Journal Article

Androgen receptor-binding sites are highly mutated in prostate cancer

Lallous, Nada, McNeill, Daniel R., Gürsoy, Attila, Morova, Tunç, Gönen, Mehmet, Dalal, Kush, Wilson, David M., Keskin, Özlem, Lack, Nathan A.

2020

Overview

Androgen receptor (AR) signalling is essential in nearly all prostate cancers. Any alterations to AR-mediated transcription can have a profound effect on carcinogenesis and tumor growth. While mutations of the AR protein have been extensively studied, little is known about those somatic mutations that occur at the non-coding regions where AR binds DNA. 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. Demonstrating this may be common to lineage-specific transcription factors, estrogen receptor binding sites were also found to have elevated rate of mutations in breast cancer. We provide evidence that these mutations at AR binding sites, and likely other related transcription factors, are caused by faulty repair of abasic sites. Overall, this work demonstrates that non-coding AR binding sites are frequently mutated in prostate cancer and can impact enhancer activity. Androgen receptor (AR) mediated transcription is critical to prostate tumorigenesis and development. Here, utilising clinical whole genome sequencing data, the authors show that the non-coding AR binding sites on DNA are frequently mutated in prostate cancer potentially due to faulty base excision repair mechanisms

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 49/15 / 49/23 / 631/67/589/466 / 631/67/69 / 631/80/86/2363 / Androgen receptors / Androgens / Animals / Base excision repair / Binding sites / Binding Sites - genetics / Breast cancer / Carcinogenesis / Carcinogens / Cell Line, Tumor / Deoxyribonucleic acid / DNA / DNA sequencing / DNA-(Apurinic or Apyrimidinic Site) Lyase / Estrogens / Gene Expression Regulation, Neoplastic / Genomes / Humanities and Social Sciences / Male / Mice / multidisciplinary / Mutation / Mutation Rate / Prostate cancer / Prostatic Neoplasms - genetics / Receptors, Androgen - genetics / Receptors, Androgen - metabolism / Receptors, Estrogen - chemistry / Receptors, Estrogen - genetics / Repair / Science / Science (multidisciplinary) / Transcription factors / Transcription Factors - metabolism / Tumorigenesis / Whole genome sequencing