Extensive androgen receptor enhancer heterogeneity in primary prostate cancers underlies transcriptional diversity and metastatic potential.
Jeroen KneppersTesa M SeversonJoseph C SiefertPieter ScholStacey E P JoostenIvan Pak Lok YuChia-Chi Flora HuangTunç MorovaUmut Berkay AltintasClaudia GiambartolomeiJi-Heui SeoSylvan C BacaIsa CarneiroEldon EmberlyBogdan PasaniucCarmen JerónimoRui M HenriqueMatthew L FreedmanLodewyk F A WesselsNathan A LackAndries M BergmanWilbert ZwartPublished in: Nature communications (2022)
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.
Keyphrases
- prostate cancer
- gene expression
- single cell
- transcription factor
- binding protein
- small cell lung cancer
- dna methylation
- end stage renal disease
- radical prostatectomy
- chronic kidney disease
- dna damage
- ejection fraction
- magnetic resonance imaging
- magnetic resonance
- climate change
- benign prostatic hyperplasia
- case report
- peritoneal dialysis
- pluripotent stem cells