Androgen receptor binding sites are highly mutated in prostate cancer

Tunc Morova,Kush Dalal,Ozlem Keskin,Mehmet Gonen,Nathan A Lack,Attila Gursoy

doi:10.1530/oncolabs.1.p030

Abstract

Searchable abstracts of presentations at key conferences in oncology ISSN 2631-4657 (online)

Highlights

Androgen receptor (AR) signalling is essential in most prostate cancers
To investigate the impact of transcription factor (TF) binding on non-coding somatic mutations, we initially quantified the mutational density at binding sites using whole-genome sequencing (WGS) of primary Prostate cancer (PCa) (n = 196) from the Pan Cancer Analysis of Whole Genome (PCAWG)
A similar trend was observed with indels at AR-binding sites (ARBS) in PCa, though not as dramatic owing to the low numbers of indels obtained by consensus mutation calling (Supplementary Fig. 1B)

Summary

Introduction

Androgen receptor (AR) signalling is essential in most prostate cancers. Any alterations to AR-mediated transcription can have a profound effect on carcinogenesis and tumor growth. Using clinical whole genome sequencing, we show that AR binding sites have a dramatically increased rate of mutations that is greater than any other transcription factor and specific to only prostate cancer. This work demonstrates that non-coding AR binding sites are frequently mutated in prostate cancer and can impact enhancer activity. Recent studies have demonstrated that transcription factor (TF) binding to DNA can correlate with a higher rate of mutations[5,6]. In PCa, recent work by several laboratories demonstrated that duplication of an AR enhancer acts as a common driver of castrate-resistant PCa25–27 Given their potential role in modifying the transcriptional landscape of PCa, a better understanding of non-coding variants is critical to identifying novel driver mutations. We found that AR binding causes a high level of somatic mutations at ARBS and that the mutations are likely caused by impaired DNA repair

Methods

Results

Conclusion