Genomic risk model to implement precision prostate cancer screening in clinical care: the ProGRESS study.
| Title: | Genomic risk model to implement precision prostate cancer screening in clinical care: the ProGRESS study. |
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| Authors: | Vassy JL; VA Boston Healthcare System, Boston, MA, USA. jvassy@bwh.harvard.edu.; Department of Medicine, Harvard Medical School, Boston, MA, USA. jvassy@bwh.harvard.edu.; Division of General Internal Medicine, Mass General Brigham, Boston, MA, USA. jvassy@bwh.harvard.edu.; Dornisch AM; Department of Radiation Medicine and Applied Sciences, University of California San Diego, La Jolla, CA, USA.; Karunamuni R; Department of Radiation Medicine and Applied Sciences, University of California San Diego, La Jolla, CA, USA.; Research Service, VA San Diego Healthcare System, San Diego, CA, USA.; Gatzen M; Broad Institute of MIT and Harvard, Cambridge, MA, USA.; Kachulis CJ; Broad Institute of MIT and Harvard, Cambridge, MA, USA.; Broad Clinical Labs, Burlington, MA, USA.; Lennon NJ; Broad Institute of MIT and Harvard, Cambridge, MA, USA.; Broad Clinical Labs, Burlington, MA, USA.; Brunette CA; VA Boston Healthcare System, Boston, MA, USA.; Department of Medicine, Harvard Medical School, Boston, MA, USA.; Danowski ME; VA Boston Healthcare System, Boston, MA, USA.; Hauger RL; Center of Excellence for Stress and Mental Health (CESAMH), VA San Diego Healthcare System, San Diego, CA, USA.; Center for Behavior Genetics of Aging, University of California San Diego, La Jolla, CA, USA.; Garraway IP; Division of Urology, VA Greater Los Angeles Healthcare System, Los Angeles, CA, USA.; Department of Urology, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA.; Kibel AS; Urology Division, Department of Surgery, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.; Lee KM; VA Informatics and Computing Infrastructure, VA Salt Lake City Healthcare System, Salt Lake City, UT, USA.; Lynch JA; VA Informatics and Computing Infrastructure, VA Salt Lake City Healthcare System, Salt Lake City, UT, USA.; Maxwell KN; Corporal Michael Crescenz Veterans Affairs Medical Center, Philadelphia, PA, USA.; Department of Medicine - Hematology/Oncology, Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA, USA.; Ratner D; VA Boston Healthcare System, Boston, MA, USA.; Rose BS; Department of Radiation Medicine and Applied Sciences, University of California San Diego, La Jolla, CA, USA.; Research Service, VA San Diego Healthcare System, San Diego, CA, USA.; Teerlink CC; VA Salt Lake City Healthcare System, Salt Lake City, UT, USA.; Division of Epidemiology, Department of Internal Medicine, University of Utah School of Medicine, Salt Lake City, UT, USA.; Xu GJ; Department of Radiation Medicine and Applied Sciences, University of California San Diego, La Jolla, CA, USA.; Research Service, VA San Diego Healthcare System, San Diego, CA, USA.; Hofherr SE; Broad Institute of MIT and Harvard, Cambridge, MA, USA.; Lafferty KA; Broad Institute of MIT and Harvard, Cambridge, MA, USA.; Broad Clinical Labs, Burlington, MA, USA.; Larkin K; Broad Institute of MIT and Harvard, Cambridge, MA, USA.; Broad Clinical Labs, Burlington, MA, USA.; Malolepsza E; Broad Institute of MIT and Harvard, Cambridge, MA, USA.; Broad Clinical Labs, Burlington, MA, USA.; Patterson CJ; Broad Institute of MIT and Harvard, Cambridge, MA, USA.; Broad Clinical Labs, Burlington, MA, USA.; Toledo DM; Broad Institute of MIT and Harvard, Cambridge, MA, USA.; Broad Clinical Labs, Burlington, MA, USA.; Donovan