Abstract
BACKGROUND
recurring hotspot mutations in isocitrate dehydrogenase (IDH) 1 enzymes, and to a lesser extent IDH2, are the main oncogenic alteration in most of lower-grade diffuse gliomas and a subset of grade 4 gliomas. Although most commonly represented by the IDH1R132H mutation, non-canonical IDH1/2-nonR132H mutations are present in about 10% of cases. As the neomorphic enzymatic activity can vary depending on the type of the hotspot mutation, a different biological behaviour may be inferred. Nevertheless, the prognostic significance of the different IDH1/2 mutations remains a matter of debate.
MATERIAL AND METHODS
we queried the OncoNeuroTek tumor bank (Pitié-Salpêtrière Hospital, Paris) to identify all registered cases of IDH-mutated diffuse gliomas. Most relevant clinical and molecular data were collected.
RESULTS
We identified 1050 IDH mutated diffuse gliomas (481 grade 2 [46%], 459 grade 3 [44%], and 110 grade 4 [10%]), of which 1007 (96%) were IDH1 mutated (934 IDH1R132H [89%] and 73 IDH-nonR132H [7%]) and 43 (4%) were IDH2 mutated (24 IDH2R172K [2%] and 19 IDH2-nonR172K [2%]). The chromosomes 1p/19q codeletion was more frequent in IDH2-mutated tumors (25/42 [60%] versus 350/918 [38%] in IDH1-mutated cases, p=0.005). Nevertheless, only IDH2R172K mutation was associated with the codeletion (18/24 [75%], versus 7/18 [39%] in IDH2-nonR172K-mutated tumors, p=0.02). IDH1-nonR132H tumors showed the lowest rate of 1p/19q codeletion (9/69 [13%], versus 341/849 [40%] in IDH1R132H-mutated cases, p<0.001). At the time of observation, 536 patients were deceased (51%), with a median overall survival (OS) of 115 months (mo., 95% CI 108–125 mo.). Median follow up for censored patients was 77 mo. Codeleted patients had a significantly longer OS compared to non-codeleted ones (179 vs. 96 mo., p<0.001). No significant differences in survival were seen when stratifying according to IDH mutation type (115 mo. for IDH1R132H vs. 136 mo. for IDH1-nonR132H vs. 112 mo. for IDH2R172K vs. 150 mo. for IDH2-nonR172K, p=0.8). No differences were seen when restricting the analysis to codeleted or not-codeleted patients only, respectively. In a multivariate analysis including the main prognostic factors (age, sex, preoperative performance status, tumor grade, surgical resection, midline location, 1p/19q codeletion, and p16 homozygous deletion), no survival difference was associated with any of the IDH mutation subtype.
CONCLUSION
although significantly different rates of 1p/19q codeletion were seen according to the four main IDH mutation subgroups, these groups does not associate with different survival profiles in our cohort.
Characterization and prognostic significance of alternative splicing events in lower‐grade diffuse gliomas