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Androgen receptor reprogramming demarcates prognostic, context-dependent gene sets in primary and metastatic prostate cancer

Severson, Tesa ; Qiu, Xintao ; Alshalalfa, Mohammed ; Sjöström, Martin LU ; Quigley, David ; Bergman, Andries ; Long, Henry ; Feng, Felix ; Freedman, Matthew L. and Zwart, Wilbert , et al. (2022) In Clinical Epigenetics 14(1).
Abstract

The androgen receptor (AR) is a prostate master transcription factor. It binds to genetic enhancers, where it regulates gene activity and plays a fundamental role in prostate pathophysiology. Previous work has demonstrated that AR-DNA binding is systematically and consistently reprogrammed during prostate tumorigenesis and disease progression. We charted these reprogrammed AR sites and identified genes proximal to them. We were able to devise gene lists based on AR status within specific histological contexts: normal prostate epithelium, primary prostate tumor, and metastatic prostate cancer. We evaluated expression of the genes in these gene sets in subjects from two distinct clinical cohorts—men treated with surgery for localized... (More)

The androgen receptor (AR) is a prostate master transcription factor. It binds to genetic enhancers, where it regulates gene activity and plays a fundamental role in prostate pathophysiology. Previous work has demonstrated that AR-DNA binding is systematically and consistently reprogrammed during prostate tumorigenesis and disease progression. We charted these reprogrammed AR sites and identified genes proximal to them. We were able to devise gene lists based on AR status within specific histological contexts: normal prostate epithelium, primary prostate tumor, and metastatic prostate cancer. We evaluated expression of the genes in these gene sets in subjects from two distinct clinical cohorts—men treated with surgery for localized prostate cancer and men with metastatic prostate cancer. Among men with localized prostate cancer, expression of genes proximal to AR sites lost in the transition from normal prostate to prostate tumor was associated with clinical outcome. Among men with metastatic disease, expression of genes proximal to AR sites gained in metastatic tumors was associated with clinical outcome. These results are consistent with the notion that AR is fundamental to both maintaining differentiation in normal prostate tissue and driving de-differentiation in advanced prostate cancer. More broadly, the study demonstrates the power of incorporating context-dependent epigenetic data into genetic analyses.

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organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
Androgen receptor, Epigenome, Prostate cancer, Transcriptome
in
Clinical Epigenetics
volume
14
issue
1
article number
60
publisher
BioMed Central (BMC)
external identifiers
  • scopus:85129444432
  • pmid:35509021
ISSN
1868-7075
DOI
10.1186/s13148-022-01278-8
language
English
LU publication?
yes
id
a8e04379-7b28-4a7a-942e-2bb66b835b94
date added to LUP
2022-07-05 14:46:08
date last changed
2024-06-11 20:12:28
@article{a8e04379-7b28-4a7a-942e-2bb66b835b94,
  abstract     = {{<p>The androgen receptor (AR) is a prostate master transcription factor. It binds to genetic enhancers, where it regulates gene activity and plays a fundamental role in prostate pathophysiology. Previous work has demonstrated that AR-DNA binding is systematically and consistently reprogrammed during prostate tumorigenesis and disease progression. We charted these reprogrammed AR sites and identified genes proximal to them. We were able to devise gene lists based on AR status within specific histological contexts: normal prostate epithelium, primary prostate tumor, and metastatic prostate cancer. We evaluated expression of the genes in these gene sets in subjects from two distinct clinical cohorts—men treated with surgery for localized prostate cancer and men with metastatic prostate cancer. Among men with localized prostate cancer, expression of genes proximal to AR sites lost in the transition from normal prostate to prostate tumor was associated with clinical outcome. Among men with metastatic disease, expression of genes proximal to AR sites gained in metastatic tumors was associated with clinical outcome. These results are consistent with the notion that AR is fundamental to both maintaining differentiation in normal prostate tissue and driving de-differentiation in advanced prostate cancer. More broadly, the study demonstrates the power of incorporating context-dependent epigenetic data into genetic analyses.</p>}},
  author       = {{Severson, Tesa and Qiu, Xintao and Alshalalfa, Mohammed and Sjöström, Martin and Quigley, David and Bergman, Andries and Long, Henry and Feng, Felix and Freedman, Matthew L. and Zwart, Wilbert and Pomerantz, Mark M.}},
  issn         = {{1868-7075}},
  keywords     = {{Androgen receptor; Epigenome; Prostate cancer; Transcriptome}},
  language     = {{eng}},
  number       = {{1}},
  publisher    = {{BioMed Central (BMC)}},
  series       = {{Clinical Epigenetics}},
  title        = {{Androgen receptor reprogramming demarcates prognostic, context-dependent gene sets in primary and metastatic prostate cancer}},
  url          = {{http://dx.doi.org/10.1186/s13148-022-01278-8}},
  doi          = {{10.1186/s13148-022-01278-8}},
  volume       = {{14}},
  year         = {{2022}},
}