JL; Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK.; Hamdy FC; Nuffield Department of Surgical Sciences, University of Oxford, Oxford, UK.; Martin RM; Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK.; NIHR Biomedical Research Centre at the University Hospitals Bristol and Weston NHS Foundation Trust and the University of Bristol, Bristol, UK.; Neal DE; Nuffield Department of Surgical Sciences, University of Oxford, Oxford, UK.; University of Cambridge, Department of Oncology, Cambridge, UK.; Cancer Research UK, Cambridge Research Institute, Cambridge, UK.; Turner EL; Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK.; Andreassen OA; Centre for Precision Psychiatry and KG Jebsen Centre for Neurodevelopment, Oslo University Hospital and University of Oslo, Oslo, Norway.; Dale AM; NORMENT, KG Jebsen Centre, Oslo University Hospital and University of Oslo, Oslo, Norway.; Department of Radiology, University of California San Diego, La Jolla, CA, USA.; Department of Neurosciences, University of California, San Diego, La Jolla, CA, USA.; Halicioglu Data Science Institute, University of California San Diego, La Jolla, CA, USA.; Mills IG; Nuffield Department of Surgical Sciences, University of Oxford, Oxford, UK.; Abraham A; Department of Oncology, Cross Cancer Institute, University of Alberta, Alberta, Canada.; Batra J; School of Biomedicine, Faculty of Health and Medical Sciences, Bond University, Gold Coast, Queensland, Australia.; Centre for Genomics and Personalised Health, School of Biomedical Sciences, Faculty of Health, Queensland University of Technology (QUT), Brisbane, Queensland, Australia.; Australian Prostate Cancer Bioresource (APCB), QUT, Brisbane, Queensland, Australia.; Translational Research Institute, QUT, Brisbane, Queensland, Australia.; Clements J; Centre for Genomics and Personalised Health, School of Biomedical Sciences, Faculty of Health, Queensland University of Technology (QUT), Brisbane, Queensland, Australia.; Australian Prostate Cancer Bioresource (APCB), QUT, Brisbane, Queensland, Australia.; Translational Research Institute, QUT, Brisbane, Queensland, Australia.; Cussenot O; Sorbonne Université, Paris, France.; Tenon Hospital, Paris, France.; Cybulski C; International Hereditary Cancer Center, Department of Genetics and Pathology, Pomeranian Medical University, Szczecin, Poland.; Eeles RA; The Institute of Cancer Research, London, UK.; Royal Marsden NHS Foundation Trust, London, UK.; Fowke JH; Division of Epidemiology, Department of Preventive Medicine, University of Tennessee Health Science Center, Memphis, TN, USA.; Grindedal EM; Department of Medical Genetics, Oslo University Hospital, Oslo, Norway.; Grönberg H; Department of Medical Epidemiology and Biostatistics, Karolinska Institute, Stockholm, Sweden.; Hamilton RJ; Dept. of Surgical Oncology, Princess Margaret Cancer Centre, Toronto, Ontario, Canada.; Dept. of Surgery (Urology), University of Toronto, Toronto, Ontario, Canada.; Lim J; Department of Surgery, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia.; Lu YJ; Centre for Cancer Biomarker and Biotherapeutics, Barts Cancer Institute, Queen Mary University of London, London, UK.; MacInnis RJ; Cancer Epidemiology Division, Cancer Council Victoria, East Melbourne, Victoria, Australia.; Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Parkville, Victoria, Australia.; Maier C; Zentrum für Humangenetik Tuebingen, Tuebingen, Germany.; Institut für Humangenetik, University of Ulm, Ulm, Germany.; Mucci LA; Department of Epidemiology, Harvard T. H. Chan School of Public Health, Boston, MA, USA.; Multigner L; Univ Rennes, Inserm, EHESP, Irset (Institut de recherche en santé, environnement et travail), Rennes, France.; Neuhausen SL; Department of Population Sciences, Beckman Research Institute of the City of Hope, Duarte, CA, USA.; Nielsen SF; Department of Clinical Biochemistry, Herlev and Gentofte Hospital, Copenhagen University Hospital, Copenhagen, Denmark.; Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.; Parent MÉ; Epidemiology and Biostatistics Unit, Centre Armand-Frappier Santé Biotechnologie, Institut national de la recherche scientifique, Laval, Quebec, Canada.; Department of Social and Preventive Medicine, School of Public Health, University of Montreal, Montreal, Quebec, Canada.; Park JY; Department of Cancer Epidemiology, Moffitt Cancer Center, Tampa, FL, USA.; Petrovics G; Uniformed Services University, Bethesda, MD, USA.; Center for Prostate Disease Research, Bethesda, MD, USA.; Plym A; Department of Medical Epidemiology and Biostatistics, Karolinska Institute, Stockholm, Sweden.; Department of Epidemiology, Harvard T. H. Chan School of Public Health, Boston, MA, USA.; Razack A; Department of Surgery, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia.; Rosenstein BS; Department of Radiation Oncology and Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.; Schleutker J; Institute of Biomedicine, University of Turku, Turku, Finland.; Department of Medical Genetics, Genomics, Laboratory Division, Turku University Hospital, Turku, Finland.; Sørensen KD; Department of Molecular Medicine, Aarhus University Hospital, Aarhus N, Denmark.; Department of Clinical Medicine, Aarhus University, Aarhus N, Denmark.; Townsend PA; 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.; The University of Surrey, Guildford, Surrey, UK.; Travis RC; Cancer Epidemiology Unit, Nuffield Department of Population Health, University of Oxford, Oxford, UK.; Vega A; Fundación Pública Galega Medicina Xenómica, Santiago de Compostela, Spain.; Instituto de Investigación Sanitaria de Santiago de Compostela, Santiago De Compostela, Spain.; Centro de Investigación en Red de Enfermedades Raras (CIBERER), Madrid, Spain.; West CML; Division of Cancer Sciences, University of Manchester, Manchester Academic Health Science Centre, Radiotherapy Related Research, The Christie Hospital NHS Foundation Trust, Manchester, UK.; Wiklund F; Department of Medical Epidemiology and Biostatistics, Karolinska Institute, Stockholm, Sweden.; Zheng W; Division of Epidemiology, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA.; Seibert TM; Department of Radiation Medicine and Applied Sciences, University of California San Diego, La Jolla, CA, USA. tseibert@health.ucsd.edu.; Research Service, VA San Diego Healthcare System, San Diego, CA, USA. tseibert@health.ucsd.edu.; Department of Radiology, University of California San Diego, La Jolla, CA, USA. tseibert@health.ucsd.edu.; Department of Bioengineering, University of California San Diego, La Jolla, CA, USA. tseibert@health.ucsd.edu.; Department of Urology, University of California San Diego, La Jolla, CA, USA. tseibert@health.ucsd.edu. |
| Corporate Authors: | Profile Steering Committee; IMPACT Study Steering Committee and Collaborators; PRACTICAL Consortium; VA Million Veteran Program |
| Source: | Nature cancer [Nat Cancer] 2026 Feb; Vol. 7 (2), pp. 352-367. Date of Electronic Publication: 2026 Jan 26. |
| Publication Type: | Journal Article |
| Language: | English |
| Journal Info: | Publisher: Nature Publishing Group Country of Publication: England NLM ID: 101761119 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 2662-1347 (Electronic) Linking ISSN: 26621347 NLM ISO Abbreviation: Nat Cancer Subsets: MEDLINE |
