Grade Group 1 Prostate Cancers Exhibit Tumor-defining Androgen Receptor–driven Programs

Simon Linder, Tesa M. Severson, Koen J.C. van der Mijn, Ekaterina Nevedomskaya, Joseph C. Siefert, Suzan Stelloo, Mark M. Pomerantz, Matthew L. Freedman, Henk van der Poel, Carmen Jerónimo, Rui Henrique, Andries M. Bergman (Corresponding author), Wilbert Zwart (Corresponding author)

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Abstract

Grade group 1 (GG1) primary prostate cancers with a pathologic Gleason score of 6 are considered indolent and generally not associated with fatal outcomes, so treatment is not indicated for most cases. These low-grade cancers have an overall negligible risk of locoregional progression and metastasis to distant organs, which is why there is an ongoing debate about whether these lesions should be reclassified as “noncancerous”. However, the underlying molecular activity of key disease drivers, such as the androgen receptor (AR), have thus far not been thoroughly characterized in low-grade tumors. Therefore, we set out to delineate the AR chromatin-binding landscape in low-grade GG1 prostate cancers to gain insights into whether these AR-driven programs are actually tumor-specific or are normal prostate epithelium-like. These analyses showed that GG1 tumors do not harbor a distinct AR cistrome and, similar to higher-grade cancers, AR preferentially binds to tumor-defining cis-regulatory elements. Furthermore, the enhancer activity of these regions and the expression of their respective target genes were not significantly different in GG1 tumors. From an epigenetic perspective, this finding supports the cancer designation currently given to these low-grade tumors and clearly distinguishes them from noncancerous benign tissue. Patient summary: We characterized the molecular activity of the androgen receptor protein, which drives prostate cancer disease, in low-grade tumors. Our results show that these tumors are true cancers and are clearly separate from benign prostate tissue despite their low clinical aggressiveness.

Original languageEnglish
Pages (from-to)455-460
Number of pages6
JournalEuropean Urology
Volume84
Issue number5
DOIs
Publication statusPublished - Nov 2023

Bibliographical note

Funding Information:
Funding/Support and role of the sponsor: This work was supported by Movember (NKI01 to A.M. Bergman and W. Zwart), the KWF Dutch Cancer Society (10084 ALPE to A.M. Bergman and W. Zwart), a KWF Dutch Cancer Society/Alpe d’HuZes Bas Mulder Award (NKI 2014-6711 to W. Zwart), The Netherlands Organization for Scientific Research (NWO-VIDI-016.156.401 to W. Zwart), and the US Department of Defense (W81XWH-19-1-0565 to M.M. Pomerantz, M.L. Freedman and W. Zwart). The sponsors played a role in the design and conduct of the study and data collection.

Keywords

  • Androgen receptor
  • Epigenomics
  • Gleason grading
  • International Society of Urological Pathology grade groups
  • Prostate cancer
  • Transcriptomics

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