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Genomic risk model to implement precision prostate cancer screening in clinical care: the ProGRESS study

Nature Cancer (2026)Cite this article

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Abstract

Precision healthcare aims to tailor disease prevention and early detection to individual risk. Prostate cancer screening may benefit from genomics-informed approaches. We developed and validated the P-CARE model, a prostate cancer risk prediction tool combining a polygenic score, family history and genetic ancestry, using data from over 585,000 male participants in the Million Veteran Program. The model was externally validated in diverse cohorts and implemented via a blended genome–exome assay for clinical use. Here we show that the P-CARE model identifies clinically meaningful gradients of prostate cancer risk among men, with higher scores associated with increased risk of any, metastatic and fatal prostate cancer. The model is now being used in a clinical trial of precision prostate cancer screening. This work demonstrates the potential for genomics-enabled health systems to improve prostate cancer screening and prevention in men. ClinicalTrials.gov registration: NCT05926102.

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Fig. 1: Translating prostate cancer genomic risk discovery to clinical trial implementation.
Fig. 2: Positive predictive value of PSA in ProtecT by P-CARE values.
Fig. 3: Prostate cancer cause-specific cumulative incidence in MVP by P-CARE strata.

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Data availability

The data generated from our analyses are included in the text, tables, figures and supplementary information. The genetic loci included in the polygenic score and their effect sizes are included in the Supplementary information. Source data for Figs. 2 and 3 and Extended Data Figs. 1 and 2 have been provided as Source Data files. All other data supporting the findings of this study are available from the corresponding author on reasonable request. It is not possible for the authors to share individual-level data from the MVP due to constraints stipulated in the informed consent. Anyone wishing to gain access to this data should inquire directly to MVP (MVPLOI@va.gov). Prostate Cancer Association Group to Investigate Cancer-Associated Alterations in the Genome (PRACTICAL) Consortium data are available upon request to the Data Access Committee (http://practical.icr.ac.uk/blog). Data from the AoU Research Program are accessible through the Researcher Workbench to researchers with an approved Data Use and Registration Agreement. Source data are provided with this paper.

Code availability

The code used for analyses is available at https://github.com/precimed/MVP-PCa-PHS.

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Acknowledgements

This research was funded by the US Department of Veterans Affairs Office of Research and Development (I01 CX002635 to J.L.V. and I01 CX001727 to R.L.H.), which played no role in the study design, data collection and analysis, decision to publish or preparation of the manuscript. It was supported using resources and facilities of the Department of VA Informatics and Computing Infrastructure (VINCI) ORD 24-VINCI-01, including writing support from K. Pridgen, under the research priority to Put VA Data to Work for Veterans (VA ORD 24-D4V). Funding for salaries includes Department of VA (VISN22 Veterans Center of Excellence for Stress and Mental Health to R.L.H.), VA Office of Research and Development (1I01CX002709 and 1I01CX002622 to K.N.M.), National Institutes of Health (NIH) (R01AG050595 to R.L.H. and K08CA215312 to K.N.M.), the Department of Defense (DOD/CDMRP PC220521 to T.M.S.), the Prostate Cancer Foundation (23CHAL12 to T.M.S., 20YOUN02 to K.N.M., 22CHAL02 to I.P.G., B.S.R. and K.N.M.), the Burroughs Wellcome Foundation (no. 1017184 to K.N.M.), Basser Center for BRCA (K.N.M.). The authors thank the MVP staff, researchers, and volunteers, who have contributed to MVP, and especially who previously served their country in the military and now generously agreed to enroll in the study (see mvp.va.gov for more information). The underlying work was based on data from the MVP, Office of Research and Development, Veterans Health Administration, and was supported by the Veterans Administration MVP award no. 000. This publication does not represent the views of the Department of VA or the US Government.

CAP: The CAP trial was funded by grants C11043/A4286, C18281/A8145, C18281/A11326, C18281/A15064 and C18281/A24432 from Cancer Research UK. The UK Department of Health, National Institute of Health Research (NIHR) provided partial funding.

ProtecT: The ProtecT trial was funded by project grants 96/20/06 and 96/20/99 from the UK National Institute for Health Research, Health Technology Assessment Programme. R.M.M. is an NIHR Senior Investigator (NIHR202411). R.M.M. is supported by a Cancer Research UK 25 (C18281/A29019) programme grant (the Integrative Cancer Epidemiology Programme). R.M.M. is also supported by the NIHR Bristol Biomedical Research Centre which is funded by the NIHR (BRC-1215-20011) and is a partnership between University Hospitals Bristol and Weston NHS Foundation Trust and the University of Bristol. Department of Health and Social Care disclaimer: The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health and Social Care. A.V. is supported by Spanish Instituto de Salud Carlos III (ISCIII) funding, an initiative of the Spanish Ministry of Economy and Innovation partially supported by European Regional Development FEDER Funds (PI22/00589, INT24/00023, DTS24/00083 and PI25/00744); and by the AECC (PRYES211091VEGA). A.S.K. is supported by NIH, grant/award numbers U01 - U01CA268810.

