Abstract 3359: TET1 mediated hypomethylation activates oncogenic signaling pathways in triple negative breast cancer

Triple negative breast cancer (TNBC) is a subtype of breast cancer that occurs in 15-20% of patients, and is defined by tumors that do not overexpress the estrogen, progesterone and HER2 receptors. This aggressive subtype has a significantly worse overall survival compared to non-TNBC and importantly, these patients lack options for targeted therapy. To identify novel subtype-specific therapeutic targets, we must first understand the biological underpinnings of the disease. DNA methylation is a hallmark of cancer, as it can regulate gene expression of both tumor suppressor genes and oncogenes. We have found that TN tumors have widespread genome-wide hypomethylation when compared to other breast cancer subtypes and normal breast controls. TET1 is a DNA demethylase that converts 5-methyl cytosine into 5-hydroxymethyl cytosine, which can be further oxidized into un-methylated cytosine. To determine if TET1 could possibly play a role in TNBC hypomethylation, we analyzed genome-wide DNA methylation, DNA mutation and RNA-seq datasets from the TCGA breast cancer cohort. We identified a subset of TN patients that upregulate TET1 and display DNA hypomethylation. To identify the hypomethylated TET1 target genes, we computed Spearman correlations between TET1 expression and methylation % for 450,000 sites (450K array) across 67 TNBC patients. Filtering for sites with r Citation Format: Charly Ryan Good, Andrew Kelly, Jozef Madzo, Jaroslav Jelinek, Jean-Pierre Issa. TET1 mediated hypomethylation activates oncogenic signaling pathways in triple negative breast cancer [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 3359. doi:10.1158/1538-7445.AM2017-3359