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.
European urology. 2023 Jun 02 [Epub ahead of print]
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, Wilbert Zwart
Division of Oncogenomics, Oncode Institute, The Netherlands Cancer Institute, Amsterdam, The Netherlands., Division of Oncogenomics, Oncode Institute, The Netherlands Cancer Institute, Amsterdam, The Netherlands; Division of Molecular Carcinogenesis, Oncode Institute, The Netherlands Cancer Institute, Amsterdam, The Netherlands., Division of Medical Oncology, The Netherlands Cancer Institute, Amsterdam, The Netherlands., Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA., The Eli and Edythe L. Broad Institute, Cambridge, MA, USA; Division of Urology, The Netherlands Cancer Institute, Amsterdam, The Netherlands., Division of Urology, The Netherlands Cancer Institute, Amsterdam, The Netherlands; Department of Urology, Amsterdam University Medical Centers, Amsterdam, The Netherlands., Cancer Biology and Epigenetics Group, Research Center of the Portuguese Oncology Institute of Porto, Porto, Portugal; Department of Pathology, Portuguese Oncology Institute of Porto, Porto, Portugal; Department of Pathology and Molecular Immunology, School of Medicine and Biomedical Sciences, University of Porto, Porto, Portugal., Division of Medical Oncology, The Netherlands Cancer Institute, Amsterdam, The Netherlands; Division of Oncogenomics, The Netherlands Cancer Institute, Amsterdam, The Netherlands. Electronic address: ., Division of Oncogenomics, Oncode Institute, The Netherlands Cancer Institute, Amsterdam, The Netherlands; Laboratory of Chemical Biology and Institute for Complex Molecular Systems, Department of Biomedical Engineering, Eindhoven University of Technology, Eindhoven, The Netherlands. Electronic address: .