CRUK and PRACTICAL Consortium: This work was supported by the Canadian Institutes of Health Research (CIHR), European Commission’s Seventh Framework Programme grant agreement no. 223175 (HEALTH-F2-2009-223175), Cancer Research UK grants (C5047/A7357, C1287/A10118, C1287/A16563, C5047/A3354, C5047/A10692 and C16913/A6135) and The NIH Cancer Post-Cancer GWAS initiative grant: no. 1 U19 CA 148537-01 (the GAME-ON initiative). We also thank the following for funding support: The Institute of Cancer Research and The Everyman Campaign, The Prostate Cancer Research Foundation, Prostate Research Campaign UK (now PCUK), The Orchid Cancer Appeal, Rosetrees Trust, The National Cancer Research Network UK and The National Cancer Research Institute (NCRI) UK. We are grateful for support of NIHR funding to the NIHR Biomedical Research Centre at The Institute of Cancer Research, The Royal Marsden NHS Foundation Trust, and Manchester NIHR Biomedical Research Centre. The Prostate Cancer Program of Cancer Council Victoria also acknowledge grant support from The National Health and Medical Research Council, Australia (126402, 209057, 251533, 396414, 450104, 504700, 504702, 504715, 623204, 940394 and 614296), VicHealth, Cancer Council Victoria, The Prostate Cancer Foundation of Australia, The Whitten Foundation, PricewaterhouseCoopers and Tattersall’s. E.A.O., D.M.K. and E.M.K. acknowledge the Intramural Program of the National Human Genome Research Institute for their support. Genotyping of the OncoArray was funded by the US NIH (U19 CA 148537 for ELucidating Loci Involved in Prostate cancer SuscEptibility (ELLIPSE) project and X01HG007492 to the Center for Inherited Disease Research under contract number HHSN268201200008I). Additional analytic support was provided by NIH NCI U01 CA188392 (PI: Schumacher). Research reported in this publication also received support from the National Cancer Institute of the NIH under award numbers U10 CA37429 (C.D. Blanke) and UM1 CA182883 (C.M. Tangen/I.M. Thompson). The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. Funding for the iCOGS infrastructure came from: the European Community’s Seventh Framework Programme under grant agreement no. 223175 (HEALTH-F2-2009-223175) (COGS), Cancer Research UK (C1287/A10118, C1287/A 10710, C12292/A11174, C1281/A12014, C5047/A8384, C5047/A15007, C5047/A10692 and C8197/A16565), the NIH (CA128978) and Post-Cancer GWAS initiative (1U19 CA 148537, 1U19 CA148065 and 1U19 CA148112 - the GAME-ON initiative), the Department of Defence (W81XWH-10-1-0341), the CIHR for the CIHR Team in Familial Risks of Breast Cancer, Komen Foundation for the Cure, the Breast Cancer Research Foundation, and the Ovarian Cancer Research Fund. PROtEuS received funding from the Canadian Cancer Society, the Cancer Research Society, the Fonds de Recherche du Québec–Santé, the Ministère du Développement Économique, de l’Innovation et de l’Exportation du Québec and the Canada Research Chairs Program

BPC3: The BPC3 was supported by the US NIH, National Cancer Institute (cooperative agreements U01-CA98233 to D.J.H., U01-CA98710 to S.M.G., U01-CA98216 to E.R. and U01-CA98758 to B.E.H., and Intramural Research Program of NIH/National Cancer Institute, Division of Cancer Epidemiology and Genetics).

CAPS: The CAPS GWAS study was supported by the Cancer Risk Prediction Center (CRisP; www.crispcenter.org), a Linneus Centre (Contract ID 70867902) financed by the Swedish Research Council, (grant no K2010-70X-20430-04-3), the Swedish Cancer Foundation (grant no 09-0677), the Hedlund Foundation, the Soederberg Foundation, the Enqvist Foundation, ALF funds from the Stockholm County Council. Stiftelsen Johanna Hagstrand och Sigfrid Linner’s Minne, Karlsson’s Fund for urological and surgical research.

PEGASUS: PEGASUS was supported by the Intramural Research Program, Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH.

Author information

Author notes

  1. These authors contributed equally: Jason L. Vassy, Anna M. Dornisch.

Authors and Affiliations

  1. VA Boston Healthcare System, Boston, MA, USA

    Jason L. Vassy, Charles A. Brunette, Morgan E. Danowski, Dmitry Ratner, J. Michael Gaziano, Jessica V. Brewer, Mary T. Brophy, Kelly Cho, Saiju Pyarajan, Luis E. Selva, Shahpoor Alex Shayan & Stacey B. Whitbourne

  2. Department of Medicine, Harvard Medical School, Boston, MA, USA

    Jason L. Vassy & Charles A. Brunette

  3. Division of General Internal Medicine, Mass General Brigham, Boston, MA, USA

    Jason L. Vassy

  4. Department of Radiation Medicine and Applied Sciences, University of California San Diego, La Jolla, CA, USA

    Anna M. Dornisch, Roshan Karunamuni, Brent S. Rose, George J. Xu & Tyler M. Seibert

  5. Research Service, VA San Diego Healthcare System, San Diego, CA, USA

    Roshan Karunamuni, Brent S. Rose, George J. Xu & Tyler M. Seibert

  6. Broad Institute of MIT and Harvard, Cambridge, MA, USA

    Michael Gatzen, Christopher J. Kachulis, Niall J. Lennon, Sean E. Hofherr, Katherine A. Lafferty, Katie Larkin, Edyta Malolepsza, Candace J. Patterson & Diana M. Toledo

  7. Broad Clinical Labs, Burlington, MA, USA

    Christopher J. Kachulis, Niall J. Lennon, Katherine A. Lafferty, Katie Larkin, Edyta Malolepsza, Candace J. Patterson & Diana M. Toledo

  8. Center of Excellence for Stress and Mental Health (CESAMH), VA San Diego Healthcare System, San Diego, CA, USA

    Richard L. Hauger

  9. Center for Behavior Genetics of Aging, University of California San Diego, La Jolla, CA, USA

    Richard L. Hauger

  10. Division of Urology, VA Greater Los Angeles Healthcare System, Los Angeles, CA, USA

    Isla P. Garraway

  11. Department of Urology, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA

    Isla P. Garraway

  12. Urology Division, Department of Surgery, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA

    Adam S. Kibel

  13. VA Informatics and Computing Infrastructure, VA Salt Lake City Healthcare System, Salt Lake City, UT, USA

    Kyung M. Lee & Julie A. Lynch

  14. Corporal Michael Crescenz Veterans Affairs Medical Center, Philadelphia, PA, USA

    Kara N. Maxwell

  15. Department of Medicine - Hematology/Oncology, Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA, USA

    Kara N. Maxwell

  16. VA Salt Lake City Healthcare System, Salt Lake City, UT, USA

    Craig C. Teerlink

  17. Division of Epidemiology, Department of Internal Medicine, University of Utah School of Medicine, Salt Lake City, UT, USA

