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

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Title: The molecular heterogeneity and clinical impact of genomic driver alterations in prostate cancer.
Authors: Pellegrina D; Computational Biology Program, Ontario Institute for Cancer Research, Toronto, ON, Canada., Kiriy D; Biotech Research & Innovation Centre (BRIC)-University of Copenhagen, Copenhagen, Denmark.; Finsen Laboratory, Copenhagen University Hospital-Rigshospitalet, Copenhagen, Denmark., C L Cheng K; Computational Biology Program, Ontario Institute for Cancer Research, Toronto, ON, Canada.; Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada., Favero F; Biotech Research & Innovation Centre (BRIC)-University of Copenhagen, Copenhagen, Denmark.; Finsen Laboratory, Copenhagen University Hospital-Rigshospitalet, Copenhagen, Denmark., Miletti E; Biotech Research & Innovation Centre (BRIC)-University of Copenhagen, Copenhagen, Denmark.; Finsen Laboratory, Copenhagen University Hospital-Rigshospitalet, Copenhagen, Denmark., Klein ZP; Computational Biology Program, Ontario Institute for Cancer Research, Toronto, ON, Canada.; Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada., Hernando B; Spanish National Cancer Research Centre (CNIO), Madrid, Spain., Olsen AV; Biotech Research & Innovation Centre (BRIC)-University of Copenhagen, Copenhagen, Denmark.; Finsen Laboratory, Copenhagen University Hospital-Rigshospitalet, Copenhagen, Denmark., Sahli A; Manchester Cancer Research Centre, The University of Manchester, Manchester, UK., Fu Y; Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia.; Department of Medical Biology, The University of Melbourne, Melbourne, VIC, Australia., Lutsik P; German Cancer Research Center (DKFZ), Heidelberg, Germany.; Department of Oncology, KU Leuven, Leuven, Belgium., Jaratlerdsiri W; Charles Perkins Centre, School of Medical Sciences, Faculty of Medicine and Health, University of Sydney, Camperdown, NSW, Australia., Hutchison WJ; Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia.; Department of Medical Biology, The University of Melbourne, Melbourne, VIC, Australia., Bova GS; Prostate Cancer Research Center, Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland., Brewer DS; Department of Metabolic Health, Norwich Medical School, University of East Anglia, Norwich, UK.; The Earlham Institute, Norwich Research Park, Norwich, UK., Brook M; The Institute of Cancer Research, London, UK., Brors B; Division Applied Bioinformatics, German Cancer Research Center (DKFZ), Heidelberg, Germany.; German Cancer Consortium (DKTK), Core Center Heidelberg, and National Center for Tumor Diseases (NCT), Heidelberg, Germany.; Medical Faculty Heidelberg and Faculty of Biosciences, Heidelberg University, Heidelberg, Germany., Butler A; Wellcome Sanger Institute, Cambridge, UK., Cancel-Tassin G; CeRePP (Centre de Recherche sur les Pathologies Prostatiques et Urologiques), Paris, France.; GRC n°5 Predictive Onco-Urology, APHP, Tenon Hospital, Sorbonne Université, Paris, France., Corcoran NM; Department of Urology, Royal Melbourne Hospital, Parkville, VIC, Australia.; Department of Surgery, The University of Melbourne, Parkville, VIC, Australia.; Department of Urology, Western Health, Victoria, Australia., Cussenot O; CeRePP (Centre de Recherche sur les Pathologies Prostatiques et Urologiques), Paris, France., Gihawi A; Charles Perkins Centre, School of Medical Sciences, Faculty of Medicine and Health, University of Sydney, Camperdown, NSW, Australia.; Norwich Medical School, University of East Anglia, Norwich, UK., Girma EG; Biotech Research & Innovation Centre (BRIC)-University of Copenhagen, Copenhagen, Denmark.; Finsen Laboratory, Copenhagen University Hospital-Rigshospitalet, Copenhagen, Denmark., Gnanapragasam VJ; Department of