Newly diagnosed prostate cancers differ dramatically in mutational composition and lethality. The most accurate clinical predictor of lethality is tumor tissue architecture, quantified as tumor grade. To interrogate the evolutionary origins of prostate cancer heterogeneity, we analyzed 666 prostate tumor whole genomes. We identified a compendium of 223 recurrently mutated driver regions, most influencing downstream mutational processes and gene expression. We identified and validated individual germline variants that predispose tumors to acquire specific somatic driver mutations: these explain heterogeneity in disease presentation and ancestry differences. High-grade tumors have a superset of the drivers in lower-grade tumors, including increased frequency of BRCA2 and MYC mutations. Grade-associated driver mutations occur early in tumor evolution, and their earlier occurrence strongly predicts cancer relapse and metastasis. Our data suggest high- and low-grade prostate tumors both emerge from a common pre-malignant field, influenced by germline genomic context and stochastic mutation-timing.
Cancer discovery. 2025 Feb 13 [Epub ahead of print]
Takafumi N Yamaguchi, Kathleen E Houlahan, Helen Zhu, Natalie Kurganovs, Julie Livingstone, Natalie S Fox, Jiapei Yuan, Jocelyn Sietsma Penington, Chol-Hee Jung, Tommer Schwarz, Weerachai Jaratlerdsiri, Job van Riet, Peter Georgeson, Stefano Mangiola, Kodi Taraszka, Robert Lesurf, Jue Jiang, Ken Chow, Lawrence E Heisler, Yu-Jia Shiah, Susmita G Ramanand, Michael J Clarkson, Anne Nguyen, Shadrielle Melijah G Espiritu, Ryan Stuchbery, Richard Jovelin, Vincent Huang, Connor Bell, Edward O'Connor, Patrick J McCoy, Christopher M Lalansingh, Marek Cmero, Adriana Salcedo, Eva K F Chan, Lydia Y Liu, Phillip D Stricker, Vinayak Bhandari, Riana M S Bornman, Dorota Hs Sendorek, Andrew Lonie, Stephenie D Prokopec, Michael Fraser, Justin S Peters, Adrien Foucal, Shingai B A Mutambirwa, Lachlan Mcintosh, Michèle Orain, Matthew Wakefield, Valérie Picard, Daniel J Park, Hélène Hovington, Michael Kerger, Alain Bergeron, Veronica Sabelnykova, Ji-Heui Seo, Mark M Pomerantz, Noah Zaitlen, Sebastian M Waszak, Alexander Gusev, Louis Lacombe, Yves Fradet, Andrew Ryan, Amar U Kishan, Martijn P Lolkema, Joachim Weischenfeldt, Bernard Têtu, Anthony J Costello, Vanessa M Hayes, Rayjean J Hung, Housheng H He, John D McPherson, Bogdan Pasaniuc, Theodorus van der Kwast, Anthony T Papenfuss, Matthew L Freedman, Bernard J Pope, Robert G Bristow, Ram S Mani, Niall M Corcoran, Jüri Reimand, Christopher M Hovens, Paul C Boutros
University of California, Los Angeles, Los Angeles, California, United States., Stanford University, Stanford, United States., University of Toronto, Toronto, Ontario, Canada., Oslo Universitetssykehus, Parkville, VIC, Australia., Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, China., Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia., University of Melbourne, Carlton, VIC, Australia., University of California, Los Angeles, United States., University of Sydney, Camperdown, Australia., Erasmus University Medical Center, Cancer Institute, Rotterdam, Netherlands., University of Melbourne, Melbourne, Australia., University of Melbourne, Melbourne, Victoria, Australia., Dana-Farber Cancer Institute, Boston, United States., Ontario Institute for Cancer Research, Toronto, ON, Canada., University of Melbourne, Parkville, Victoria, Australia., Ontario Institute for Cancer Research, Canada., The University of Texas Southwestern Medical Center, Dallas, TX, United States., Royal Melbourne Hospital and the University of Melbourne, Melbourne, Australia., University of Melbourne, Parkville, Australia., Ontario Institute for Cancer Research, Toronto, Canada., Epworth Hospital, Richmond, Australia., Dana-Farber Cancer Institute, Boston, MA, United States., Departments of Human Genetics & Urology, Jonsson Comprehensive Cancer Center and Institute for Precision Health, University of California, Los Angeles, USA Ontario Institute for Cancer Research, Toronto, Canada Departments of Medical Biophysics & Pharmacology and Toxicology, University of Toronto, Toronto, Canada, United States., NSW Health Pathology, St Leonards, NSW, Australia., St. Vincent's Prostate Cancer Center, Darlinghurst, NSW, Australia., University of Toronto, Toronto, Canada., University of Pretoria, Pretoria, Gauteng, South Africa., University of Melbourne, Melbourne., University Health Network, Toronto, Ontario, Canada., Princess Margaret Cancer Centre, Toronto, Ontario, Canada., Royal Melbourne Hospital, Melbourne, Australia., Sefako Makgatho Health Science University, South Africa., Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria, Australia., IUCPQ-Université Laval, Québec, Québec, Canada., CHU de Québec-Université Laval, Quebec City, Quebec, Canada., University of Melbourne, North Melbourne, Victoria, Australia., Centre de recherche du CHU de Québec, Québec, Québec, Canada., University of Melbourne, Parkville, VIC, Australia., CHU de Québec-Université Laval, Quebec, Quebec, Canada., Dana-Farber Cancer Institute, BOSTON, Massachusetts, United States., University of California, Los Angeles, California, United States., École Polytechnique Fédérale de Lausanne, Lausanne, Switzerland., Université Laval, Québec, Québec, Canada., CHU de Québec-Université Laval, Quebec, Québec, Canada., TissuPath, Mount Waverley, Victoria, Australia., David Geffen School of Medicine at the University of California, Los Angeles, Los Angeles, California, United States., Amgen (Netherlands), Breda, Netherlands., University of Copenhagen, Copenhagen, Denmark., CHU de Québec, Quebec, Canada., University of Sydney, Camperdown, NSW, Australia., Sinai Health System, Toronto, Canada., Princess Margaret Cancer Centre, Toronto, Ontario,, Canada., University of California, Davis, Sacramento, CA, United States., David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, United States., University of Toronto, Toronto, ON, Canada., University of Manchester, Manchester, United Kingdom., The University of Texas Southwestern Medical Center, Dallas, United States., Royal Melbourne Hospital, Australia.