Abstract LB-097: DNA methylation at enhancers distinguishes distinct breast cancer lineages

Abstract

Abstract Breast cancers exhibit genome-wide aberrant DNA methylation patterns. To investigate how these affect the transcriptome and which changes are linked to transformation or progression we applied genome-wide expression-methylation quantitative trait loci (emQTL) analysis between 5meCpG and gene expression. We find that on a whole genome scale, DNA methylation and gene expression have remarkably and reproducibly conserved patterns of association, both in cis and in trans, which lead to identify distinct transcriptional networks and specific disease cell lineages deviating from the normal tissue. In three breast cancer cohorts (n=104, n=253 and n=330), we invariably identify enhancers whose DNA methylation tethers the binding of three key transcription factors in breast cancer in a lineage specific manner. Our emQTL analysis also identifies tumor infiltrating immune cell signatures. Using ChromHMM segmentation and ChIP-seq associated TF binding regions, we identify enhancers and TF binding sites around emQTLs-CpGs. We functionally validate the genes associated with these CpGs using knock-down by siRNA and applying GRO-seq analysis after transcriptional stimulation with estrogen. DNA methylation at TF binding regions is considered an early event during normal breast cell transformation into estrogen dependent breast cancer. Two distinct key gene regulatory networks reported here are prominently altered by DNA methylation. Citation Format: Thomas Fleischer, Xavier Tekpli, Anthony Mathelier, Shixiong Wang, Daniel Nebdal, Hari P. Dhakal, Kristine Kleivi Sandberg, Ellen Schliting, Oslo Breast Cancer Research Consortium (OSBREAC), Anne-Lise Børresen-Dale, Elin Borgen, Bjørn Naume, Ragnhild Eskeland, Arnoldo Frigessi, Jörg Tost, Antoni Hurtado, Vessela N. Kristensen. DNA methylation at enhancers distinguishes distinct breast cancer lineages [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 LB-097. doi:10.1158/1538-7445.AM2017-LB-097