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

Author

Listed:
  • Jeroen Kneppers

    (Netherlands Cancer Institute)

  • Tesa M. Severson

    (Netherlands Cancer Institute
    Netherlands Cancer Institute)

  • Joseph C. Siefert

    (Netherlands Cancer Institute
    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
    University of California Los Angeles)

  • Ji-Heui Seo

    (University of California Los Angeles
    Dana-Farber Cancer Institute)

  • 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
    Dana Farber Cancer Institute)

  • Lodewyk F. A. Wessels

    (Netherlands Cancer Institute)

  • Nathan A. Lack

    (University of British Columbia
    Koç University
    Koç University)

  • Andries M. Bergman

    (Netherlands Cancer Institute
    Netherlands Cancer Institute)

  • Wilbert Zwart

    (Netherlands Cancer Institute
    Eindhoven University of Technology)

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.

Suggested Citation

  • 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, 2022. "Extensive androgen receptor enhancer heterogeneity in primary prostate cancers underlies transcriptional diversity and metastatic potential," Nature Communications, Nature, vol. 13(1), pages 1-16, December.
  • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-35135-2
    DOI: 10.1038/s41467-022-35135-2
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