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

Jeroen Kneppers, Tesa M. Severson, Joseph C. Siefert, Pieter Schol, Stacey E. P. Joosten, Ivan Pak Lok Yu, Chia-Chi Flora Huang, Tunç Morova, Umut Berkay Altıntaş, Claudia Giambartolomei, Ji-Heui Seo, Sylvan C. Baca, Isa Carneiro, Eldon Emberly, Bogdan Pasaniuc, Carmen Jerónimo, Rui Henrique, Matthew L. Freedman, Lodewyk F. A. Wessels, Nathan A. Lack, Andries M. Bergman () and Wilbert Zwart ()
Additional contact information
Jeroen Kneppers: Netherlands Cancer Institute
Tesa M. Severson: Netherlands Cancer Institute
Joseph C. Siefert: Netherlands Cancer Institute
Pieter Schol: Netherlands Cancer Institute
Stacey E. P. Joosten: Netherlands Cancer Institute
Ivan Pak Lok Yu: University of British Columbia
Chia-Chi Flora Huang: University of British Columbia
Tunç Morova: University of British Columbia
Umut Berkay Altıntaş: Koç University
Claudia Giambartolomei: Istituto Italiano di Tecnologia
Ji-Heui Seo: University of California Los Angeles
Sylvan C. Baca: Dana-Farber Cancer Institute
Isa Carneiro: Portuguese Oncology Institute of Porto and Porto Comprehensive Cancer Center
Eldon Emberly: Simon Fraser University
Bogdan Pasaniuc: University of California Los Angeles
Carmen Jerónimo: Portuguese Oncology Institute of Porto and Porto Comprehensive Cancer Center
Rui Henrique: Portuguese Oncology Institute of Porto and Porto Comprehensive Cancer Center
Matthew L. Freedman: Dana-Farber Cancer Institute
Lodewyk F. A. Wessels: Netherlands Cancer Institute
Nathan A. Lack: University of British Columbia
Andries M. Bergman: Netherlands Cancer Institute
Wilbert Zwart: Netherlands Cancer Institute

Nature Communications, 2022, vol. 13, issue 1, 1-16

Abstract: Abstract 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.

Date: 2022
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DOI: 10.1038/s41467-022-35135-2

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