    Craig C. Teerlink & Lisa Cannon-Albright

  18. Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK

    Jenny L. Donovan, Richard M. Martin & Emma L. Turner

  19. Nuffield Department of Surgical Sciences, University of Oxford, Oxford, UK

    Freddie C. Hamdy, David E. Neal, Ian G. Mills, Freddie C. Hamdy & Freddie C. Hamdy

  20. NIHR Biomedical Research Centre at the University Hospitals Bristol and Weston NHS Foundation Trust and the University of Bristol, Bristol, UK

    Richard M. Martin

  21. University of Cambridge, Department of Oncology, Cambridge, UK

    David E. Neal

  22. Cancer Research UK, Cambridge Research Institute, Cambridge, UK

    David E. Neal

  23. Centre for Precision Psychiatry and KG Jebsen Centre for Neurodevelopment, Oslo University Hospital and University of Oslo, Oslo, Norway

    Ole A. Andreassen

  24. NORMENT, KG Jebsen Centre, Oslo University Hospital and University of Oslo, Oslo, Norway

    Anders M. Dale

  25. Department of Radiology, University of California San Diego, La Jolla, CA, USA

    Anders M. Dale & Tyler M. Seibert

  26. Department of Neurosciences, University of California, San Diego, La Jolla, CA, USA

    Anders M. Dale

  27. Halicioglu Data Science Institute, University of California San Diego, La Jolla, CA, USA

    Anders M. Dale

  28. Department of Oncology, Cross Cancer Institute, University of Alberta, Alberta, Canada

    Aswin Abraham

  29. School of Biomedicine, Faculty of Health and Medical Sciences, Bond University, Gold Coast, Queensland, Australia

    Jyotsna Batra

  30. Centre for Genomics and Personalised Health, School of Biomedical Sciences, Faculty of Health, Queensland University of Technology (QUT), Brisbane, Queensland, Australia

    Jyotsna Batra & Judith Clements

  31. Australian Prostate Cancer Bioresource (APCB), QUT, Brisbane, Queensland, Australia

    Jyotsna Batra & Judith Clements

  32. Translational Research Institute, QUT, Brisbane, Queensland, Australia

    Jyotsna Batra & Judith Clements

  33. Sorbonne Université, Paris, France

    Olivier Cussenot

  34. Tenon Hospital, Paris, France

    Olivier Cussenot

  35. International Hereditary Cancer Center, Department of Genetics and Pathology, Pomeranian Medical University, Szczecin, Poland

    Cezary Cybulski

  36. The Institute of Cancer Research, London, UK

    Rosalind A. Eeles, Zsofia Kote-Jarai & Sara Benlloch

  37. Royal Marsden NHS Foundation Trust, London, UK

    Rosalind A. Eeles

  38. Division of Epidemiology, Department of Preventive Medicine, University of Tennessee Health Science Center, Memphis, TN, USA

    Jay H. Fowke

  39. Department of Medical Genetics, Oslo University Hospital, Oslo, Norway

    Eli Marie Grindedal

  40. Department of Medical Epidemiology and Biostatistics, Karolinska Institute, Stockholm, Sweden

    Henrik Grönberg, Anna Plym & Fredrik Wiklund

  41. Dept. of Surgical Oncology, Princess Margaret Cancer Centre, Toronto, Ontario, Canada

    Robert J. Hamilton & Robert J. Hamilton

  42. Dept. of Surgery (Urology), University of Toronto, Toronto, Ontario, Canada

    Robert J. Hamilton & Robert J. Hamilton

  43. Department of Surgery, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia

    Jasmine Lim & Azad Razack

  44. Centre for Cancer Biomarker and Biotherapeutics, Barts Cancer Institute, Queen Mary University of London, London, UK

    Yong-Jie Lu

  45. Cancer Epidemiology Division, Cancer Council Victoria, East Melbourne, Victoria, Australia

    Robert J. MacInnis

  46. Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Parkville, Victoria, Australia

    Robert J. MacInnis, Graham G. Giles & Robert J. MacInnis

  47. Zentrum für Humangenetik Tuebingen, Tuebingen, Germany

    Christiane Maier

  48. Institut für Humangenetik, University of Ulm, Ulm, Germany

    Christiane Maier

  49. Department of Epidemiology, Harvard T. H. Chan School of Public Health, Boston, MA, USA

    Lorelei A. Mucci & Anna Plym

  50. Univ Rennes, Inserm, EHESP, Irset (Institut de recherche en santé, environnement et travail), Rennes, France

    Luc Multigner

  51. Department of Population Sciences, Beckman Research Institute of the City of Hope, Duarte, CA, USA

    Susan L. Neuhausen

  52. Department of Clinical Biochemistry, Herlev and Gentofte Hospital, Copenhagen University Hospital, Copenhagen, Denmark

    Sune F. Nielsen

  53. Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark

    Sune F. Nielsen, Børge G. Nordestgaard & Sune F. Nielsen

  54. Epidemiology and Biostatistics Unit, Centre Armand-Frappier Santé Biotechnologie, Institut national de la recherche scientifique, Laval, Quebec, Canada

    Marie-Élise Parent

  55. Department of Social and Preventive Medicine, School of Public Health, University of Montreal, Montreal, Quebec, Canada