| Imprint Name(s): | Original Publication: [London] : Nature Publishing Group, [2020]- |
| MeSH Terms: | Prostatic Neoplasms*/genetics ; Prostatic Neoplasms*/diagnosis ; Early Detection of Cancer*/methods ; Genomics*/methods ; Precision Medicine*/methods; Male ; Humans ; Middle Aged ; Aged ; Risk Assessment ; Genetic Predisposition to Disease ; Risk Factors |
| 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 .; (© 2026. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.) |
| Competing Interests: | 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. |
| References: | Khan, S. S. et al. Development and validation of the American Heart Association’s PREVENT equations. Circulation 149, 430–449 (2024). (PMID: 3794708510.1161/CIRCULATIONAHA.123.067626); Huntley, C. et al. Utility of polygenic risk scores in UK cancer screening: a modelling analysis. Lancet Oncol. 24, 658–668 (2023). (PMID: 3717870810.1016/S1470-2045(23)00156-0); Barkas, F. et al. Advancements in risk stratification and management strategies in primary cardiovascular prevention. Atherosclerosis 395, 117579 (2024). (PMID: 3882484410.1016/j.atherosclerosis.2024.117579); Hao, L. et al. Development of a clinical polygenic risk score assay and reporting workflow. Nat. Med. 28, 1006–1013 (2022). (PMID: 35437332911713610.1038/s41591-022-01767-6); Lennon, N. J. et al. Selection, optimization and validation of ten chronic disease polygenic risk scores for clinical implementation in diverse US populations. Nat. Med. 30, 480–487 (2024). (PMID: 383743461087896810.1038/s41591-024-02796-z); Roundtable on Translating Genomic-Based Research for Health; Board on Health Sciences Policy; Institute of Medicine. Genomics-Enabled Learning Health Care Systems: Gathering and Using Genomic Information to Improve Patient Care and Research: Workshop Summary (National Academies Press, 2015).; Mucci, L. A. et al. Familial risk and heritability of cancer among twins in Nordic countries. JAMA 315, 68–76 (2016). (PMID: 26746459549811010.1001/jama.2015.17703); Hall, R., Bancroft, E., Pashayan, N., Kote-Jarai, Z. & Eeles, R. A. Genetics of prostate cancer: a review of latest evidence. J. Med. Genet. 61, 915–926 (2024). (PMID: 3913796310.1136/jmg-2024-109845); Grossman, D. C. et al. Screening for prostate cancer: US Preventive Services Task Force recommendation statement. JAMA 319, 1901–1913 (2018). (PMID: 2980101710.1001/jama.2018.3710); Garraway, I. P. et al. Prostate cancer foundation screening guidelines for black men in the United States. NEJM Evid. 3, EVIDoa2300289 (2024). (PMID: 3881516810.1056/EVIDoa2300289); Jackson, S. D. et al. Screening asymptomatic men for prostate cancer: a comparison of international guidelines on prostate-specific antigen testing. J. Med. Screen. 29, 268–271 (2022). (PMID: 36062629957442310.1177/09691413221119238); Loeb, S. et al. Overdiagnosis and overtreatment of prostate cancer. Eur. Urol. 65, 1046–1055 (2014). (PMID: 24439788411333810.1016/j.eururo.2013.12.062); Ilic, D. et al. Prostate cancer screening with prostate-specific antigen (PSA) test: a systematic review and meta-analysis. Brit. Med. J. 362, k3519 (2018). (PMID: 30185521628337010.1136/bmj.k3519); Hugosson, J. et al. A 16-yr follow-up of the European randomized study of screening for prostate cancer. Eur. Urol. 76, 43–51 (2019). (PMID: 30824296751369410.1016/j.eururo.2019.02.009); Paschen, U. et al. Assessment of prostate-specific antigen screening: an evidence-based report by the German Institute for Quality and Efficiency in Health Care. BJU Int 129, 280–289 (2022). (PMID: 3396133710.1111/bju.15444); Stone, B. V. et al. The association of county-level prostate-specific antigen screening with metastatic prostate cancer and prostate cancer mortality. Eur. Urol. Oncol. 