Abstract 5377: Intragenic DNA methylation and increased gene expression: New directions from pan-cancer analysis

Abstract

Abstract Purpose: While the impact of DNA methylation at the promoter region as a repressive influence is well-known, the vast majority of DNA methylation actually occurs outside of the promoter region. The function of intragenic DNA methylation remains incompletely understood. Here, we investigate how intragenic DNA methylation impacts gene expression, and how these modifications differ between normal and corresponding cancer tissues. Methods: A pan-cancer analysis of gene expression array data was integrated with Illumina 450k methylation array data across ten tumor types to produce correlation values between DNA methylation and gene expression at distinct loci on a genome-wide basis. The probes exhibiting a significant correlation between gene expression and DNA methylation were selected for further analysis. Results: We uncovered robust positive correlations between gene expression and 3’ methylation in 3,200 genes, with 590 genes in bladder cancer, and 256 genes in squamous cell lung carcinoma displaying a correlation coefficient of >0.5. Furthermore, we observed 44 genes with a correlation coefficient of >0.7 in at least two tissue types. The majority of genes with the strongest correlations are transcription factors known to play roles in differentiation and development, with an enrichment of zinc finger and homeobox-containing genes. Further analysis of these genes exhibit divergent 3’ methylation when comparing normal and tumor tissues. Importantly, the extent of 3’ methylation of these genes is associated with patient overall survival in 5 of the 10 tumor types analyzed, strongly suggesting that this process plays a role in cancer pathogenesis. Conclusion: DNA methylation of the 3’ region is a functionally and clinically relevant epigenetic modification, and may serve as a novel target for inhibiting tumorigenesis and tumor progression. Citation Format: Michael H. McGuire, Shelley Herbrich, Sherry Wu, Ying Wang, Rajesha Rupaimoole, Hui Yao, Kshipra Gharpure, Gabriel Lopez-Berestein, Keith Baggerly, Anil Sood. Intragenic DNA methylation and increased gene expression: New directions from pan-cancer analysis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5377. doi:10.1158/1538-7445.AM2017-5377