Abstract 3352: Genome-wide enhancer identify signature predictive of metastatic phenotypes in bladder cancers

Abstract

Abstract In urothelial bladder cancer accurate identification of grade and stage is critical for optimal treatment to achieve robust disease control and long-term survival. However, among the initially superficial tumors, which are non-invasive and highly treatable, 20 to 25 % recur, progress to invasive tumors, and metastasize during the patients’ lifetime. Thus, the challenge is to provide risk stratification during the initial diagnosis in order to identify those patients who are unlikely to progress while offering radical therapy to those who are at risk. To address this issue, the field has heavily focused on the discovery of few mutations in potential driver genes. However, recent findings indicate that deregulation of enhancers can play a major role in cancer progression. In this study, we employed DNase-Seq to detect enhancer activities genome-wide in 16 bladder cancer cell lines (BLCs) that included three lineages (T24, UMUC3, 253J lineages) with different tumorigenic and metastatic potentials, and thus represent models of cancer progression and metastasis development. We analyzed the gain and loss of enhancer activity in each BLC lineages as well as in metastatic cell lines relative to non-metastatic cell lines. Our analysis in the T24 lineage revealed a striking feature, a dramatic loss of intronic and distal DHSs (DNase I Hypersensitive sites), during the initial transition to tumorigenic type. During metastatic progression, new enhancer classes emerged and there was an enrichment for association with target organ-specific genes. The analysis of differential DHSs between metastatic and non-metastatic BLCs identified an enhancer signature enriched with lost DHSs in metastatic BLCs where nearby genes were associated with cellular movement/invasion functions. Lost DHSs were also present near key factors such as PPARG, RXRA, FOXA1, TP63, and GATA3, which play a role in urothelial development and differentiation, and the transcription activity of those genes were correlated with the change of enhancer activity. This study identified a set of DHSs that are associated with cancer progression in bladder cancer, and provides a potential clinical application for developing prognostic markers to predict the risk of developing aggressive disease. Citation Format: Sohyoung Kim, Lyuba Varticovski, Qizong Lao, Songjoon Baek, Michael L. Nickerson, Myong-Hee Sung, Lars Grontved, Thompson Bethtrice, Dan Theodorescu, Piyush K. Agarwal, Michael Dean, Gordon Hager. Genome-wide enhancer identify signature predictive of metastatic phenotypes in bladder cancers [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 3352. doi:10.1158/1538-7445.AM2017-3352