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

• Published in: European urology 2023-11, Vol.84 (5), p.455-460
• Main Authors: Linder, Simon, Severson, Tesa M., van der Mijn, Koen J.C., Nevedomskaya, Ekaterina, Siefert, Joseph C., Stelloo, Suzan, Pomerantz, Mark M., Freedman, Matthew L., van der Poel, Henk, Jerónimo, Carmen, Henrique, Rui, Bergman, Andries M., Zwart, Wilbert
• Format: Article
• Language: English
• Subjects: Androgen receptor; Epigenomics; Gleason grading; International Society of Urological Pathology grade groups; Prostate cancer; Transcriptomics
• ISSN: 0302-2838; 1873-7560
• DOI: 10.1016/j.eururo.2023.05.032

We show that the gene regulatory potential of the androgen receptor, the driver of prostate cancer disease, in low-risk grade group 1 lesions is very similar to that in higher-grade tumors and distinctly different from that in normal prostate epithelium, positioning grade group 1 lesions as bona fide cancers from an epigenetic perspective. 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. 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.