The molecular heterogeneity and clinical impact of genomic driver alterations in prostate cancer

Prostate cancer is a common malignancy with a heterogeneous disease course. Prior studies have identified a paucity of point mutations in protein-coding genes and only a few clinically relevant driver alterations. Here, using the Pan Prostate Cancer Group whole genome sequencing dataset from 1001 men, we perform an integrative analysis of cancer driver genes by quantifying recurrent genomic alterations among small mutations, structural variants, and copy number alterations in 961 primary prostate tumour samples. We identify at least one recurrent somatic or germline alteration in 97% of tumours and identify putative driver genes and mechanisms of dysregulation including frequently altered regulatory elements. A prominent example is the activation of oncogenes by structural variation-mediated hijacking of onco-enhancers of the solute carrier gene family including SLC30A4. Other recurrent alterations including FOXA1, MDM4, COL5A1, TP53, and BRCA1 stratify with metastatic disease, with additional drivers enriched in African-ancestry tumours. One quarter of tumours have acquired genome-informed therapeutic targets. Unsupervised analysis of alterations reveals four oncotypes with distinct genetic and clinical characteristics, including two clinically unfavourable oncotypes with shorter metastasis-free survival. Our study uncovers the full spectrum and recurrence patterns of genomic driver alterations in primary prostate cancers and delivers targets for biomarker development, mechanistic studies, and potential therapeutic interventions. The identification of clinically relevant driver alterations in prostate cancer remains elusive. Here, integrative analysis of cancer driver genes using the Pan Prostate Cancer Group whole genome sequencing dataset from 1,001 men identifies four oncotypes, two of which are associated with poor clinical outcomes.

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Publication Details

Journal
Nature Communications
Published
2026-10-16
DOI
https://doi.org/10.1038/s41467-026-77900-7
Primary Topic
Prostate Cancer Treatment and Research
Type
article
Field-Weighted Citation Impact
0.00

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article

The molecular heterogeneity and clinical impact of genomic driver alterations in prostate cancer

Pavlo Lutsik, David C. Wedge, Thorsten Schlomm, Francesco Favero et al.
Nature Communications
Prostate Cancer Treatment and Research
article

The molecular heterogeneity and clinical impact of genomic driver alterations in prostate cancer

Pavlo Lutsik, David C. Wedge, Thorsten Schlomm, Francesco Favero, Clarissa Gerhäuser, Diogo Vieira da Silva Pellegrina, Rosalind A. Eeles, Géraldine Cancel‐Tassin, Lúcio Rezende Queiroz, Bárbara Hernando, G. Steven Bova, Daria Kiriy, Lena Voith von Voithenberg, G. Maria Jakobsdottir, Philippe Lamy, Robert Glen Bristow, André Vidas Olsen, Vincent J. Gnanapragasam, Andreas J Gruber, Takafumi N. Yamaguchi, Vanessa M. Hayes, Abraham Gihawi, Olivier Cussenot, Tobias Rausch, Etsehiwot Girum Girma, Joachim Weischenfeldt, Atef Sahli, Weerachai Jaratlerdsiri, Geoff Macintyre, Housheng Hansen He, Zsofia Kote‐Jarai, Mark N. Brook, Anthony T. Papenfuss, Bernard J. Pope, Benedikt Brors, Brian D. Robinson, Francesca Khani, Yunfan Fu, Yaobo Xu, Stefano Mangiola, Massimo F. Loda, Anis Hamid, William J. Hutchison, Ramyar Molania, Luigi Marchionni, Christopher M. Hovens, Karina Dalsgaard Sørensen, Claudio Zanettini, Daniel S. Brewer, Sebastian Uhrig, Jüri Reimand, Zoe P. Klein, Gregory Leeman, Niall M. Corcoran, Kevin C.L. Cheng, Colin S. Cooper, Adam P. Butler, Chol‐Hee Jung, Pan Prostate Cancer Group, Enrichetta Miletti, Eddie Luidy L. Imada
article en

Abstract

Prostate cancer is a common malignancy with a heterogeneous disease course. Prior studies have identified a paucity of point mutations in protein-coding genes and only a few clinically relevant driver alterations. Here, using the Pan Prostate Cancer Group whole genome sequencing dataset from 1001 men, we perform an integrative analysis of cancer driver genes by quantifying recurrent genomic alterations among small mutations, structural variants, and copy number alterations in 961 primary prostate tumour samples. We identify at least one recurrent somatic or germline alteration in 97% of tumours and identify putative driver genes and mechanisms of dysregulation including frequently altered regulatory elements. A prominent example is the activation of oncogenes by structural variation-mediated hijacking of onco-enhancers of the solute carrier gene family including SLC30A4. Other recurrent alterations including FOXA1, MDM4, COL5A1, TP53, and BRCA1 stratify with metastatic disease, with additional drivers enriched in African-ancestry tumours. One quarter of tumours have acquired genome-informed therapeutic targets. Unsupervised analysis of alterations reveals four oncotypes with distinct genetic and clinical characteristics, including two clinically unfavourable oncotypes with shorter metastasis-free survival. Our study uncovers the full spectrum and recurrence patterns of genomic driver alterations in primary prostate cancers and delivers targets for biomarker development, mechanistic studies, and potential therapeutic interventions. The identification of clinically relevant driver alterations in prostate cancer remains elusive. Here, integrative analysis of cancer driver genes using the Pan Prostate Cancer Group whole genome sequencing dataset from 1,001 men identifies four oncotypes, two of which are associated with poor clinical outcomes.

Nature CommunicationsVol. 17(1)
University of East Anglia (GB), Ontario Institute for Cancer Research (CA), University of Copenhagen (DK), The University of Sydney (AU), The Royal Melbourne Hospital (AU), Royal Marsden NHS Foundation Trust (GB), Institute of Cancer Research (GB), University of California, Los Angeles (US), The University of Melbourne (AU), Tampere University (FI), German Cancer Research Center (DE), University of Toronto (CA), University of Konstanz (DE), Walter and Eliza Hall Institute of Medical Research (AU), Aarhus University (DK), Heidelberg University (DE), Norwich Research Park (GB), Manchester Academic Health Science Centre (GB), Aarhus University Hospital (DK), Cambridge University Hospitals NHS Foundation Trust (GB), Wellcome Sanger Institute (GB), Copenhagen University Hospital (DK), Princess Margaret Cancer Centre (CA), Rigshospitalet (DK), University of Manchester (GB), Melbourne Bioinformatics (AU), Sorbonne Université (FR), University of Oxford (GB), Spanish National Cancer Research Centre (ES), Assistance Publique – Hôpitaux de Paris (FR), Earlham Institute (GB), Victorian Comprehensive Cancer Centre (AU), National Center for Tumor Diseases (DE), Western Health (AU), Cancer Research UK Manchester Institute (GB), The Christie Hospital (GB), The Christie NHS Foundation Trust (GB), European Molecular Biology Laboratory (DE), Hôpital Tenon (FR), Weill Cornell Medicine (US), University of Tampere (FI), Onco-Urologie Prédictive (FR), UCLA Jonsson Comprehensive Cancer Center, Deutsches Konsortium für Translationale Krebsforschung (DE), Cancer Research UK Manchester Centre, Adelaide University (AU), The University of Adelaide (AU), University of Pretoria (ZA), Charité - Universitätsmedizin Berlin (DE), KU Leuven (BE)
Ontario Institute for Cancer Research, Canadian Institutes of Health Research
Good health and well-being
Openalex Percentile: Top 12%
Prostate Cancer Treatment and Research
DOIOpen Access PDFOpenAlex
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