Androgen receptor reprogramming demarcates prognostic, context-dependent gene sets in primary and metastatic prostate cancer
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 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.
Document Details
- Document Type
- Pub Defense Publication
- Publication Date
- May 04, 2022
- Source ID
- 10.1186/s13148-022-01278-8
Entities
People
- Andries Bergman
- David Quigley
- Felix Y. Feng
- Henry Long
- Mark M. Pomerantz
- Martin Sjöström
- Matthew L Freedman
- Mohammed Alshalalfa
- Tesa Severson
- Wilbert Zwart
- Xintao Qiu
Organizations
- KWF Kankerbestrijding
- Prostate Cancer Foundation
- United States Department of Defense