7, 563–569 (2024). (PMID: 3815505910.1016/j.euo.2023.11.020); Iyer, H. S. et al. Access to prostate-specific antigen testing and mortality among men with prostate cancer. JAMA Netw. Open 7, e2414582 (2024). (PMID: 388332521115115610.1001/jamanetworkopen.2024.14582); Pagadala, M. S. et al. Polygenic risk of any, metastatic, and fatal prostate cancer in the Million Veteran Program. J. Natl Cancer Inst. 115, 190–199 (2023). (PMID: 36305680990596910.1093/jnci/djac199); Martin, R. M. et al. Prostate-specific antigen screening and 15-year prostate cancer mortality: a secondary analysis of the CAP randomized clinical trial. JAMA 331, 1460–1470 (2024). (PMID: 385811981099900410.1001/jama.2024.4011); National Comprehensive Cancer Network. NCCN Guidelines: Prostate Cancer Early Detection, version 2 (NCCN, 2024).; Wei, J. T. et al. Early detection of prostate cancer: AUA/SUO guideline part I: prostate cancer screening. J. Urol. 210, 46–53 (2023). (PMID: 370965821106075010.1097/JU.0000000000003491); Parker, C. et al. Prostate cancer: ESMO clinical practice guidelines for diagnosis, treatment and follow-up. Ann. Oncol. 31, 1119–1134 (2020). (PMID: 3259379810.1016/j.annonc.2020.06.011); Mottet, N. et al. EAU-EANM-ESTRO-ESUR-SIOG guidelines on prostate cancer-2020 update. part 1: screening, diagnosis, and local treatment with curative intent. Eur. Urol. 79, 243–262 (2021). (PMID: 3317272410.1016/j.eururo.2020.09.042); Huynh-Le, M.-P. et al. Age dependence of modern clinical risk groups for localized prostate cancer: a population-based study. Cancer 126, 1691–1699 (2020). (PMID: 31899813710348610.1002/cncr.32702); Hou, K. et al. Calibrated prediction intervals for polygenic scores across diverse contexts. Nat. Genet. 56, 1386–1396 (2024). (PMID: 388865871146519210.1038/s41588-024-01792-w); Moreno-Grau, S. et al. Polygenic risk score portability for common diseases across genetically diverse populations. Hum. Genomics 18, 93 (2024). (PMID: 392189081136785710.1186/s40246-024-00664-y); Roth, J. A., Gulati, R., Gore, J. L., Cooperberg, M. R. & Etzioni, R. Economic analysis of prostate-specific antigen screening and selective treatment strategies. JAMA Oncol. 2, 890–898 (2016). (PMID: 27010943494541410.1001/jamaoncol.2015.6275); Shoag, J. E., Nyame, Y. A., Gulati, R., Etzioni, R. & Hu, J. C. Reconsidering the trade-offs of prostate cancer screening. N. Engl. J. Med. 382, 2465–2468 (2020). (PMID: 32558473749120110.1056/NEJMsb2000250); Bergengren, O. et al. 2022 Update on prostate cancer epidemiology and risk factors-a systematic review. Eur. Urol. 84, 191–206 (2023). (PMID: 372023141085191510.1016/j.eururo.2023.04.021); Das, H. & Rodriguez, R. Health care disparities in urologic oncology: a systematic review. Urology 136, 9–18 (2020). (PMID: 3177054810.1016/j.urology.2019.09.058); Riviere, P. et al. Survival of African American and non-Hispanic white men with prostate cancer in an equal-access health care system. Cancer 126, 1683–1690 (2020). (PMID: 3198448210.1002/cncr.32666); Dess, R. T. et al. Association of black race with prostate cancer-specific and other-cause mortality. JAMA Oncol. 5, 975–983 (2019). (PMID: 31120534654711610.1001/jamaoncol.2019.0826); Huynh-Le, M.