1. Androgen receptor-binding sites are highly mutated in prostate cancer
- Author
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Nada Lallous, Attila Gursoy, Ozlem Keskin, Tunç Morova, Daniel R. McNeill, David M. Wilson, Nathan A. Lack, Kush Dalal, Mehmet Gönen, Morova, Tunç, Lack, Nathan A., Gönen, Mehmet (ORCID 0000-0002-2483-075X & YÖK ID 237468), Gürsoy, Attila (ORCID 0000-0002-2297-2113 & YÖK ID 8745), Keskin Özkaya, Zehra Özlem (ORCID 0000-0002-4202-4049 & YÖK ID 26605), McNeill, Daniel R., Wilson, David M., III, Lallous, Nada, Dalal, Kush, Koç University Research Center for Translational Medicine (KUTTAM) / Koç Üniversitesi Translasyonel Tıp Araştırma Merkezi (KUTTAM), School of Medicine, College of Engineering, Department of Industrial Engineering, Department of Computer Engineering, and Department of Chemical and Biological Engineering
- Subjects
Male ,0301 basic medicine ,Science ,General Physics and Astronomy ,Hormone receptors ,Biology ,medicine.disease_cause ,Article ,Multidisciplinary sciences ,General Biochemistry, Genetics and Molecular Biology ,Androgen receptor binding ,Mice ,03 medical and health sciences ,Prostate cancer ,0302 clinical medicine ,Mutation Rate ,Cell Line, Tumor ,DNA-(Apurinic or Apyrimidinic Site) Lyase ,Cancer genomics ,medicine ,Animals ,Androgen receptor ,Estrogen receptor ,Transcription factor ,lcsh:Science ,Enhancer ,Binding Sites ,Multidisciplinary ,Estrogen receptor binding ,Prostatic Neoplasms ,General Chemistry ,Base excision repair ,medicine.disease ,Gene Expression Regulation, Neoplastic ,030104 developmental biology ,Receptors, Estrogen ,Receptors, Androgen ,030220 oncology & carcinogenesis ,Mutation ,Cancer research ,lcsh:Q ,Carcinogenesis ,Transcription Factors - Abstract
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
- Published
- 2020