Surgery, Urology, University of Cambridge & Cambridge University Hospitals NHS Trust, Cambridge Urology Translational Research and Clinical Trials (Office), Cambridge Biomedical Campus, Addenbrooke's Hospital Site, Cambridge, UK., Hamid AA; Department of Surgery, The University of Melbourne, Parkville, VIC, Australia., He HH; Department of Medical Biophysics, Princess Margaret Cancer Centre, University Health Network; University of Toronto, Toronto, ON, Canada., Imada ELL; Department of Pathology and Laboratory Medicine, Weill Cornell Medical College, New York, NY, USA., Jakobsdottir GM; Division of Cancer Sciences, The University of Manchester, Manchester, UK.; Christie Hospital, The Christie NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester, UK., Jung CH; Melbourne Bioinformatics, The University of Melbourne, Parkville, VIC, Australia., Khani F; Department of Pathology and Laboratory Medicine, Weill Cornell Medical College, New York, NY, USA., Kote-Jarai Z; The Institute of Cancer Research, London, UK.; The Royal Marsden NHS Foundation Trust, London, UK., Lamy P; Department of Molecular Medicine, Aarhus University Hospital, Aarhus, Denmark.; Department of Clinical Medicine, Aarhus University, Aarhus, Denmark., Leeman G; Wellcome Sanger Institute, Cambridge, UK., Loda M; Department of Pathology and Laboratory Medicine, Weill Cornell Medical College, New York, NY, USA.; Nuffield Department of Surgical Sciences, University of Oxford, Oxford, UK., Molania R; Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia.; Department of Medical Biology, The University of Melbourne, Melbourne, VIC, Australia., Queiroz LR; Department of Pathology and Laboratory Medicine, Weill Cornell Medical College, New York, NY, USA., Rausch T; Genome Biology, European Molecular Biology Laboratory (EMBL), Heidelberg, Germany., Robinson B; Department of Pathology and Laboratory Medicine, Weill Cornell Medical College, New York, NY, USA., Sørensen KD; Department of Molecular Medicine, Aarhus University Hospital, Aarhus, Denmark.; Department of Clinical Medicine, Aarhus University, Aarhus, Denmark., Uhrig S; Division Applied Bioinformatics, German Cancer Research Center (DKFZ), Heidelberg, Germany., Xu Y; Wellcome Sanger Institute, Cambridge, UK., Yamaguchi TN; Jonsson Comprehensive Cancer Center, University of California-Los Angeles, Los Angeles, CA, USA., Zanettini C; Department of Pathology and Laboratory Medicine, Weill Cornell Medical College, New York, NY, USA., Mangiola S; Adelaide University, Adelaide, SA, Australia., Voith von Voithenberg L; German Cancer Research Center (DKFZ), Heidelberg, Germany., Marchionni L; Department of Pathology and Laboratory Medicine, Weill Cornell Medical College, New York, NY, USA., Papenfuss AT; Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia.; Department of Medical Biology, The University of Melbourne, Melbourne, VIC, Australia., Pope B; Department of Surgery, The University of Melbourne, Parkville, VIC, Australia.; Melbourne Bioinformatics, The University of Melbourne, Bedford Street, North Melbourne, Victoria, Australia.; Australian BioCommons, The University of Melbourne, North Melbourne, VIC, Australia., Hayes VM; Charles Perkins Centre, School of Medical Sciences, Faculty of Medicine and Health, University of Sydney, Camperdown, NSW, Australia.; Norwich Medical School, University of East Anglia, Norwich, UK.; Manchester Cancer Research Centre, University of Manchester, Manchester, UK.; School of Health Systems and Public Health, University of Pretoria, Pretoria, South Africa., Schlomm T; Department of Urology, Charité-Universitätsmedizin Berlin, Berlin, Germany., Bristow RG; Manchester Cancer Research Centre and Cancer Research UK Manchester Institute, The University of Manchester, Manchester, UK.; Christie NHS Foundation Trust, Manchester, UK.; Div