P14.48 Identification of subsets of IDH-mutant glioblastomas with distinct epigenetic and copynumber alterations and stratified clinical risks

Abstract

Abstract BACKGROUND 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. MATERIAL AND METHODS We conducted methylation profiles and estimated copy number variations in 64 IDH-mutant glioblastomas. RESULTS Our results showed that 10.9%, 53.1%, and 35.9% of tumors belonged to Codel, G-CIMPhigh, 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) and Codel groups (P=0.009). CDKN2A deletion (37.5%) was the most common gene copy number variation, and was associated with G-CIMP-low subgroup (P=0.001). Other frequent copy number changes included MET (4.7%), CCND2 (17.2%), PDGFRA (14.1%), CDK4 (12.5%), and EGFR (12.5%) amplification. Both CDKN2A deletion (P=0.008) 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 (Codel), Group 2 (GCIMP- high), Group 3 (G-CIMP-low without CDKN2A and MET alterations), and Group 4 (G-CIMP-low with CDKN2A/MET alteration). Survival analysis revealed Group 1 had a favorable OS (median survival: 41.3 months), while Groups 2 and 3 exhibited an intermediate OS (median survival: 20.6 and 21.8 months, respectively). Group 4 exhibited the worst OS (median survival: 8.4 months). Multivariable analysis confirmed the independent prognostic significance of our Groups. CONCLUSION IDH-mutant glioblastomas should be stratified for risk with combined epigenetic signature and CDKN2A/MET status and some cases have poor outcome.