Survival outcomes in glioma patients with noncanonical IDH mutations: Beyond diagnostic improvements.

Abstract

2028 Background: According to the 2016 WHO classification of Central Nervous System tumors, the assessment of exon 4 mutations in IDH1 or IDH2 genes is an essential step in the characterization of gliomas. The R132H mutation is the most frequent alteration in IDH1 gene, however other non-canonical IDH mutations have been identified. The aim of this study was to evaluate the prognostic role of IDH non-canonical mutations. Methods: We analyzed our institutional data warehouse for all consecutive patients (pts) with newly diagnosed, histologically proven grade II – IV IDH mutant gliomas. IDH sequencing was performed using the 454 GS-Junior next generation sequencer (NGS) (Roche Diagnostic, Mannheim, Germany). All analyses were performed on DNA from formalin fixed and paraffin embedded (FFPE) specimens. Results: The analysis included 493 pts with IDH mutations. We found 279 (56.6%) grade 2, 173 grade 3 (35.1%) gliomas, and 41 (8.3%) IDH mutant glioblastoma. Canonical IDH1 R132H mutation was found in 428 pts (86.8%). The remaining pts showed IDH2 (3.9%) or IDH 1 non-canonical mutations (mainly R132C, R132G, R132S – 9.3%). Median follow-up time was 80.5 months. Pts with non-canonical mutations showed a younger median age (32 vs 39 years, p < 0.001). Other clinical characteristics and treatments were similar across IDH groups. Median survival was 145 months (95%CI: 137.7 - 152.9) and 198.6 (95%CI 155.2– 242.1) in patients with IDH R132H and non-canonical mutations, respectively (p = 0.013). In multivariate analysis grading (p < 0.001), extent of surgery (p < 0.001), 1p19q codeletion (p = 0.003) and presence of non-canonical mutations (p = 0.022) showed a significant role for improved survival. Conclusions: Detecting non-canonical IDH1 mutations is essential for diagnosis and for prognosis in patients with gliomas. Differential enzymatic activity of non-canonical IDH1 mutations, resulting in different levels 2-hydroxyglutaratecould be the reason of improved survival.