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Integrated signatures define mutational processes in prostate cancer.
Gruber, A. J. ; Olsen, A. V. ; Hernando, B. ; Cheng, K. C. L. ; Gerhäuser, C.DKFZ* ; Torres, M. ; Favero, F. ; Kiriy, D. ; Fernández-Sanromán, Á. ; Roldan-Romero, J. M. ; Barton, L. ; Pellegrina, D. ; Bova, G. S. ; Brewer, D. S. ; Brook, M. N. ; Brors, B.DKFZ* ; Butler, A. ; Cancel-Tassin, G. ; Corcoran, N. M. ; Cussenot, O. ; Gihawi, A. ; Girma, E. G. ; Gnanapragasam, V. J. ; Hamid, A. A. ; Hayes, V. M. ; He, H. H. ; Hovens, C. M. ; Imada, E. L. ; Jakobsdottir, G. M. ; Jung, C.-H. ; Khani, F. ; Kote-Jarai, Z. ; Lamy, P. ; Leeman, G. ; Loda, M. ; Lutsik, P.DKFZ* ; Marchionni, L. ; Molania, R. ; Papenfuss, A. T. ; Pope, B. ; Queiroz, L. R. ; Rausch, T. ; Robinson, B. ; Sahli, A. ; Sørensen, K. D. ; Yamaguchi, T. N. ; Uhrig, S.DKFZ* ; Xu, Y. ; Zanettini, C. ; Group, P. P. C. (Collaboration Author) ; Simon, R. ; Sauter, G. ; Eeles, R. A. ; Cooper, C. S. ; Bristow, R. G. ; Wedge, D. C. ; Schlomm, T. ; Macintyre, G. ; Reimand, J. ; Weischenfeldt, J. ; Bergeron, A. (Contributor) ; Rubin, A. F. (Contributor) ; Lamb, A. D. (Contributor) ; Berlin, A. (Contributor) ; Ziuboniewicz, A. S. (Contributor) ; Erickson, A. (Contributor) ; Ryan, A. (Contributor) ; Lynch, A. G. (Contributor) ; Faini, A. C. (Contributor) ; Nguyen, A. (Contributor) ; Warren, A. (Contributor) ; Sankar, A. (Contributor) ; Mehmood, A. (Contributor) ; Schlotmann, B. C. (Contributor)DKFZ* ; Lim, B. (Contributor) ; Campbell, B. K. (Contributor) ; Feran, B. (Contributor) ; Massie, C. E. (Contributor) ; Hong, C. (Contributor) ; Foster, C. (Contributor) ; Plass, C. (Contributor)DKFZ* ; Wirth, C. (Contributor) ; Collins, C. (Contributor) ; Grima, C. (Contributor) ; Woodcock, D. J. (Contributor) ; Barrowdale, D. (Contributor) ; Park, D. J. (Contributor) ; Esentürk, E. (Contributor) ; Baena, E. (Contributor) ; Falkenbach, F. (Contributor)DKFZ* ; Pederzoli, F. (Contributor) ; Kerry, G. (Contributor) ; Fanelli, G. N. (Contributor) ; Hall, G. (Contributor) ; Dev, H. (Contributor) ; Sültmann, H. (Contributor)DKFZ* ; Pakula, H. (Contributor) ; Mills, I. (Contributor) ; Korbel, J. (Contributor)DKFZ* ; Ureta, J. (Contributor)DKFZ* ; Heilmann, J. (Contributor)DKFZ* ; Zhang, J. (Contributor) ; Penington, J. S. (Contributor) ; Jiang, J. (Contributor) ; Bedő, J. (Contributor) ; Peters, J. S. (Contributor) ; Raine, K. (Contributor) ; Chow, K. (Contributor) ; Furlano, K. (Contributor)DKFZ* ; Feuerbach, L. (Contributor)DKFZ* ; von Voithenberg, L. V. (Contributor) ; Cmero, M. (Contributor) ; Graefen, M. (Contributor) ; Hong, M. K. H. (Contributor) ; Wakefield, M. (Contributor) ; Nykter, M. (Contributor) ; Cheung, M. (Contributor) ; Borre, M. (Contributor) ; Clarkson, M. J. (Contributor) ; Kerger, M. (Contributor) ; Scherer, M. (Contributor)DKFZ* ; Omar, M. (Contributor) ; Mensah, N. (Contributor) ; Kurganovs, N. (Contributor) ; Dennis, N. (Contributor) ; Al-Muftah, N. (Contributor) ; Pirhady, P. (Contributor) ; McCoy, P. (Contributor) ; Georgeson, P. (Contributor) ; Van Loo, P. (Contributor) ; Dundee, P. (Contributor) ; Nuzzo, P. V. (Contributor) ; Tennstedt, P. (Contributor) ; Phal, P. M. (Contributor) ; Lach, R. (Contributor) ; Batra, R. N. (Contributor)DKFZ* ; Pacey, S. (Contributor) ; Pereira, R. R. (Contributor) ; Dong, R. (Contributor) ; Carelli, R. (Contributor) ; Stuchbery, R. (Contributor) ; Norden, S. (Contributor) ; Olofinsae, S. (Contributor) ; Rodrigues, S. (Contributor) ; Mangiola, S. (Contributor) ; Keane, T. (Contributor) ; Milne-Clark, T. (Contributor) ; Costello, T. (Contributor) ; Haberland, V. (Contributor) ; Holmes, V. (Contributor) ; Jaratlerdsiri, W. (Contributor) ; Burns, W. (Contributor) ; Dinalankara, W. (Contributor) ; Hutchison, W. J. (Contributor) ; He, X. (Contributor) ; Pan, Y. (Contributor) ; Lu, Y.-J. (Contributor) ; Fu, Y. (Contributor) ; Fradet, Y. (Contributor)
2026
Nature Publ. Group
London [u.a.]
Abstract: Prostate cancer follows a long and heterogeneous disease course with incompletely understood aetiology1. 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.
Note: #DKTKZFB26# / #NCTZFB26# / epub
Contributing Institute(s):
- Epigenomik (B370)
- Angewandte Bioinformatik (B330)
- DKTK HD zentral (HD01)
- Krebsgenomforschung (B063)
- Mechanismen der genetischen Variation und Datenwissenschaft (B480)
- Klinische Epidemiologie der Krebsfrüherkennung (C070)
- Koordinierungsstelle NCT Heidelberg (HD02)
Research Program(s):
- 312 - Funktionelle und strukturelle Genomforschung (POF4-312) (POF4-312)
Appears in the scientific report
2026
Database coverage:
; BIOSIS Previews ; Biological Abstracts ; Chemical Reactions ; Clarivate Analytics Master Journal List ; Current Contents - Agriculture, Biology and Environmental Sciences ; Current Contents - Life Sciences ; Current Contents - Physical, Chemical and Earth Sciences ; DEAL Nature ; Ebsco Academic Search ; Essential Science Indicators ; IF >= 60 ; Index Chemicus ; JCR ; SCOPUS ; Science Citation Index Expanded ; Web of Science Core Collection ; Zoological Record
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