    Marie-Élise Parent

  56. Department of Cancer Epidemiology, Moffitt Cancer Center, Tampa, FL, USA

    Jong Y. Park

  57. Uniformed Services University, Bethesda, MD, USA

    Gyorgy Petrovics

  58. Center for Prostate Disease Research, Bethesda, MD, USA

    Gyorgy Petrovics

  59. Department of Radiation Oncology and Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA

    Barry S. Rosenstein

  60. Institute of Biomedicine, University of Turku, Turku, Finland

    Johanna Schleutker

  61. Department of Medical Genetics, Genomics, Laboratory Division, Turku University Hospital, Turku, Finland

    Johanna Schleutker

  62. Department of Molecular Medicine, Aarhus University Hospital, Aarhus N, Denmark

    Karina Dalsgaard Sørensen

  63. Department of Clinical Medicine, Aarhus University, Aarhus N, Denmark

    Karina Dalsgaard Sørensen

  64. Division of Cancer Sciences, Manchester Cancer Research Centre, Faculty of Biology, Medicine and Health, Manchester Academic Health Science Centre, NIHR Manchester Biomedical Research Centre, Health Innovation Manchester, University of Manchester, Manchester, UK

    Paul A. Townsend

  65. The University of Surrey, Guildford, Surrey, UK

    Paul A. Townsend, Paul A. Townsend & Hardev Pandha

  66. Cancer Epidemiology Unit, Nuffield Department of Population Health, University of Oxford, Oxford, UK

    Ruth C. Travis

  67. Fundación Pública Galega Medicina Xenómica, Santiago de Compostela, Spain

    Ana Vega

  68. Instituto de Investigación Sanitaria de Santiago de Compostela, Santiago De Compostela, Spain

    Ana Vega

  69. Centro de Investigación en Red de Enfermedades Raras (CIBERER), Madrid, Spain

    Ana Vega

  70. Division of Cancer Sciences, University of Manchester, Manchester Academic Health Science Centre, Radiotherapy Related Research, The Christie Hospital NHS Foundation Trust, Manchester, UK

    Catharine M. L. West & Catharine M. L. West

  71. Division of Epidemiology, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA

    Wei Zheng & William J. Blot

  72. Department of Bioengineering, University of California San Diego, La Jolla, CA, USA

    Tyler M. Seibert

  73. Department of Urology, University of California San Diego, La Jolla, CA, USA

    Tyler M. Seibert

  74. Oncogenetics Team, Genetics and Epidemiology, The Institute of Cancer Research, London, UK

    Rosalind A. Eeles, Elizabeth K. Bancroft, Eva McGrowder, Zsofia Kote-Jarai, Mark N. Brook, Elizabeth C. Page, Jana McHugh, Holly Ni Raghallaigh, Alexander Dias, Christos Mikropoulos, Elizabeth K. Bancroft & Elizabeth C. Page

  75. The Royal Marsden NHS Foundation Trust, London, UK

    Elizabeth K. Bancroft, Denzil James, Pardeep Kumar, Steve Hazell, Aslam Sohaib, Netty Kinsella & Declan Cahill

  76. Genomic medicine, Division of Evolution infection and genomic sciences, University of Manchester, Manchester, UK

    Elizabeth K. Bancroft & D. Gareth Evans

  77. Parkville Familial Cancer Centre, Peter MacCallum Cancer Centre and The Royal Melbourne Hospital, Melbourne, Victoria, Australia

    Geoffrey J. Lindeman

  78. Cancer Biology and Stem Cells Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia

    Geoffrey J. Lindeman & Paul James

  79. Department of Medicine, The University of Melbourne, Parkville, Victoria, Australia

    Geoffrey J. Lindeman & Vincent Khoo

  80. Wessex Clinical Genetics Service, Princess Anne Hospital, Southampton, UK

    Lucy Side & Diana M. Eccles

  81. Department of Clinical Genetics, University Hospital of Southern Denmark, Vejle Hospital, Vejle, Denmark

    Karina Rønlund

  82. John and Carol Walter Center for Urological Health, Division of Urology, Endeavor Health NorthShore University HealthSystem, Evanston, IL, USA

    Brian T. Helfand

  83. Department of Genetics and Pathology, International Hereditary Cancer Center, Pomeranian Medical University in Szczecin, Szczecin, Poland

    Cezary Cybulski & Jan Lubinski

  84. Department of Clinical Genetics, Birmingham Women’s Hospital, Birmingham, UK

    Kai-Ren Ong

  85. Hereditary Cancer Program, Catalan Institute of Oncology, ICO-IDIBELL (Bellvitge Biomedical Research Institute), 08908 Barcelona, CIBERONC, Madrid, Spain

    Monica Salinas

  86. Sheffield Clinical Genetics Service, Sheffield Children’s NHS Foundation Trust, Sheffield, UK

    Jackie Cook

  87. Basser Research Center, University of Pennsylvania, Philadelphia, PA, USA

    Kara Maxwell

  88. Department of Laboratory Genetics and IPO Porto Research Center, Portuguese Oncology Institute (IPO Porto), Porto, Portugal