-P. et al. Prostate cancer risk stratification improvement across multiple ancestries with new polygenic hazard score. Prostate Cancer Prostatic Dis. 25, 755–761 (2022). (PMID: 35152271937223210.1038/s41391-022-00497-7); Karunamuni, R. A. et al. Performance of African-ancestry-specific polygenic hazard score varies according to local ancestry in 8q24. Prostate Cancer Prostatic Dis. 25, 229–237 (2022). (PMID: 3412780110.1038/s41391-021-00403-7); Wang, A. et al. Characterizing prostate cancer risk through multi-ancestry genome-wide discovery of 187 novel risk variants. Nat. Genet. 55, 2065–2074 (2023). (PMID: 379459031084147910.1038/s41588-023-01534-4); Kachuri, L. et al. Genetically adjusted PSA levels for prostate cancer screening. Nat. Med. 29, 1412–1423 (2023). (PMID: 372642061028756510.1038/s41591-023-02277-9); Huynh-Le, M.-P. et al. Polygenic hazard score is associated with prostate cancer in multi-ethnic populations. Nat. Commun. 12, 1236 (2021). (PMID: 33623038790261710.1038/s41467-021-21287-0); Mavaddat, N. et al. Incorporating alternative polygenic risk scores into the BOADICEA breast cancer risk prediction model. Cancer Epidemiol. Biomark. 32, 422–427 (2023). (PMID: 10.1158/1055-9965.EPI-22-0756); Yang, X. et al. Prospective validation of the BOADICEA multifactorial breast cancer risk prediction model in a large prospective cohort study. J. Med. Genet. 59, 1196–1205 (2022). (PMID: 36162852969182210.1136/jmg-2022-108806); Darst, B. F. et al. Combined effect of a polygenic risk score and rare genetic variants on prostate cancer risk. Eur. Urol. 80, 134–138 (2021). (PMID: 33941403828632910.1016/j.eururo.2021.04.013); Hughley, R. W. et al. Polygenic risk score modifies prostate cancer risk of pathogenic variants in men of African ancestry. Cancer Res. Commun. 3, 2544–2550 (2023). (PMID: 380149101072039010.1158/2767-9764.CRC-23-0022); Kang, J. H. et al. Polygenic risk and rare variant gene clustering enhance cancer risk stratification for breast and prostate cancers. Commun. Biol. 7, 1289 (2024). (PMID: 393848791146468810.1038/s42003-024-06995-9); Callender, T. et al. Polygenic risk-tailored screening for prostate cancer: a benefit–harm and cost-effectiveness modelling study. PLoS Med. 16, e1002998 (2019). (PMID: 31860675692463910.1371/journal.pmed.1002998); Callender, T., Emberton, M., Morris, S., Pharoah, P. D. P. & Pashayan, N. Benefit, harm, and cost-effectiveness associated with magnetic resonance imaging before biopsy in age-based and risk-stratified screening for prostate cancer. JAMA Netw. Open 4, e2037657 (2021). (PMID: 33704474795330910.1001/jamanetworkopen.2020.37657); Dixon, P., Keeney, E., Taylor, J., Wordsworth, S. & Martin, R. Can polygenic risk scores contribute to cost-effective cancer screening? A systematic review. Genet. Med. 24, 1604–1617 (2022). (PMID: 35575786761423510.1016/j.gim.2022.04.020); Jiang, S. et al. Cost-effectiveness of population-wide genomic screening for Lynch syndrome and polygenic risk scores to inform colorectal cancer screening. Genet. Med. 27, 101285 (2025). (PMID: 3936075210.1016/j.gim.2024.101285); Guzauskas, G. F. et al. Population genomic screening for three common hereditary conditions: a cost-effectiveness analysis. Ann. Intern. Med. 176, 585–595 (2023). (PMID: 371559861179182910.7326/M22-0846); Lacaze, P. et al. Combined population genomic screening for three high-risk conditions in Australia: a modelling study. eClinicalMedicine 66, 102297 (2023). (PMID: 381925931077216310.1016/j.eclinm.2023.102297); Wongvibulsin, S., Wu, K. C. & Zeger, S. L. Clinical risk prediction with random forests for survival, longitudinal, and multivariate (RF-SLAM) data analysis. BMC Med. Res. Methodol. 