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Evaluating approaches for constructing polygenic risk scores for prostate cancer in men of African and European ancestry

Darst BF 1 , Shen J 2 , Madduri RK 3 , Rodriguez AA 3 , Xiao Y 3 , Sheng X 2 Show all authors , Saunders EJ 4 , Dadaev T 4 , Brook MN 4 , Hoffmann TJ 5 , Muir K 6 , Wan P 2 , Le Marchand L 7 , Wilkens L 7 , Wang Y 8 , Schleutker J 9 , MacInnis RJ 10 , Cybulski C 11 , Neal DE 12 , Nordestgaard BG 13 , Nielsen SF 13 , Batra J 14 , Clements JA 14 , Cancer BioResource AP 15 , Grönberg H 16 , Pashayan N 17 , Travis RC 18 , Park JY 19 , Albanes D 20 , Weinstein S 20 , Mucci LA 21 , Hunter DJ 22 , Penney KL 23 , Tangen CM 24 , Hamilton RJ 25 , Parent MÉ 26 , Stanford JL 27 , Koutros S 20 , Wolk A 28 , Sørensen KD 29 , Blot WJ 30 , Yeboah ED 31 , Mensah JE 31 , Lu YJ 32 , Schaid DJ 33 , Thibodeau SN 34 , West CM 35 , Maier C 36 , Kibel AS 37 , Cancel-Tassin G 38 , Menegaux F 39 , John EM 40 , Grindedal EM 41 , Khaw KT 42 , Ingles SA 43 , Vega A 44 , Rosenstein BS 45 , Teixeira MR 46 , NC-LA PCaP Investigators 47 , Kogevinas M 48 , Cannon-Albright L 49 , Huff C 50 , Multigner L 51 , Kaneva R 52 , Leach RJ 53 , Brenner H 54 , Hsing AW 55 , Kittles RA 56 , Murphy AB 57 , Logothetis CJ 58 , Neuhausen SL 59 , Isaacs WB 60 , Nemesure B 61 , Hennis AJ 62 , Carpten J 63 , Pandha H 64 , De Ruyck K 65 , Xu J 66 , Razack A 67 , Teo SH 68 , Canary PASS Investigators 69 , Newcomb LF 69 , Fowke JH 70 , Neslund-Dudas C 71 , Rybicki BA 71 , Gamulin M 72 , Usmani N 73 , Claessens F 74 , Gago-Dominguez M 75 , Castelao JE 76 , Townsend PA 77 , Crawford DC 78 , Petrovics G 79 , Casey G 80 , Roobol MJ 81 , Hu JF 82 , Berndt SI 20 , Van Den Eeden SK 83 , Easton DF 84 , Chanock SJ 20 , Cook MB 20 , Wiklund F 16 , Witte JS 85 , Eeles RA 86 , Kote-Jarai Z 87 , Watya S 88 , Gaziano JM 89 , Justice AC 90 , Conti DV 2 , Haiman CA 2

Affiliations 

  • 1 Center for Genetic Epidemiology, Department of Population and Public Health Sciences, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA; Division of Public Health Sciences, Fred Hutchinson Cancer Center, Seattle, WA, USA. Electronic address: bdarst@usc.edu
  • 2 Center for Genetic Epidemiology, Department of Population and Public Health Sciences, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
  • 3 Argonne National Laboratory, Lemont, IL, USA
  • 4 The Institute of Cancer Research, London, UK
  • 5 Department of Epidemiology and Biostatistics, University of California, San Francisco, San Francisco, CA, USA
  • 6 Division of Population Health, Health Services Research and Primary Care, School of Health Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK
  • 7 Epidemiology Program, University of Hawaii Cancer Center, Honolulu, HI, USA
  • 8 Department of Population Science, American Cancer Society, Atlanta, GA, USA
  • 9 Institute of Biomedicine, University of Turku, Turku, Finland
  • 10 Cancer Epidemiology Division, Cancer Council Victoria, Melbourne, VIC, Australia; Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Carlton, VIC, Australia
  • 11 International Hereditary Cancer Center, Department of Genetics and Pathology, Pomeranian Medical University, Szczecin, Poland
  • 12 Nuffield Department of Surgical Sciences, University of Oxford, John Radcliffe Hospital, Headington, Oxford, UK; University of Cambridge, Department of Oncology, Addenbrooke's Hospital, Cambridge, UK; Cancer Research UK, Cambridge Research Institute, Li Ka Shing Centre, Cambridge, UK
  • 13 Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark; Department of Clinical Biochemistry, Herlev and Gentofte Hospital, Copenhagen University Hospital, Herlev, Denmark
  • 14 Australian Prostate Cancer Research Centre-Qld, Institute of Health and Biomedical Innovation and School of Biomedical Sciences, Queensland University of Technology, Brisbane, QLD, Australia; Translational Research Institute, Brisbane, QLD, Australia
