The Germline and Somatic Origins of Prostate Cancer Heterogeneity
Takafumi N. Yamaguchi, Kathleen E. Houlahan, Helen Zhu, Natalie J. 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 M. 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 Liu, Phillip D. Stricker, Vinayak Bhandari, Riana Bornman, Dorota H.S. Sendorek, Andrew Lonie, Stephenie D. Prokopec, Michael Fraser, Justin S. Peters, Adrien Foucal, Shingai B.A. Mutambirwa, Lachlan McIntosh, Michèle Orain, Matthew J. Wakefield, Valérie Picard, Daniel J. Park, Hélène Hovington, Michael Kerger, Alain Bergeron, Veronica Y. 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 Hansen He, John D. McPherson, Bogdan Paşaniuc, 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
Abstract
Abstract 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 premalignant field, influenced by germline genomic context and stochastic mutation timing. Significance: This study uncovered 223 recurrently mutated driver regions using the largest cohort of prostate tumors to date. It reveals associations between germline SNPs, somatic drivers, and tumor aggression, offering significant insights into how prostate tumor evolution is shaped by germline factors and the timing of somatic mutations.