20, 1 (2019). (PMID: 31888507693775410.1186/s12874-019-0863-0); Loef, B. et al. Using random forest to identify longitudinal predictors of health in a 30-year cohort study. Sci. Rep. 12, 10372 (2022). (PMID: 35725920920952110.1038/s41598-022-14632-w); Gaziano, J. M. et al. Million Veteran Program: a mega-biobank to study genetic influences on health and disease. J. Clin. Epidemiol. 70, 214–223 (2016). (PMID: 2644128910.1016/j.jclinepi.2015.09.016); Bick, A. G. et al. Genomic data in the All of Us Research Program. Nature 627, 340–346 (2024). (PMID: 10.1038/s41586-023-06957-x); Hunter-Zinck, H. et al. Genotyping array design and data quality control in the Million Veteran Program. Am. J. Hum. Genet. 106, 535–548 (2020). (PMID: 32243820711855810.1016/j.ajhg.2020.03.004); Pagadala, M. S. et al. Agent orange exposure and prostate cancer risk in the Million Veteran Program. Acta Oncol. Stockh. Swed. 63, 373–378 (2024). (PMID: 10.2340/1651-226X.2024.25053); Alba, P. R. et al. Ascertainment of veterans with metastatic prostate cancer in electronic health records: demonstrating the case for natural language processing. JCO Clin. Cancer Inform. 5, 1005–1014 (2021). (PMID: 3457063010.1200/CCI.21.00030); Amos, C. I. et al. The OncoArray Consortium: a network for understanding the genetic architecture of common cancers. Cancer Epidemiol. Biomark. 26, 126–135 (2017). (PMID: 10.1158/1055-9965.EPI-16-0106); Eeles, R. A. et al. Identification of 23 new prostate cancer susceptibility loci using the iCOGS custom genotyping array. Nat. Genet. 45, 385–391. e1–2 (2013). (PMID: 23535732383279010.1038/ng.2560); Huynh-Le, M.-P. et al. Common genetic and clinical risk factors: association with fatal prostate cancer in the Cohort of Swedish Men. Prostate Cancer Prostatic Dis. 24, 845–851 (2021). (PMID: 33723363838733210.1038/s41391-021-00341-4); Discacciati, A. et al. Coffee consumption and risk of localized, advanced and fatal prostate cancer: a population-based prospective study. Ann. Oncol. 24, 1912–1918 (2013). (PMID: 2350882310.1093/annonc/mdt105); Hamdy, F. C. et al. Fifteen-year outcomes after monitoring, surgery, or radiotherapy for prostate cancer. N. Engl. J. Med. 388, 1547–1558 (2023). (PMID: 3691253810.1056/NEJMoa2214122); Gudmundsson, J. et al. Genome-wide associations for benign prostatic hyperplasia reveal a genetic correlation with serum levels of PSA. Nat. Commun. 9, 4568 (2018). (PMID: 30410027622456310.1038/s41467-018-06920-9); Chen, F. et al. Evidence of novel susceptibility variants for prostate cancer and a multiancestry polygenic risk score associated with aggressive disease in men of African ancestry. Eur. Urol. 84, 13–21 (2023). (PMID: 368721331042481210.1016/j.eururo.2023.01.022); Karunamuni, R. A. et al. Additional SNPs improve risk stratification of a polygenic hazard score for prostate cancer. Prostate Cancer Prostatic Dis. 24, 532–541 (2021). (PMID: 33420416815799310.1038/s41391-020-00311-2); Tibshirani, R. Regression shrinkage and selection via the LASSO. J. R. Stat. Soc. Ser. B Methodol. 58, 267–288 (1996). (PMID: 10.1111/j.2517-6161.1996.tb02080.x); Tibshirani, R. The LASSO method for variable selection in the Cox model. Stat. Med. 16, 385–395 (1997). (PMID: 904452810.1002/(SICI)1097-0258(19970228)16:43.0.CO;2-3); Li, Y. et al. FastPop: a rapid principal component derived method to infer intercontinental ancestry using genetic data. BMC Bioinform. 17, 122 (2016). (PMID: 10.1186/s12859-016-0965-1); Auton, A. et al. A global reference for human genetic variation. Nature 526, 68–74 (2015). (PMID: 26432245475047810.1038/nature15393); Friedman, J. H., Hastie, T. & Tibshirani, R. Regularization paths for generalized linear models via coordinate descent. J. Stat. Softw. 