  • 15 Translational Research Institute, Brisbane, QLD, Australia; Australian Prostate Cancer Research Centre-Qld, Queensland University of Technology, Brisbane, QLD, Australia; Prostate Cancer Research Program, Monash University, Melbourne, VIC, Australia; Dame Roma Mitchell Cancer Centre, University of Adelaide, Adelaide, SA, Australia; Chris O'Brien Lifehouse and The Kinghorn Cancer Centre, Sydney, NSW, Australia
  • 16 Department of Medical Epidemiology and Biostatistics, Karolinska Institute, Stockholm, Sweden
  • 17 University College London, Department of Applied Health Research, London, UK; Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Strangeways Research Laboratory, Cambridge, UK
  • 18 Cancer Epidemiology Unit, Nuffield Department of Population Health, University of Oxford, Oxford, UK
  • 19 Department of Cancer Epidemiology, Moffitt Cancer Center, Tampa, FL, USA
  • 20 Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, Bethesda, MD, USA
  • 21 Department of Epidemiology, Harvard T. H. Chan School of Public Health, Boston, MA, USA
  • 22 Nuffield Department of Population Health, University of Oxford, Oxford, UK
  • 23 Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital/Harvard Medical School, Boston, MA, USA
  • 24 SWOG Statistical Center, Fred Hutchinson Cancer Center, Seattle, WA, USA
  • 25 Department of Surgical Oncology, Princess Margaret Cancer Centre, Toronto, ON, Canada; Department of Surgery (Urology), University of Toronto, Toronto, ON, Canada
  • 26 Epidemiology and Biostatistics Unit, Centre Armand-Frappier Santé Biotechnologie, Institut national de la recherche scientifique, Laval, QC, Canada; Department of Social and Preventive Medicine, School of Public Health, University of Montreal, Montreal, QC, Canada
  • 27 Division of Public Health Sciences, Fred Hutchinson Cancer Center, Seattle, WA, USA; Department of Epidemiology, School of Public Health, University of Washington, Seattle, WA, USA
  • 28 Division of Nutritional Epidemiology, Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden; Department of Surgical Sciences, Uppsala University, Uppsala, Sweden
  • 29 Department of Molecular Medicine, Aarhus University Hospital, Aarhus N, Denmark; Department of Clinical Medicine, Aarhus University, Aarhus N, Denmark
  • 30 Division of Epidemiology, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA; International Epidemiology Institute, Rockville, MD, USA
  • 31 University of Ghana Medical School, Accra, Ghana; Korle Bu Teaching Hospital, Accra, Ghana
  • 32 Centre for Biomarkers and Biotherapeutics, Barts Cancer Institute, Queen Mary University of London, John Vane Science Centre, London, UK
  • 33 Department of Quantitative Health Sciences, Mayo Clinic, Rochester, MN, USA
  • 34 Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA
  • 35 Division of Cancer Sciences, University of Manchester, Manchester Academic Health Science Centre, Radiotherapy Related Research, The Christie Hospital NHS Foundation Trust, Manchester, UK
  • 36 Humangenetik Tuebingen, Tuebingen, Germany
  • 37 Division of Urologic Surgery, Brigham and Women's Hospital, Boston, MA, USA
  • 38 CeRePP, Tenon Hospital, Paris, France; Sorbonne Universite, GRC 5 Predictive Onco-urology, Tenon Hospital, Paris, France
  • 39 "Exposome and Heredity", CESP (UMR 1018), Faculté de Médecine, Université Paris-Saclay, Inserm, Gustave Roussy, Villejuif, France
  • 40 Department of Epidemiology & Population Health, Stanford University School of Medicine, Stanford, CA, USA; Department of Medicine, Division of Oncology, Stanford University School of Medicine, Stanford, CA, USA; Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA, USA
  • 41 Department of Medical Genetics, Oslo University Hospital, Oslo, Norway
  • 42 Clinical Gerontology Unit, University of Cambridge, Cambridge, UK
  • 43 Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
  • 44 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
  • 45 Department of Radiation Oncology and Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA
