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Causes of evolutionary divergence in prostate cancer

Esentürk, E.
; 
Sahli, A.
; 
Haberland, V.
; 
Ziuboniewicz, A.
; 
Wirth, C.
; 
Bova, G. S.
; 
Bristow, R. G.
; 
Brook, M. N.
; 
Brors, B.
; 
Butler, A.
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Abstract
Cancer progression involves the sequential accumulation of genetic alterations that cumulatively shape the tumour phenotype. In prostate cancer, tumours can follow divergent evolutionary trajectories that lead to distinct subtypes, but the causes of this divergence remain unclear. While causal inference could elucidate the factors involved, conventional methods are unsuitable due to the possibility of unobserved confounders and ambiguity in the direction of causality. Here, we propose a method that circumvents these issues and apply it to genomic data from 829 prostate cancer patients. We identify several genetic alterations that drive divergence as well as others that prevent this transition, locking tumours into one trajectory. Further analysis reveals that these genetic alterations may cause each other, implying a positive-feedback loop that accelerates divergence. Our findings provide insights into how cancer subtypes emerge and offer a foundation for genomic surveillance strategies aimed at monitoring the progression of prostate cancer.
Authors
Esentürk, E.
Sahli, A.
Haberland, V.
Ziuboniewicz, A.
Wirth, C.
Bova, G. S.
Bristow, R. G.
Brook, M. N.
Brors, B.
Butler, A.
Cancel-Tassin, G.
Cheng, K. C.
Cooper, C. S.
Corcoran, N. M.
Cussenot, O.
Eeles, R. A.
Favero, F.
Gerhauser, C.
Gihawi, A.
Girma, E. G.
Gnanapragasam, V. J.
Gruber, A. J.
Hamid, 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.
Marchionni, L.
Molania, R.
Papenfuss, A. T.
Pellegrina, D.
Pope, B.
Queiroz, L. R.
Rausch, T.
Reimand, J.
Robinson, B.
Schlomm, T.
Sørensen, K. D.
Uhrig, S.
Weischenfeldt, J.
Xu, Y.
Yamaguchi, T. N.
Zanettini, C.
Lynch, A. G.
Wedge, D. C.
Brewer, D. S.
Woodcock, D. J.
Affiliation
Nuffield Department of Medicine, University of Oxford, UK. Manchester Cancer Research Centre, The University of Manchester, UK. Norwich Medical School, University of East Anglia, UK. Nuffield Department of Surgical Sciences, University of Oxford, UK. Prostate Cancer Research Center, Faculty of Medicine and Health Technology, Tampere University, Finland. Manchester Cancer Research Centre and Cancer Research UK Manchester Institute, The University of Manchester, UK. Christie NHS Foundation Trust, UK. Div Cancer Sciences, Faculty of Biology, Medicine & Health, University of Manchester, UK. The Institute of Cancer Research, UK. Division Applied Bioinformatics, German Cancer Research Center (DKFZ), Germany. German Cancer Consortium (DKTK), Core Center Heidelberg, and National Center for Tumor Diseases (NCT), Germany. Medical Faculty Heidelberg and Faculty of Biosciences, Heidelberg University, Germany. Wellcome Sanger Institute, UK. CeRePP (Centre de Recherche sur les Pathologies Prostatiques et Urologiques), France. Sorbonne Université, GRC n°5 Predictive Onco-Urology, APHP, Tenon Hospital, France. Computational Biology Program, Ontario Institute for Cancer Research, Canada. Department of Medical Biophysics, University of Toronto, Canada. Department of Urology, Royal Melbourne Hospital, Australia. Department of Surgery, The University of Melbourne, Australia. Department of Urology, Western Health, Australia. The Royal Marsden NHS Foundation Trust, London & Sutton. Biotech Research & Innovation Centre (BRIC) - University of Copenhagen, Denmark. Finsen Laboratory, Copenhagen University Hospital - Rigshospitalet, Denmark. Division Cancer Epigenomics, German Cancer Research Center (DKFZ), Germany. 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, S Wards Building, UK. University of Konstanz, Germany. School of Medical Sciences, University of Sydney, Faculty of Medicine & Health, Australia. School of Health Systems & Public Health, University of Pretoria, South Africa. Manchester Cancer Research Centre, University of Manchester, UK. Princess Margaret Cancer Centre, University Health Network; Department of Medical Biophysics, University of Toronto, Canada. Department of Surgery, The Collaborative Centre for Genomic Cancer Medicine, The University of Melbourne, Australia. Department of Pathology and Laboratory Medicine, Weill Cornell Medical College, USA. Division of Cancer Sciences, The University of Manchester, UK. Christie Hospital, The Christie NHS Foundation Trust, Manchester Academic Health Science Centre, UK. Melbourne Bioinformatics, The University of Melbourne, Australia. Department of Molecular Medicine, Aarhus University Hospital, Denmark. Department of Clinical Medicine, Aarhus University, Denmark. Department of Oncology, KU Leuven, Belgium. Walter and Eliza Hall Institute of Medical Research, Australia. Department of Medical Biology, The University of Melbourne, Australia. Australian BioCommons, The University of Melbourne, Australia. Genome Biology, European Molecular Biology Laboratory (EMBL), Germany. Department of Molecular Genetics, University of Toronto, Canada. Department of Urology, Charité - Universitätsmedizin Berlin, Germany. Jonsson Comprehensive Cancer Center, University of California - Los Angeles, USA. School of Medicine, School of Mathematics & Statistics, University of St Andrews, UK. Metabolic Health research centre, Norwich Medical School, University of East Anglia, UK. The Earlham Institute, UK.
Description
Date
2025
Publisher
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All Christie Publications
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Type
Preprint
Citation
Esentürk E, Sahli A, Haberland V, Ziuboniewicz A, Wirth C, Bova GS, et al. Causes of evolutionary divergence in prostate cancer. aRxiv. 2025 Mar 17. PubMed PMID: 40166741. Pubmed Central PMCID: PMC11957227. Epub 2025/04/01. eng.
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URI
https://christie.openrepository.com/handle/10541/627571
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