    Manuel R. Teixeira

  89. West of Scotland Genetic Service, Queen Elizabeth University Hospital, Glasgow, UK

    Rosemarie Davidson

  90. Karolinska University Hospital and Karolinska Institutet, Stockholm, Sweden

    Annelie Liljegren

  91. Northern Genetics Service, Newcastle upon Tyne Hospitals, Newcastle upon Tyne, UK

    Ashraf Azzabi

  92. East Anglian Medical Genetics Service, Cambridge University Hospitals NHS Trust, Cambridge, UK

    Marc Tischkowitz

  93. Department of Clinical Genetics, Royal Devon and Exeter Hospital, Exeter, UK

    Ruth Cleaver

  94. University of Leicester, Leicester, UK

    Julian Barwell

  95. Division of Psychosocial Research and Epidemiology, Netherlands Cancer Institute, Amsterdam, The Netherlands

    Neil K. Aaronson

  96. Cancer Genetics Unit & Academic Urology Unit, The Royal Marsden NHS Foundation Trust, London, UK

    Audrey Ardern-Jones & Vincent Khoo

  97. Department of urology, Erasmus University Medical Center, Rotterdam, The Netherlands

    Chris H. Bangma

  98. Hospital Universitario 12 de Octubre, Madrid, Spain

    Elena Castro

  99. Division of Radiotherapy and Imaging, The Institute of Cancer Research, London, UK

    David Dearnaley & Vincent Khoo

  100. Cancer Sciences, The University of Southampton, Southampton, UK

    Diana M. Eccles

  101. Imperial College Healthcare NHS Trust, London, UK

    Alison Falconer

  102. Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden

    Henrik Gronberg, Fredrik Wiklund & Henrik Grönberg

  103. Churchill Hospital, Oxford, UK

    Freddie C. Hamdy

  104. St George’s Hospital, Tooting, London, UK

    Vincent Khoo

  105. Department of Translational Medicine, Lund University, Malmö, Sweden

    Hans Lilja

  106. Departments of Pathology and Laboratory Medicine, Surgery and Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY, USA

    Hans Lilja

  107. Royal Surrey Hospital, Guildford, UK

    Christos Mikropoulos

  108. University College London Hospitals NHS Foundation Trust, London, UK

    Anita Mitra

  109. Centre for Cancer Screening, Prevention and Early Diagnosis, Wolfson Institute of Population Health, Queen Mary University of London, Charterhouse Square, London, UK

    Judith Offman

  110. Technion-Israel Institute of Technology, Haifa, Israel

    Gad Rennert

  111. Nottingham City Hospital, Nottingham, UK

    Mohnish Suri

  112. Center for Genetic Epidemiology, Department of Preventive Medicine, Keck School of Medicine, University of Southern California/Norris Comprehensive Cancer Center, Los Angeles, CA, USA

    Christopher A. Haiman & David V. Conti

  113. Department of Population and Quantitative Health Sciences, Case Western Reserve University, Cleveland, OH, USA

    Fredrick R. Schumacher

  114. Seidman Cancer Center, University Hospitals, Cleveland, OH, USA

    Fredrick R. Schumacher

  115. Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Strangeways Research Laboratory, Cambridge, UK

    Sara Benlloch & Ali Amin Al Olama

  116. University of Cambridge, Department of Clinical Neurosciences, Stroke Research Group, R3, Box 83, Cambridge Biomedical Campus, Cambridge, UK

    Ali Amin Al Olama

  117. Division of Population Health, Health Services Research and Primary Care, University of Manchester, Oxford Road, Manchester, UK

    Kenneth R. Muir

  118. Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, Bethesda, MD, USA

    Sonja I. Berndt, Stephen Chanock, Demetrius Albanes, Stephanie J. Weinstein & Stella Koutros

  119. Department of Population Science, American Cancer Society, 250 Williams Street, Atlanta, GA, USA

    Ying Wang

  120. SWOG Statistical Center, Fred Hutchinson Cancer Research Center, Seattle, WA, USA

    Catherine M. Tangen

  121. Department of Public Health & Primary Care, Strangeways Research Laboratory, Cambridge, UK

    Nora Pashayan

  122. Department of Applied Health Research, University College London, London, UK

    Nora Pashayan

  123. Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden

    Alicja Wolk

  124. CeRePP, Tenon Hospital, Paris, France

    Géraldine Cancel-Tassin

  125. Sorbonne Universite, GRC n°5, AP-HP, Tenon Hospital, Paris, France

    Géraldine Cancel-Tassin

  126. Nuffield Department of Surgical Sciences, University of Oxford, Room 6603, Level 6, John Radcliffe Hospital, Headington, UK

    David E. Neal

  127. University of Cambridge, Department of Oncology, Box 279, Addenbrooke’s Hospital, Cambridge, UK

    David E. Neal

  128. Cancer Research UK, Cambridge Research Institute, Li Ka Shing Centre, Cambridge, UK

    David E. Neal

  129. Faculty of Medical Science, University of Oxford, John Radcliffe Hospital, Oxford, UK

    Freddie C. Hamdy

  130. Department of Preventive Medicine, Keck School of Medicine, University of Southern California/Norris Comprehensive Cancer Center, Los Angeles, CA, USA

    Sue Ann Ingles

  131. Department of Radiation Oncology and Department of Genetics and Genomic Sciences, Box 1236, Icahn School of Medicine at Mount Sinai, New York, NY, USA

    Barry S. Rosenstein

  132. Centre for Cancer Biomarker and Biotherapeutics, Barts Cancer Institute, Queen Mary University of London, John Vane Science Centre, London, UK

    Yong-Jie Lu

  133. Cancer Epidemiology Division, Cancer Council Victoria, 200 Victoria Parade, East Melbourne, Victoria, Australia

    Graham G. Giles & Robert J. MacInnis

  134. Precision Medicine, School of Clinical Sciences at Monash Health, Monash University, Clayton, Victoria, Australia

    Graham G. Giles

  135. Division of Urologic Surgery, Brigham and Womens Hospital, Boston, MA, USA

    Adam S. Kibel

  136. ISGlobal, Barcelona, Spain

    Manolis Kogevinas

  137. IMIM (Hospital del Mar Medical Research Institute), Barcelona, Spain

    Manolis Kogevinas

  138. Universitat Pompeu Fabra (UPF), Barcelona, Spain

    Manolis Kogevinas

  139. CIBER Epidemiología y Salud Pública (CIBERESP), Madrid, Spain

    Manolis Kogevinas

  140. Channing Division of Network Medicine, Department of Medicine, Brigham and Women’s Hospital/Harvard Medical School, Boston, MA, USA