  • 46 Department of Genetics, Portuguese Oncology Institute of Porto (IPO-Porto), Porto, Portugal; Biomedical Sciences Institute (ICBAS), University of Porto, Porto, Portugal
  • 47 Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA; Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA; Epidemiology Branch, National Institute of Environmental Health Sciences, Research Triangle Park, NC, USA
  • 48 ISGlobal, Barcelona, Spain; IMIM (Hospital del Mar Medical Research Institute), Barcelona, Spain; Universitat Pompeu Fabra (UPF), Barcelona, Spain; CIBER Epidemiología y Salud Pública (CIBERESP), Madrid, Spain
  • 49 Division of Epidemiology, Department of Internal Medicine, University of Utah School of Medicine, Salt Lake City, UT, USA; George E. Wahlen Department of Veterans Affairs Medical Center, Salt Lake City, UT, USA
  • 50 Department of Epidemiology, The University of Texas M. D. Anderson Cancer Center, Houston, TX, USA
  • 51 University Rennes, Inserm, EHESP, Irset (Institut de recherche en santé, environnement et travail), Rennes, France
  • 52 Molecular Medicine Center, Department of Medical Chemistry and Biochemistry, Medical University of Sofia, Sofia, Bulgaria
  • 53 Department of Urology, Cancer Therapy and Research Center, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA
  • 54 Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany; German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany; Division of Preventive Oncology, German Cancer Research Center (DKFZ) and National Center for Tumor Diseases (NCT), Heidelberg, Germany
  • 55 Department of Medicine and Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA, USA
  • 56 Division of Health Equities, Department of Population Sciences, City of Hope, Duarte, CA, USA
  • 57 Department of Urology, Northwestern University, Chicago, IL, USA
  • 58 The University of Texas M. D. Anderson Cancer Center, Department of Genitourinary Medical Oncology, Houston, TX, USA
  • 59 Department of Population Sciences, Beckman Research Institute of the City of Hope, Duarte, CA, USA
  • 60 James Buchanan Brady Urological Institute, Johns Hopkins Hospital and Medical Institution, Baltimore, MD, USA
  • 61 Department of Family, Population and Preventive Medicine, Stony Brook University, Stony Brook, NY, USA
  • 62 Department of Family, Population and Preventive Medicine, Stony Brook University, Stony Brook, NY, USA; Chronic Disease Research Centre and Faculty of Medical Sciences, University of the West Indies, Bridgetown, Barbados
  • 63 Department of Translational Genomics, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
  • 64 Faculty of Health and Medical Sciences, The University of Surrey, Guildford, Surrey, UK
  • 65 Ghent University, Faculty of Medicine and Health Sciences, Basic Medical Sciences, Gent, Belgium
  • 66 Program for Personalized Cancer Care and Department of Surgery, NorthShore University HealthSystem, Evanston, IL, USA
  • 67 Department of Surgery, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia
  • 68 Cancer Research Malaysia (CRM), Outpatient Centre, Subang Jaya Medical Centre, Subang Jaya, Selangor, Malaysia
  • 69 Division of Public Health Sciences, Fred Hutchinson Cancer Center, Seattle, WA, USA; Department of Urology, University of Washington, Seattle, WA, USA
  • 70 Division of Epidemiology, Department of Preventive Medicine, The University of Tennessee Health Science Center, Memphis, TN, USA
  • 71 Department of Public Health Sciences, Henry Ford Hospital, Detroit, MI, USA
  • 72 Department of Oncology, University Hospital Centre Zagreb, University of Zagreb School of Medicine, Zagreb, Croatia
  • 73 Department of Oncology, Cross Cancer Institute, University of Alberta, Edmonton, AB, Canada; Division of Radiation Oncology, Cross Cancer Institute, Edmonton, AB, Canada
  • 74 Molecular Endocrinology Laboratory, Department of Cellular and Molecular Medicine, Leuven, Belgium
