0.28-0.81) as compared to those with IDH1 R132H mutation. Conclusion Non-canonical IDH1 mutations occur in 7.9% of IDH mutated gliomas and recognize a specific subgroup of patients with an improved survival despite a lower rate of 1p19q codeletion. Data about the type of IDH mutation should be collected in clinical practice and within interventional trials as this could be a critical variable for an improved patient’s stratification and selection.

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“…The noncanonical IDH1 mutations were associated by two studies with astrocytoma IDH-mutant, younger age and localization in the posterior fossa in comparison with IDH1 R132H mutation [20,21]. Despite a discrepancy between those two studies, a meta-analysis supported the positive prognostic value of noncanonical mutations [22].…”