    Kathryn L. Penney

  141. Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA, USA

    Janet L. Stanford & Lisa F. Newcomb

  142. Department of Epidemiology, School of Public Health, University of Washington, Seattle, WA, USA

    Janet L. Stanford

  143. Department of Clinical Biochemistry, Herlev and Gentofte Hospital, Copenhagen University Hospital, Herlev, Denmark

    Børge G. Nordestgaard & Sune F. Nielsen

  144. Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany

    Hermann Brenner

  145. German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany

    Hermann Brenner

  146. Humangenetik Tuebingen, Tuebingen, Germany

    Christiane Maier

  147. The University of Texas M. D. Anderson Cancer Center, Department of Genitourinary Medical Oncology, Houston, TX, USA

    Jeri Kim

  148. Departments of Epidemiology & Population Health and of Medicine, Division of Oncology, Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA, USA

    Esther M. John

  149. Department of Laboratory Genetics, Portuguese Oncology Institute of Porto (IPO Porto) / Porto Comprehensive Cancer Center, Porto, Portugal

    Manuel R. Teixeira

  150. Cancer Genetics Group, IPO Porto Research Center (CI-IPOP) / RISE@CI-IPOP (Health Research Network), Portuguese Oncology Institute of Porto (IPO Porto) / Porto Comprehensive Cancer Center, Porto, Portugal

    Manuel R. Teixeira

  151. School of Medicine and Biomedical Sciences (ICBAS), University of Porto, Porto, Portugal

    Manuel R. Teixeira

  152. Ghent University, Faculty of Medicine and Health Sciences, Basic Medical Sciences, Gent, Belgium

    Kim De Ruyck

  153. Department of Urology, University of Washington, Seattle, WA, USA

    Lisa F. Newcomb

  154. Institute of Human Genetics, University of Regensburg, and Institute of Clinical Human Genetics, University Hospital Regensburg, Regensburg, Germany

    Davor Lessel

  155. Molecular Medicine Center, Department of Medical Chemistry and Biochemistry, Medical University of Sofia, Sofia, Bulgaria

    Radka Kaneva

  156. Department of Oncology, Cross Cancer Institute, University of Alberta, Edmonton, Alberta, Canada

    Nawaid Usmani

  157. Division of Radiation Oncology, Cross Cancer Institute, Edmonton, Alberta, Canada

    Nawaid Usmani

  158. Molecular Endocrinology Laboratory, Department of Cellular and Molecular Medicine, KU Leuven, Leuven, Belgium

    Frank Claessens

  159. Division of Cancer Sciences, Manchester Cancer Research Centre, Faculty of Biology, Medicine and Health, Manchester Academic Health Science Centre, NIHR Manchester Biomedical Research Centre, Health Innovation Manchester, Univeristy of Manchester, Manchester, UK

    Paul A. Townsend

  160. Genetic Oncology Unit, CHUVI Hospital, Complexo Hospitalario Universitario de Vigo, Instituto de Investigación Biomédica Galicia Sur (IISGS), Vigo (Pontevedra), Spain

    Jose Esteban Castelao

  161. Department of Urology, Erasmus University Medical Center, Cancer Institute, Rotterdam, The Netherlands

    Monique J. Roobol

  162. “Exposome and Heredity”, CESP (UMR 1018), Faculté de Médecine, Université Paris-Saclay, Inserm, Gustave Roussy, Villejuif, France

    Florence Menegaux

  163. Clinical Gerontology Unit, University of Cambridge, Cambridge, UK

    Kay-Tee Khaw

  164. George E. Wahlen Department of Veterans Affairs Medical Center, Salt Lake City, UT, USA

    Lisa Cannon-Albright

  165. Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA

    Stephen N. Thibodeau

  166. Nuffield Department of Population Health, University of Oxford, Oxford, UK

    David J. Hunter

  167. Program in Genetic Epidemiology and Statistical Genetics, Department of Epidemiology, Harvard School of Public Health, Boston, MA, USA

    Peter Kraft

  168. International Epidemiology Institute, Rockville, MD, USA

    William J. Blot

  169. Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, UK

    Elio Riboli

  170. US Department of Veterans Affairs, Washington, DC, USA

    Sumitra Muralidhar, Jennifer Moser & Jennifer E. Deen

  171. VA Palo Alto Health Care System, Palo Alto, CA, USA

    Philip S. Tsao & Lori Churby

  172. VA Tennessee Valley Healthcare System, Nashville, TN, USA

    Adriana Hung

  173. Philadelphia VA Medical Center, Philadelphia, PA, USA

    Dave Oslin

  174. Durham VA Medical Center, Durham, NC, USA

    Deepak Voora

  175. VA Salt Lake City Health Care System, Salt Lake City, UT, UK

    Jacob T. Kean

  176. New Mexico VA Health Care System, Albuquerque, NM, USA

    Robert Ringer

  177. Canandaigua VA Medical Center, Canandaigua, NY, USA

    Brady Stephens

Authors
  1. Jason L. Vassy
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  2. Anna M. Dornisch
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  3. Roshan Karunamuni
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  4. Michael Gatzen
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  6. Niall J. Lennon
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  7. Charles A. Brunette
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  8. Morgan E. Danowski
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  14. Kara N. Maxwell
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  15. Dmitry Ratner
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  16. Brent S. Rose
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  17. Craig C. Teerlink
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  18. George J. Xu
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  19. Sean E. Hofherr
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  20. Katherine A. Lafferty
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  21. Katie Larkin
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  23. Candace J. Patterson
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  24. Diana M. Toledo
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  25. Jenny L. Donovan
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  26. Freddie C. Hamdy
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  27. Richard M. Martin
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  28. David E. Neal
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  29. Emma L. Turner
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  30. Ole A. Andreassen
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  31. Anders M. Dale
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  32. Ian G. Mills
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  33. Aswin Abraham
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  34. Jyotsna Batra
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  35. Judith Clements
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  36. Olivier Cussenot
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  37. Cezary Cybulski
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  38. Rosalind A. Eeles
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  39. Jay H. Fowke
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  40. Eli Marie Grindedal
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  41. Henrik Grönberg
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  42. Robert J. Hamilton
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  43. Jasmine Lim
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  44. Yong-Jie Lu
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  45. Robert J. MacInnis
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  46. Christiane Maier
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  47. Lorelei A. Mucci
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  48. Luc Multigner
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  49. Susan L. Neuhausen
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  50. Sune F. Nielsen
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  51. Marie-Élise Parent
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  52. Jong Y. Park
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  53. Gyorgy Petrovics
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  63. Fredrik Wiklund
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  64. Wei Zheng
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  65. Tyler M. Seibert
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Consortia

