Combined epigenetic signature and gene copy number variations in IDH-mutant glioblastomas showed varied risk stratification

Abstract

Abstract The number of IDH-mutant glioblastoma examined in the literature and TCGA is few. We used Infinium MethylationEPIC BeadChip array to classify 64 IDH-mutant-GBM into methylation groups. Gene copy number variations were determined from methylation. 53.1%, 35.9%, and 10.9% of tumors belonged to G-CIMP-high, G-CIMP-low and codel groups respectively. G-CIMP-low group of IDH-mutant glioblastoma was associated with worse survival as compared to G-CIMP-high (p=0.005) and Codel groups (p=0.009). CDKN2A deletion (24/64; 37.5%) was the most common gene copy number variation, and was significantly associated with GCIMP-low subgroup (p=0.001). Amplification of MET was identified in 3/64 (9.4%), CCND2 11/64 (17.2%), PDGFRA 9/64 (14.1%), CDK4 8/64 (12.5%) and EGFR 8/64 cases (12.5%). Both CDKN2A deletion (p=0.008) and MET amplification (p<0.001) were associated with poor survival. Combined methylation signature and gene copy number variations separated IDH-mutant glioblastoma into Group 1 (codeleted), Group 2 (GCIMP-high without CDKN2A deletion), Group 3 (GCIMP-high with CDKN2A deletion), Group 4 (GCIMP-low without CDKN2A and MET alterations), and Group 5 (GCIMP-low with CDKN2A and/or MET alterations). Group 1 had a favorable overall survival with a median survival of 1240 days. Groups 2, 3, and 4 exhibited an intermediate outcome with a median survival of 536, 619, and 655 days respectively. Group 5 exhibited a poor outcome with a median survival of 255 days. Groups based on combined methylation signature and CDKN2A/MET status are an independent prognostic factor. Conclusion: IDH mutant glioblastomas should be stratified for risk with combined epigenetic signature and CDKN2A/MET status and some cases have unfavorable outcomes.