  • 75 Genomic Medicine Group, Galician Foundation of Genomic Medicine, Instituto de Investigacion Sanitaria de Santiago de Compostela (IDIS), Complejo Hospitalario Universitario de Santiago, Servicio Galego de Saúde, SERGAS, Santiago de Compostela, Spain; University of California San Diego, Moores Cancer Center, La Jolla, CA, USA
  • 76 Genetic Oncology Unit, CHUVI Hospital, Complexo Hospitalario Universitario de Vigo, Instituto de Investigación Biomédica Galicia Sur (IISGS), Vigo (Pontevedra), Spain
  • 77 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
  • 78 Case Western Reserve University, Department of Population and Quantitative Health Sciences, Cleveland Institute for Computational Biology, Cleveland, OH, USA
  • 79 Center for Prostate Disease Research, Uniformed Services University, Bethesda, MD, USA
  • 80 Center for Public Health Genomics, Department of Public Health Sciences, University of Virginia, Charlottesville, VA, USA
  • 81 109 Department of Urology, Erasmus University Medical Center, Cancer Institute, Rotterdam, the Netherlands
  • 82 The University of Miami School of Medicine, Sylvester Comprehensive Cancer Center, Miami, FL, USA
  • 83 Division of Research, Kaiser Permanente, Northern California, Oakland, CA, USA; Department of Urology, University of California San Francisco, San Francisco, CA, USA
  • 84 Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Strangeways Research Laboratory, Cambridge, UK
  • 85 Department of Epidemiology and Population Health, Department of Biomedical Data Science, Stanford Cancer Institute, Stanford, CA, USA
  • 86 The Institute of Cancer Research, Sutton, London, UK; Royal Marsden NHS Foundation Trust, London, UK
  • 87 The Institute of Cancer Research, Sutton, London, UK
  • 88 School of Public Health, Makerere University College of Health Sciences, Kampala, Uganda
  • 89 VA Boston Healthcare System, Boston, MA, USA; Department of Medicine, Harvard Medical School, Boston, MA, USA; Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA
  • 90 VA Connecticut Healthcare System, West Haven, CT, USA; Yale School of Medicine, New Haven, CT, USA
Am J Hum Genet, 2023 Jul 06;110(7):1200-1206.
PMID: 37311464 DOI: 10.1016/j.ajhg.2023.05.010

Abstract

Genome-wide polygenic risk scores (GW-PRSs) have been reported to have better predictive ability than PRSs based on genome-wide significance thresholds across numerous traits. We compared the predictive ability of several GW-PRS approaches to a recently developed PRS of 269 established prostate cancer-risk variants from multi-ancestry GWASs and fine-mapping studies (PRS269). GW-PRS models were trained with a large and diverse prostate cancer GWAS of 107,247 cases and 127,006 controls that we previously used to develop the multi-ancestry PRS269. Resulting models were independently tested in 1,586 cases and 1,047 controls of African ancestry from the California Uganda Study and 8,046 cases and 191,825 controls of European ancestry from the UK Biobank and further validated in 13,643 cases and 210,214 controls of European ancestry and 6,353 cases and 53,362 controls of African ancestry from the Million Veteran Program. In the testing data, the best performing GW-PRS approach had AUCs of 0.656 (95% CI = 0.635-0.677) in African and 0.844 (95% CI = 0.840-0.848) in European ancestry men and corresponding prostate cancer ORs of 1.83 (95% CI = 1.67-2.00) and 2.19 (95% CI = 2.14-2.25), respectively, for each SD unit increase in the GW-PRS. Compared to the GW-PRS, in African and European ancestry men, the PRS269 had larger or similar AUCs (AUC = 0.679, 95% CI = 0.659-0.700 and AUC = 0.845, 95% CI = 0.841-0.849, respectively) and comparable prostate cancer ORs (OR = 2.05, 95% CI = 1.87-2.26 and OR = 2.21, 95% CI = 2.16-2.26, respectively). Findings were similar in the validation studies. This investigation suggests that current GW-PRS approaches may not improve the ability to predict prostate cancer risk compared to the PRS269 developed from multi-ancestry GWASs and fine-mapping.

* Title and MeSH Headings from MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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