Profile Steering Committee

  • Rosalind A. Eeles
  • , Elizabeth K. Bancroft
  • , Eva McGrowder
  • , Zsofia Kote-Jarai
  • , Mark N. Brook
  • , Elizabeth C. Page
  • , Jana McHugh
  • , Holly Ni Raghallaigh
  • , Denzil James
  • , Pardeep Kumar
  • , Steve Hazell
  • , Aslam Sohaib
  • , Alexander Dias
  • , Christos Mikropoulos
  • , Netty Kinsella
  •  & Declan Cahill

IMPACT Study Steering Committee and Collaborators

  • Rosalind A. Eeles
  • , Elizabeth K. Bancroft
  • , Elizabeth C. Page
  • , Mark N. Brook
  • , Zsofia Kote-Jarai
  • , D. Gareth Evans
  • , Geoffrey J. Lindeman
  • , Paul James
  • , Lucy Side
  • , Karina Rønlund
  • , Brian T. Helfand
  • , Cezary Cybulski
  • , Kai-Ren Ong
  • , Monica Salinas
  • , Jackie Cook
  • , Kara Maxwell
  • , Manuel R. Teixeira
  • , Rosemarie Davidson
  • , Annelie Liljegren
  • , Ashraf Azzabi
  • , Marc Tischkowitz
  • , Ruth Cleaver
  • , Julian Barwell
  • , Neil K. Aaronson
  • , Audrey Ardern-Jones
  • , Chris H. Bangma
  • , Elena Castro
  • , David Dearnaley
  • , Diana M. Eccles
  • , Alison Falconer
  • , Henrik Gronberg
  • , Freddie C. Hamdy
  • , Vincent Khoo
  • , Hans Lilja
  • , Jan Lubinski
  • , Christos Mikropoulos
  • , Anita Mitra
  • , Judith Offman
  • , Gad Rennert
  •  & Mohnish Suri

PRACTICAL Consortium

  • Rosalind A. Eeles
  • , Christopher A. Haiman
  • , Zsofia Kote-Jarai
  • , Fredrick R. Schumacher
  • , Sara Benlloch
  • , Ali Amin Al Olama
  • , Kenneth R. Muir
  • , Sonja I. Berndt
  • , David V. Conti
  • , Fredrik Wiklund
  • , Stephen Chanock
  • , Ying Wang
  • , Catherine M. Tangen
  • , Jyotsna Batra
  • , Judith Clements
  • , Henrik Grönberg
  • , Nora Pashayan
  • , Johanna Schleutker
  • , Demetrius Albanes
  • , Stephanie J. Weinstein
  • , Alicja Wolk
  • , Catharine M. L. West
  • , Lorelei A. Mucci
  • , Géraldine Cancel-Tassin
  • , Stella Koutros
  • , Karina Dalsgaard Sørensen
  • , Eli Marie Grindedal
  • , David E. Neal
  • , Freddie C. Hamdy
  • , Jenny L. Donovan
  • , Ruth C. Travis
  • , Robert J. Hamilton
  • , Sue Ann Ingles
  • , Barry S. Rosenstein
  • , Yong-Jie Lu
  • , Graham G. Giles
  • , Robert J. MacInnis
  • , Adam S. Kibel
  • , Ana Vega
  • , Manolis Kogevinas
  • , Kathryn L. Penney
  • , Jong Y. Park
  • , Janet L. Stanford
  • , Cezary Cybulski
  • , Børge G. Nordestgaard
  • , Sune F. Nielsen
  • , Hermann Brenner
  • , Christiane Maier
  • , Jeri Kim
  • , Esther M. John
  • , Manuel R. Teixeira
  • , Susan L. Neuhausen
  • , Kim De Ruyck
  • , Azad Razack
  • , Lisa F. Newcomb
  • , Davor Lessel
  • , Radka Kaneva
  • , Nawaid Usmani
  • , Frank Claessens
  • , Paul A. Townsend
  • , Jose Esteban Castelao
  • , Monique J. Roobol
  • , Florence Menegaux
  • , Kay-Tee Khaw
  • , Lisa Cannon-Albright
  • , Hardev Pandha
  • , Stephen N. Thibodeau
  • , David J. Hunter
  • , Peter Kraft
  • , William J. Blot
  •  & Elio Riboli

VA Million Veteran Program

  • Sumitra Muralidhar
  • , Jennifer Moser
  • , Jennifer E. Deen
  • , Philip S. Tsao
  • , J. Michael Gaziano
  • , Adriana Hung
  • , Dave Oslin
  • , Deepak Voora
  • , Jessica V. Brewer
  • , Mary T. Brophy
  • , Kelly Cho
  • , Lori Churby
  • , Jacob T. Kean
  • , Saiju Pyarajan
  • , Robert Ringer
  • , Luis E. Selva
  • , Shahpoor Alex Shayan
  • , Brady Stephens
  •  & Stacey B. Whitbourne

