Abstract 5338: Comprehensive pan-cancer genomic analysis reveals link between 3'UTR DNA methylation and increased gene expression

Abstract

Abstract Investigations into the function of non-promoter DNA methylation have yielded new insights into epigenetic regulation of gene expression. Previous studies have highlighted the importance of distinguishing between DNA methylation in discrete functional regions (e.g. promoter, gene body, enhancer); however, the relationship between DNA methylation outside of the promoter region and gene expression in cancer requires further exploration. Through integrated analysis of gene expression and DNA methylation profiles (>3,000 samples across multiple cancer types and corresponding normal tissues), we uncovered an enrichment of DNA methylation sites within the 3'UTR in which DNA methylation is strongly positively correlated with gene expression. In 5 of 10 tumor types examined, DNA methylation of the 3'UTR is associated with patient survival in a significant number of genes. Filtering for genes in which 3'UTR DNA methylation, relative to gene body DNA methylation, is more strongly correlated with gene expression yields a list of genes enriched for functions involving T cell activation. The immune checkpoint gene HAVCR2 (TIM-3) shows a substantial increase in 3'UTR DNA methylation, but not adjacent exonic/intronic, or promoter DNA methylation, upon T cell stimulation and upregulation of gene expression. Furthermore, this increase in HAVCR2 gene expression can be abrogated by treatment with demethylating agents. These findings implicate the 3'UTR as a functionally relevant DNA methylation site, particularly in regard to T cell activity. Additionally, they reveal a novel mechanism by which HAVCR2 is upregulated in T cells, providing a new means of targeting immune checkpoint blockade. Finally, these data offer a selective marker for choosing patients that could respond to the combination therapy of PD-1/PD-L1 inhibition and demethylating agents. Citation Format: Michael H. McGuire. Comprehensive pan-cancer genomic analysis reveals link between 3'UTR DNA methylation and increased gene expression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5338.