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., Brook, Mark N., Brors, Benedikt, Butler, Adam, Cancel-Tassin, Géraldine, Corcoran, Niall M., Cussenot, Olivier, Gihawi, Abraham, 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., 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 (In Press)

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Abstract

Prostate cancer follows a long and heterogeneous disease course with incompletely understood aetiology. Here, we dissect the mutational processes shaping the genomes of 959 donors from the Pan Prostate Cancer Group (PPCG) and assess their clinical relevance. By integrating de novo extracted single base substitution, indel 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 (HRD), 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 integrated mutational footprints as a unifying framework, and highlights their potential to improve both risk stratification and biomarker-guided treatment selection.

Item Type:	Article
Additional Information:	Data availability: Data availability is described in our companion manuscript24. Data not described in the companion manuscript were downloaded from the Gene Expression Omnibus (GEO) under accession GSE7007912 and https://gdc.cancer.gov/about-data/publications/ATACseq-AWG95. Access to raw, processed and clinical data from the Hartwig Medical Foundation can be requested at https://www.hartwigmedicalfoundation.nl/en/data/data-access-request/. XML files used to construct the TCGA clinical data can be accessed through the Genomic Data Commons portal, and the procedure for requesting access to controlled genomic data is outlined at https://gdc.cancer.gov/access-data/obtaining-access-controlled-data. Code availability: The source code for reproducing analyses and figures is available at https://github.com/panprostate/mutational-signatures and an archived copy of the code is available on Zenodo (https://zenodo.org/17721485) (and will be made publicly available at the time of acceptance). A private source code link is available to the reviewers: https://gitfront.io/r/jweischenfeldt/1hSc9A4s8d9U/ppcg-mutational-signature-paper/
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
Depositing User:	LivePure Connector
Date Deposited:	27 Feb 2026 14:30
Last Modified:	27 Feb 2026 16:30
URI:	https://ueaeprints.uea.ac.uk/id/eprint/102103
DOI:

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