Extensive androgen receptor enhancer heterogeneity in primary prostate cancers underlies transcriptional diversity and metastatic potential

Androgen receptor (AR) drives prostate cancer (PCa) development and progression. AR chromatin binding profiles are highly plastic and form recurrent programmatic changes that differentiate disease stages, subtypes and patient outcomes. While prior studies focused on concordance between patient subgroups, inter-tumor heterogeneity of AR enhancer selectivity remains unexplored. Here we report high levels of AR chromatin binding heterogeneity in human primary prostate tumors, that overlap with heterogeneity observed in healthy prostate epithelium. Such heterogeneity has functional consequences, as somatic mutations converge on commonly-shared AR sites in primary over metastatic tissues. In contrast, less-frequently shared AR sites associate strongly with AR-driven gene expression, while such heterogeneous AR enhancer usage also distinguishes patients’ outcome. These findings indicate that epigenetic heterogeneity in primary disease is directly informative for risk of biochemical relapse. Cumulatively, our results illustrate a high level of AR enhancer heterogeneity in primary PCa driving differential expression and clinical impact.
We would like to acknowledge the NKI Genomics Core Facility for Illumina sequencing and bioinformatics support and the NKI Research High-Performance Computing (RHPC) facility for computational infrastructure. We express gratitude to all members of the Zwart and Bergman lab, and members of the NKI Oncogenomics division for helpful scientific discussion. This work was supported by the Prostate Cancer Foundation (21CHAL04), Department of Defense (W81XWH-21-1-0234, W81XWH-19-1-0565), Oncode Institute and Alpe d’HuZes/KWF Dutch Cancer Society (10084).