Endocrine Abstracts (2016) 42 IL8 | DOI: 10.1530/endoabs.42.IL8

The Androgen Receptor chromatin landscape in prostate tumors: biomarker discovery and beyond

Suzan Stelloo, Ekaterina Nevedomskaya, Karianne Schuurman, Lodewyk FA Wessels, Rui Henrique, Carmen Jerónimo, Andries M Bergman & Wilbert Zwart

Department of Pathology, Erasmus Medical Center, Rotterdam, The Netherlands

The androgen receptor (AR) plays a pivotal role in prostate cancer development, progression and hormone-therapy resistant disease. AR requires a permissive epigenetic state at distinct chromatin regions to facilitate gene expression programs. The vast majority of AR sites are found at active enhancer regions, hallmarked by histone modification H3K27Ac and devoid of repressive markers including H3K27me3. In search for novel biomarkers for prostate cancer prognostication, we performed chromatin immunoprecipitation followed by massive parallel sequencing (ChIP-seq) on AR from surgical specimens. Distinct subsets of AR binding sites were identified that enabled patient stratification on outcome, yielding a novel gene expression-based biomarker that functions synergistically with standard clinicopathological features1. To further understand epigenetic regulation and AR genomics in larger patient series, we determined AR chromatin binding in 100 primary prostate cancers, along with histone modifications H3K4me3, H3K27me3 and H3K27Ac, gene expression and copy number profiles. The integrative analysis of these large datasets will provide information on I) distinct profiles of AR and histone modifications that may be bear prognostic potential, and II) the potential existence of distinct epigenetic subtypes in prostate cancer. Ultimately, we aim to further understand epigenetic regulation in prostate cancer along with its clinical implications on a genome-wide scale.

1Stelloo S, Nevedomkaya E, et al. Androgen receptor profiling predicts prostate cancer outcome. EMBO molecular medicine, 2015.

DOI: 10.1530/endoabs.42.IL8

Biographical details: Wilbert Zwart is a junior groupleader at the Netherlands Cancer Institute, department of Molecular Pathology, where he started his independent lab in 2011. He obtained his BSc and MSc at the University of Utrecht. He received his Ph.D. (cum laude) at the University of Leiden, based on his work at the Netherlands Cancer Institute in the groups of dr. Rob Michalides and prof. dr. Jacques Neefjes. His postdoctoral work was with dr. Jason Carroll at Cancer Research UK, Cambridge Research Institute, where he studied cofactor genomics in breast cancer. His lab studies hormone receptor function and transcriptional regulation in breast, prostate and endometrial cancer, in search for biomarkers and novel targets for therapeutic interventions. E-mail: w.zwart@nki.nl

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