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

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
  • 2 Argonne National Laboratory, Lemont, IL, USA
  • 3 The Institute of Cancer Research, London, UK
  • 4 Department of Epidemiology and Biostatistics, University of California, San Francisco, CA, USA
  • 5 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
  • 6 Epidemiology Program, University of Hawaii Cancer Center, Honolulu, HI, USA
  • 7 Department of Population Science, American Cancer Society, Atlanta, GA, USA
  • 8 Institute of Biomedicine, University of Turku, Finland
  • 9 Cancer Epidemiology Division, Cancer Council Victoria, Melbourne, Australia
  • 10 International Hereditary Cancer Center, Department of Genetics and Pathology, Pomeranian Medical University, Szczecin, Poland
  • 11 Nuffield Department of Surgical Sciences, University of Oxford, John Radcliffe Hospital, Headington, Oxford, UK
  • 12 Faculty of Health and Medical Sciences, University of Copenhagen, Denmark
  • 13 Australian Prostate Cancer Research Centre-Qld, Institute of Health and Biomedical Innovation and School of Biomedical Sciences, Queensland University of Technology, Brisbane, Australia
  • 14 Department of Medical Epidemiology and Biostatistics, Karolinska Institute, Stockholm, Sweden
  • 15 University College London, Department of Applied Health Research, London, UK
  • 16 Cancer Epidemiology Unit, Nuffield Department of Population Health, University of Oxford, Oxford, UK
  • 17 Department of Cancer Epidemiology, Moffitt Cancer Center, Tampa, FL, USA
  • 18 Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, Bethesda, MD, USA
  • 19 Department of Epidemiology, Harvard T. H. Chan School of Public Health, Boston, MA, USA
  • 20 Nuffield Department of Population Health, University of Oxford, Oxford, UK
  • 21 Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital/Harvard Medical School, Boston, MA, USA
  • 22 SWOG Statistical Center, Fred Hutchinson Cancer Center, Seattle, WA, USA
  • 23 Dept. of Surgical Oncology, Princess Margaret Cancer Centre, Toronto, