PATH-15. IDENTIFICATION OF SUBSETS OF IDH-MUTANT GLIOBLASTOMAS WITH DISTINCT EPIGENETIC AND COPY NUMBER ALTERATIONS AND STRATIFIED CLINICAL RISKS

Abstract

Abstract IDH-mutant glioblastoma is classified by the 2016 CNS WHO as a group with good prognosis. However, the actual number of cases examined in the literature is relatively small. We hypothesize that IDH-mutant glioblastoma is not a uniform group and should be further stratified. We conducted methylation profiles and estimated copy number variations of 57 IDH-mutant glioblastomas. Our results showed that 59.6%, and 40.4% of tumors belonged to G-CIMP-high and G-CIMP-low methylation subgroups, respectively. G-CIMP-low subgroup was associated with significantly worse OS as compared to G-CIMP-high (P=0.005). CDKN2A deletion (42.1%) was the most common gene copy number variation, and was significantly associated with G-CIMP-low subgroup (P=0.004). Other frequent copy number changes included MET (5.3%), CCND2 (19.3%), PDGFRA (14.0%), CDK4 (12.3%), and EGFR (12.3%) amplification. Both CDKN2A deletion (P=0.036) and MET amplification (P< 0.001) were associated with poor OS in IDH-mutant glioblastomas. Combined epigenetic signatures and gene copy number variations separated IDH-mutant glioblastomas into Group 1 (G-CIMP-high), Group 2 (G-CIMP-low without CDKN2A nor MET alterations), and Group 3 (G-CIMP-low with CDKN2A and/or MET alterations). Survival analysis revealed Groups 1 and 2 exhibited a favorable OS (median survival: 619 days (20.6 months), and 655 days (21.8 months), respectively). Group 3 exhibited a significant shorter OS (median survival: 252 days (8.4 months)). Multivariable analysis confirmed the independent prognostic significance of our Groups. IDH-mutant glioblastomas should be stratified for risk with combined epigenetic signature and CDKN2A/MET status and some cases have poor outcome.