Prostate cancer is characterized by profound clinical and molecular heterogeneity. While its genomic heterogeneity is well-characterized, its epigenomic heterogeneity remains less understood. We therefore created a compendium of 3,001 multi-ancestry prostate methylomes spanning normal tissue through localized disease of all grades to poly-metastatic disease. A subset of 884 samples had multi-omic DNA and/or RNA characterization. We identify four epigenomic subtypes that risk-stratify patients and reflect distinct evolutionary trajectories. We demonstrate extensive regulatory interplay between DNA copy number and methylation, with transcriptional consequences that vary across genes and disease stages. We define epigenetic dysregulation signatures for 15 important clinico-molecular features, creating predictive models for each. For example, we identify specific epigenetic features that predict patient outcome and are synergistic with clinical prognostic features. These results define a complex interplay between tumour genetics and epigenetics that converges to modify gene-expression programs and clinical presentation, in part through modulation of epigenetic aging.
Cancer discovery. 2026 Jun 17 [Epub ahead of print]
Jaron Arbet, Takafumi N Yamaguchi, Yu-Jia Shiah, Rupert Hugh-White, Adriana Wiggins, Jieun Oh, Nicole Zeltser, Tsumugi Gebo, Adrien Foucal, Robert Lesurf, Chol-Hee Jung, Rachel M A Dang, Raag Agrawal, Julie Livingstone, Adriana Salcedo, Cindy Q Yao, Shadrielle Melijah G Espiritu, Kathleen Houlahan, Fouad Yousif, Lawrence E Heisler, Anthony T Papenfuss, Michael Fraser, Bernard J Pope, Amar U Kishan, Alejandro Berlin, Melvin L K Chua, Niall M Corcoran, Theodorus van der Kwast, Christopher M Hovens, Robert G Bristow, Paul C Boutros
Beckman Research Institute Duarte United States., University of California, Los Angeles Los Angeles, California United States., Ontario Institute for Cancer Research Canada., Sanford Burnham Prebys Medical Discovery Institute Los Angeles, California United Kingdom., Ontario Institute for Cancer Research Toronto, ON Canada., University of Melbourne Carlton, VIC Australia., University of California, Los Angeles Los Angeles, CA United States., University of California, Los Angeles United States., Ontario Institute for Cancer Research Toronto Canada., McMaster University Canada., Walter and Eliza Hall Institute of Medical Research Parkville, Victoria Australia., Princess Margaret Cancer Centre Toronto, Ontario Canada., University of Melbourne Melbourne Australia., David Geffen School of Medicine at the University of California, Los Angeles Los Angeles, California United States., University of Toronto Canada., National Cancer Centre Singapore Singapore Singapore., Royal Melbourne Hospital Australia., University of Toronto Toronto, ON Canada., University of Melbourne Parkville, VIC Australia., University of Manchester Manchester United Kingdom., Sanford Burnham Prebys Medical Discovery Institute La Jolla, California United States.