33, 1–22 (2010). (PMID: 20808728292988010.18637/jss.v033.i01); Wendt, F. R. et al. Modeling the longitudinal changes of ancestry diversity in the Million Veteran Program. Hum. Genomics 17, 46 (2023). (PMID: 372689961023911110.1186/s40246-023-00487-3); Huynh-Le, M.-P. et al. A genetic risk score to personalize prostate cancer screening, applied to population data. Cancer Epidemiol. Biomarkers Prev. 29, 1731–1738 (2020). (PMID: 32581112748362710.1158/1055-9965.EPI-19-1527); Seibert, T. M. et al. Polygenic hazard score to guide screening for aggressive prostate cancer: development and validation in large scale cohorts. Brit. Med. J. 360, j5757 (2018). (PMID: 29321194575909110.1136/bmj.j5757); Karunamuni, R. A. et al. African-specific improvement of a polygenic hazard score for age at diagnosis of prostate cancer. Int. J. Cancer 148, 99–105 (2021). (PMID: 3293042510.1002/ijc.33282); Yeh, H. C., Duncan, B. B., Schmidt, M. I., Wang, N. Y. & Brancati, F. L. Smoking, smoking cessation, and risk for type 2 diabetes mellitus: a cohort study. Ann. Intern. Med. 152, 10–17 (2010). (PMID: 20048267572625510.7326/0003-4819-152-1-201001050-00005); Brentnall, A. R., Cuzick, J., Buist, D. S. M. & Bowles, E. J. A. Long-term accuracy of breast cancer risk assessment combining classic risk factors and breast density. JAMA Oncol. 4, e180174 (2018). (PMID: 29621362614301610.1001/jamaoncol.2018.0174); Wang, T. J. et al. Plasma natriuretic peptide levels and the risk of cardiovascular events and death. N. Engl. J. Med. 350, 655–663 (2004). (PMID: 1496074210.1056/NEJMoa031994); DeFelice, M. et al. Blended genome exome (BGE) as a cost efficient alternative to deep whole genomes or arrays. Preprint at bioRxiv https://doi.org/10.1101/2024.04.03.587209 (2024).; Rubinacci, S., Hofmeister, R. J., Sousa da Mota, B. & Delaneau, O. Imputation of low-coverage sequencing data from 150,119 UK Biobank genomes. Nat. Genet. 55, 1088–1090 (2023). (PMID: 373862501033592710.1038/s41588-023-01438-3); Tiao, G. & Goodrich, J. gnomAD v3.1 new content, methods, annotations, and data availability. https://gnomad.broadinstitute.org/news/2020-10-gnomad-v3-1-new-content-methods-annotations-and-data-availability/#the-gnomad-hgdp-and-1000-genomes-callset (2023).; Babadi, M. et al. GATK-gCNV enables the discovery of rare copy number variants from exome sequencing data. Nat. Genet. 55, 1589–1597 (2023). (PMID: 376049631090401410.1038/s41588-023-01449-0); National Comprehensive Cancer Network. NCCN Guidelines: Genetic/familial High-risk Assessment: Colorectal, version 2 (NCCN, 2023).; National Comprehensive Cancer Network. NCCN Guidelines: Genetic/familial High-risk Assessment: Breast, Ovarian, And Pancreatic, version 3 (NCCN, 2024).; Farmer, G. D., Gray, H., Chandratillake, G., Raymond, F. L. & Freeman, A. L. J. Recommendations for designing genetic test reports to be understood by patients and non-specialists. Eur. J. Hum. Genet. 28, 885–895 (2020). (PMID: 32024982731672210.1038/s41431-020-0579-y) |
| Grant Information: | I01 CX002635 United States CX CSRD VA; PRYES211091VEGA Albert Einstein Cancer Center (AECC); I01CX002635 U.S. Department of Veterans Affairs (Department of Veterans Affairs) |
| Molecular Sequence: | ClinicalTrials.gov NCT05926102 |
| Entry Date(s): | Date Created: 20260126 Date Completed: 20260307 Latest Revision: 20260519 |
| Update Code: | 20260519 |
| PubMed Central ID: | PMC13181739 |
| DOI: | 10.1038/s43018-025-01103-0 |
| PMID: | 41588240 |
| Database: | MEDLINE |
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