Contributions

J.L.V., A.M. Dornisch and T.M.S. conceived and designed the study, oversaw data analysis, interpreted results, and drafted the manuscript. R.K. contributed to study design, supervised analytic workflows and provided domain expertise in polygenic risk modeling. M.G., C.J.K., N.J.L., S.E.H., K.A.L., K.L., E.M., C.J.P. and D.M.T. coordinated sequencing, bioinformatics and data curation. C.A.B., M.E.D. and D.R. assisted with data interpretation, visualization and manuscript preparation. R.L.H., I.P.G., K.M.L., J.A.L., K.N.M., B.S. Rose, C.C.T., A.S.K. and G.J.X. provided expertise in prostate cancer phenotyping and critical review of study design and interpretation. J.L.D., F.H., R.M.M., D.E.N., E.L.T., O.A.A., A.M. Dale, I.G.M., A.A., J.B., J.C., O.C., C.C., R.A.E., J.H.F., E.M.G., H.G., R.J.H., J.L., Y.J.L., R.J.M., C.M., L.A.M., L.M., S.L.N., S.F.N., M.E.P., J.Y.P., G.P., A.P., A.R., B.S. Rosenstein, J.S., K.D.S., P.A.T., R.C.T., A.V., C.M.L.W., F.W. and W.Z. contributed data from consortium studies, performed genotyping and quality control and reviewed the manuscript for intellectual content. J.L.V. served as principal investigator and corresponding author. All authors reviewed the results and approved the final manuscript.

Corresponding authors

Correspondence to Jason L. Vassy or Tyler M. Seibert.

Ethics declarations

Competing interests

N.L. has received speaking honoraria from Illumina and is an advisory board member for FYR Diagnostics and Everygene; N.L. has also received research collaborative funding (for work unrelated to this publication) from Illumina and PacBio. J.A.L., K.M.L. and C.T.C. report grants from Alnylam Pharmaceuticals, Astellas Pharma, AstraZeneca Pharmaceuticals, Biodesix, Celgene Corporation, Cerner Enviza, GSK, IQVIA, Janssen Pharmaceuticals, Novartis International and the Parexel International Corporation through the University of Utah or Western Institute for Veteran Research outside the submitted work. A.S.K. reports funding (for work unrelated to this publication) from Janssen, Pfizer, Profound, Bristol Myers Squibb and Merck. S.L.D. reports grants from AstraZeneca Pharmaceuticals, Biodesix, Myriad Genetic Laboratories, Parexel, Moderna, GlaxoSmithKline, Cerner Enviza, Janssen Research & Development, Celgene, Novartis Pharmaceuticals, IQVIA, Astellas Pharma and Alnylam Pharmaceuticals. R.A.E. reports speaking honoraria from GU-ASCO, Janssen, University of Chicago and the Dana Farber Cancer Institute, educational honorarium from Bayer and Ipsen, being a member of external expert committee to AstraZeneca UK and Member of Active Surveillance Movember Committee and is a member of the Scientific Advisory Board of Our Future Health; she additionally 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. L.A.M. reports research funding from AstraZeneca to Harvard University; she holds equity in Convergent Therapeutics. T.M.S. reports honoraria from Varian Medical Systems, WebMD, GE Healthcare and Janssen; he has an equity interest in CorTechs Labs and serves on its Scientific Advisory Board; he receives research funding from GE Healthcare through the University of California, San Diego. These companies might potentially benefit from the research results. The terms of this arrangement have been reviewed and approved by the University of California, San Diego in accordance with its conflict-of-interest policies. All other authors declare no competing interests.

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Nature Cancer thanks Irajizad Ehsan, Fumitaka Koga, Shintaro Narita and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Extended data

Extended Data Fig. 1 Positive predictive value of PSA in ProtecT by P-CARE values stratified by PSA values.

Illustrated are mean PPV (95% CI) for various PSA levels (all ( ≥ 3 ng/mL), 3–4 ng/mL, 4-10 ng/mL, and >10 ng/mL) for clinically significant prostate cancer among three groups of men in the ProtecT study (n = 6,411): all men (regardless of P-CARE value), men in the top 20% of P-CARE values (P-CARE80), and men in the top 5% of P-CARE values (P-CARE95). Abbreviations: CI, confidence interval; P-CARE, Prostate CA Risk and Evaluation; PPV, positive predictive value; ProtecT, Prostate Testing for Cancer and Treatment; PSA, prostate-specific antigen.

Source data

Extended Data Fig. 2 Percentage of true positive cases in ProtecT across P-CARE categories.

Illustrated are the percentage of true positive cases for various PSA levels among 6,411 men in the ProtecT Study (all values ≥ 3 ng/mL, 3-4 ng/mL, 4-10 ng/mL, and >10 ng/mL) for clinically significant prostate cancer stratified by P-CARE risk percentiles, with comparisons between the top 5% (P-CARE95) and top 20% (P-CARE80). Error bars represent 95% confidence intervals.

Source data

Extended Data Fig. 3 Odds of prostate cancer in All of Us Research Program by P-CARE category.

Shown are the odds ratios for an individual to be diagnosed with prostate cancer in the low and high P-CARE categories, relative to the average P-CARE category, derived from logistic regression models controlling for age. Error bars correspond to the 95% confidence intervals, and the shown ancestries are the predictions provided by All of Us. Abbreviations: P-CARE, Prostate CAncer Risk and Evaluation.

Source data

Supplementary information

Supplementary Information

Template of laboratory report package for ProGRESS clinical trial, and MVP Consortium Members

Reporting Summary

Supplementary Table 1–14

Supplementary Tables 1–14

Source data

Source Data Fig. 2

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Source Data Fig. 3

Statistical source data.

Source Data Extended Data Fig. 1

Statistical source data.

Source Data Extended Data Fig. 2

Statistical source data.

Source Data Extended Data Fig. 3

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Vassy, J.L., Dornisch, A.M., Karunamuni, R. et al. Genomic risk model to implement precision prostate cancer screening in clinical care: the ProGRESS study. Nat Cancer (2026). https://doi.org/10.1038/s43018-025-01103-0

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