BIOM-13. COMBINED MGMT PROMOTER METHYLATION AND LOW GENE BODY METHYLATION IS A SUPERIOR PREDICTOR OF ALKYLATING AGENT RESPONSE THAN PROMOTER METHYLATION ALONE IN GLIOBLASTOMA

Abstract BACKGROUND The DNA methylation status of the promoter region of O-6-methylguanine-DNA methyltransferase (MGMT) is a critical predictor of temozolomide response in newly diagnosed glioblastoma. However, MGMT-STP27, the dominant method for MGMT promoter methylation determination from methylation array data, considers only methylation probes located in the promoter region. In this study, we propose a robust MGMT classifier that considers MGMT methylation probes in both the promoter and gene body regions. METHODS We leveraged glioblastoma DNA methylation and/or gene expression data published by the TCGA (N=312), GLASS (N=276), and Capper et al. (N=535). We correlated MGMT gene expression and MGMT probe methylation in datasets with paired expression and methylation data. We formulated an MGMT methylation score that measured the difference between MGMT promoter probe methylation and gene body probe methylation. We then compared the prognostic utility of this score with the MGMT-STP27 model on patients treated with upfront alkylating agents in multiple datasets in both univariate and multivariate analyses. RESULTS We found that MGMT expression was prognostic in TCGA (OS HR=1.5, p=0.027, PFS HR=1.9, p=0.001) and GLASS (OS HR=1.4, p=0.088, PFS HR=1.6, p=0.03) glioblastomas among patients treated with alkylating agents. MGMT expression was negatively correlated with MGMT promoter methylation and positively correlated with MGMT gene body methylation. We defined an MGMT score as the difference between the average MGMT DNA methylation in negatively correlated promoter probes and the average methylation in positively correlated gene body probes. This score was prognostic in the TCGA (OS HR=1.6, p=0.003, PFS HR=1.6, p=0.001) and GLASS (OS HR=3.1, p=0.01, PFS HR=3.9, p=0.004) and was also superior to the MGMT-STP27 classifiers in multivariate analyses (TCGA p=0.03). CONCLUSION Overall, we defined an MGMT methylation score that considers promoter and gene body methylation and may be a superior predictor of glioblastoma response to alkylating agents compared to MGMT-STP27.