Cancer Sciences, Faculty of Biology, Medicine & Health, University of Manchester, Manchester, UK., Hovens CM; Department of Surgery, The Collaborative Centre for Genomic Cancer Medicine, The University of Melbourne, Parkville, VC, Australia., Eeles RA; The Institute of Cancer Research, London, UK.; The Royal Marsden NHS Foundation Trust, London, UK., Cooper CS; Norwich Medical School, University of East Anglia, Norwich, UK., Gerhauser C; German Cancer Research Center (DKFZ), Heidelberg, Germany., Macintyre G; Spanish National Cancer Research Centre (CNIO), Madrid, Spain., Gruber AJ; University of Konstanz, Konstanz, Germany., Wedge DC; Manchester Cancer Research Centre, The University of Manchester, Manchester, UK., Weischenfeldt J; Biotech Research & Innovation Centre (BRIC)-University of Copenhagen, Copenhagen, Denmark. joachim.weischenfeldt@bric.ku.dk.; Finsen Laboratory, Copenhagen University Hospital-Rigshospitalet, Copenhagen, Denmark. joachim.weischenfeldt@bric.ku.dk.; Department of Urology, Charité-Universitätsmedizin Berlin, Berlin, Germany. joachim.weischenfeldt@bric.ku.dk., Reimand J; Computational Biology Program, Ontario Institute for Cancer Research, Toronto, ON, Canada. juri.reimand@utoronto.ca.; Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada. juri.reimand@utoronto.ca.; Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada. juri.reimand@utoronto.ca.
Corporate Authors: Pan Prostate Cancer Group
Source: Nature communications [Nat Commun] 2026 Oct 16; Vol. 17 (1). Date of Electronic Publication: 2026 Oct 16.
Publication Type: Journal Article
Language: English
Journal Info: Publisher: Nature Pub. Group Country of Publication: England NLM ID: 101528555 Publication Model: Electronic Cited Medium: Internet ISSN: 2041-1723 (Electronic) Linking ISSN: 20411723 NLM ISO Abbreviation: Nat Commun Subsets: MEDLINE
Imprint Name(s): Original Publication: [London] : Nature Pub. Group
MeSH Terms: Prostatic Neoplasms*/genetics , Prostatic Neoplasms*/pathology , Prostatic Neoplasms*/mortality , Genetic Heterogeneity*, Hepatocyte Nuclear Factor 3-alpha/genetics ; Oncogenes/genetics ; Humans ; Male ; DNA Copy Number Variations ; Gene Expression Regulation, Neoplastic ; Mutation ; Genomics ; Whole Genome Sequencing
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.
(© 2026. The Author(s).)
Competing Interests: Competing interests: (V.J.G.): Honoraria from Janssen and JEB as a speaker. Member of external expert committee to AstraZeneca UK. (R.A.E.): Honoraria from GU-ASCO, Janssen, University of Chicago, Dana Farber Cancer Institute USA as a speaker. Educational honorarium from Bayer and Ipsen, member of external expert committee to AstraZeneca UK and Member of Active Surveillance Movember Committee. Member of the SAB of Our Future Health. Undertakes private practice as a sole trader at The Royal Marsden NHS Foundation Trust and 90 Sloane Street SW1X 9PQ and 280 Kings Road SW3 4NX, London, UK. (G.M.): co-founder, director and shareholder of Tailor Bio Ltd. The remaining authors declare no competing interests.
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Grant Information: PJT-162410 Gouvernement du Canada | Canadian Institutes of Health Research (Instituts de Recherche en Santé du Canada); PJT-197925 Gouvernement du Canada | Canadian Institutes of Health Research (Instituts de Recherche en Santé du Canada); Investigator Award Ontario Institute for Cancer Research (Institut Ontarien de Recherche sur le Cancer)
Substance Nomenclature: 0 (Hepatocyte Nuclear Factor 3-alpha)
0 (FOXA1 protein, human)
Entry Date(s): Date Created: 20261016 Date Completed: 20261016 Latest Revision: 20261020
Update Code: 20261020
PubMed Central ID: PMC13675244
DOI: 10.1038/s41467-026-77900-7
PMID: 42888190
Database: MEDLINE
Description
ISSN:2041-1723
DOI:10.1038/s41467-026-77900-7