Androgen receptor profiling predicts prostate cancer outcome.

Suzan Stelloo,Jeroen de Jong,Ekaterina Nevedomskaya,Henk G van der Poel,Geert JLH van Leenders,Wilbert Zwart,Andries M Bergman,Guido Jenster,Lodewyk FA Wessels

doi:10.15252/emmm.201505424

Abstract

Prostate cancer is the second most prevalent malignancy in men. Biomarkers for outcome prediction are urgently needed, so that high-risk patients could be monitored more closely postoperatively. To identify prognostic markers and to determine causal players in prostate cancer progression, we assessed changes in chromatin state during tumor development and progression. Based on this, we assessed genomewide androgen receptor/chromatin binding and identified a distinct androgen receptor/chromatin binding profile between primary prostate cancers and tumors with an acquired resistance to therapy. These differential androgen receptor/chromatin interactions dictated expression of a distinct gene signature with strong prognostic potential. Further refinement of the signature provided us with a concise list of nine genes that hallmark prostate cancer outcome in multiple independent validation series. In this report, we identified a novel gene expression signature for prostate cancer outcome through generation of multilevel genomic data on chromatin accessibility and transcriptional regulation and integration with publically available transcriptomic and clinical datastreams. By combining existing technologies, we propose a novel pipeline for biomarker discovery that is easily implementable in other fields of oncology.

Highlights

Prostate cancer is the second most prevalent malignancy in men
Actual transcription factor binding was mapped with Chromatin immunoprecipitation (ChIP)-seq to identify sites that are differentially bound between two sample groups
The rationale for not applying endocrine therapies in the adjuvant management of prostate cancer after prostatectomy is provided by multiple clinical trials, which illustrated limited to no clinical benefit of blocking Androgen receptor (AR) function on disease-free survival of the entire population (Zincke et al, 2001; Dorff et al, 2011; Miocinovic et al, 2011; Siddiqui et al, 2011; Briganti et al, 2012; Schubert et al, 2012; Tsurumaki Sato et al, 2014)

Summary

Introduction

Prostate cancer is the second most prevalent malignancy in men. Biomarkers for outcome prediction are urgently needed, so that high-risk patients could be monitored more closely postoperatively. To identify prognostic markers and to determine causal players in prostate cancer progression, we assessed changes in chromatin state during tumor development and progression. We assessed genomewide androgen receptor/chromatin binding and identified a distinct androgen receptor/chromatin binding profile between primary prostate cancers and tumors with an acquired resistance to therapy. These differential androgen receptor/chromatin interactions dictated expression of a distinct gene signature with strong prognostic potential. We identified a novel gene expression signature for prostate cancer outcome through generation of multilevel genomic data on chromatin accessibility and transcriptional regulation and integration with publically available transcriptomic and clinical datastreams. We propose a novel pipeline for biomarker discovery that is implementable in other fields of oncology

Methods

Results

Conclusion