Integrated signatures define mutational processes in prostate cancer

Gruber, Andreas J., Olsen, André V., Hernando, Barbara, Cheng, Kevin C. L., Gerhäuser, Clarissa, Torres, Marina, Favero, Francesco, Kiriy, Daria, Fernández-Sanromán, Angel, Roldan-Romero, Juan Maria, Barton, Lucy, Pellegrina, Diogo, Bova, G. Steven, Brewer, Daniel S. ORCID: https://orcid.org/0000-0003-4753-9794, Brook, Mark N., Brors, Benedikt, Butler, Adam, Cancel-Tassin, Géraldine, Corcoran, Niall M., Cussenot, Olivier, Gihawi, Abraham ORCID: https://orcid.org/0000-0002-3676-5561, Girma, Etsehiwot G., Gnanapragasam, Vincent J., Hamid, Anis, Hayes, Vanessa M., He, Housheng Hansen, Hovens, Christopher M., Imada, Eddie L., Jakobsdottir, G. Maria M., Jung, Chol-Hee, Khani, Francesca, Kote-Jarai, Zsofia, Lamy, Philippe, Leeman, Gregory, Loda, Massimo, Lutsik, Pavlo, Marchionni, Luigi, Molania, Ramyar, Papenfuss, Anthony, Pope, Bernard, Queiroz, Lucio R., Rausch, Tobias, Robinson, Brian, Sahli, Atef, Sørensen, Karina D., Yamaguchi, Takafumi N., Uhrig, Sebastian, Xu, Yaobo, Zanettini, Claudio, Simon, Ronald, Sauter, Guido, Eeles, Ros A., Cooper, Colin S. ORCID: https://orcid.org/0000-0003-2013-8042, Bristow, Robert G., Wedge, David C., Schlomm, Thorsten, Macintyre, Geoff, Reimand, Jüri and Weischenfeldt, Joachim (2026) Integrated signatures define mutational processes in prostate cancer. Nature. ISSN 0028-0836

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Abstract

Prostate cancer follows a long and heterogeneous disease course with incompletely understood aetiology 1. Here we dissect the mutational processes shaping the genomes of 959 donors from the Pan Prostate Cancer Group and assess their clinical relevance. By integrating de novo extracted single-base substitution, insertion–deletion and copy-number signatures with six novel complex structural variant signatures, we identify eight integrated mutational footprints (IMFs) that collectively explain the mutational processes in 85% of primary prostate cancer genomes. IMFs were strongly influenced by regional biases in the genome, most prevalently androgen receptor-mediated mutagenesis and replication stress. Four IMFs, present in 37% of primary tumours, were significantly associated with shorter time to metastasis. These included reactive oxygen-species-driven mutagenesis and both canonical and non-canonical homologous recombination deficiency, the latter being enriched in patients of African ancestry. Extending to the metastatic setting, we found that IMFs predicted sensitivity to androgen receptor pathway inhibitors. Taken together, our study delineates the aetiologies and mutational processes that drive the genomic and clinical heterogeneity of prostate cancer, introduces IMFs as a unifying framework, and highlights their potential to improve both risk stratification and biomarker-guided treatment selection.

Item Type:	Article
Uncontrolled Keywords:	sdg 3 - good health and well-being,4* ,/dk/atira/pure/sustainabledevelopmentgoals/good_health_and_well_being
Faculty \ School:	Faculty of Medicine and Health Sciences > Norwich Medical School Faculty of Science > School of Chemistry, Pharmacy and Pharmacology
UEA Research Groups:	Faculty of Medicine and Health Sciences > Research Groups > Cancer Studies Faculty of Medicine and Health Sciences > Research Centres > Metabolic Health
Related URLs:	https://www.scopus.com/pages/publication...
Depositing User:	LivePure Connector
Date Deposited:	18 Sep 2026 09:31
Last Modified:	30 Sep 2026 10:42
URI:	https://ueaeprints.uea.ac.uk/id/eprint/104585
DOI:	10.1038/s41586-026-10468-w

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