Abstract 5461: The role of gene body cytosine modifications in MGMT expression and sensitivity to temozolomide

Abstract

Abstract The goal of precision medicine is to use patient-specific markers to design individualized treatment strategies. Promoter methylation of O6-methylguanine-DNA methyltransferase (MGMT), which encodes for the DNA repair protein MGMT, has been shown to predict glioblastoma patient survival after treatment with temozolomide. Unfortunately, there is no approved therapeutic alternative for patients whose tumors have an unmethylated MGMT promoter and are unlikely to respond to temozolomide treatment. Promoter methylation status of MGMT is used to predict expression levels of MGMT, despite some observed discordance between promoter methylation and protein levels. We hypothesized that incorporation of MGMT gene body cytosine modification levels in models of temozolomide response may lead to better prediction of MGMT expression levels and, more importantly, improved methods of prediction for glioblastoma patient response to temozolomide. Using 91 human glioblastoma samples from The Cancer Genome Atlas, we observed significant variation in MGMT expression levels in patients with an unmethylated promoter, with higher levels of gene body cytosine modification correlating with higher gene expression levels. Furthermore, inducing hypomethylation across the MGMT gene body with decitabine resulted in decreased levels of MGMT gene expression in lymphoblastoid and glioblastoma cell lines. These data indicate an important functional role for gene body cytosine modifications in maintaining gene expression levels. We reasoned that the decrease in MGMT expression induced by decitabine might render resistant glioblastoma cell lines more sensitive to temozolomide. Indeed, MGMT-expressing glioblastoma cell lines pre-treated with decitabine became significantly more sensitive to temozolomide-induced cytotoxicity. Overall, our results demonstrate a functional role for gene body cytosine modification in regulating gene expression of MGMT and suggest that patients with an unmethylated MGMT promoter could benefit from pre-treatment with decitabine to increase tumor sensitivity to temozolomide. Citation Format: Erika L. Moen, Amy L. Stark, Wei Zhang, M. Eileen Dolan, Lucy A. Godley. The role of gene body cytosine modifications in MGMT expression and sensitivity to temozolomide. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 5461. doi:10.1158/1538-7445.AM2014-5461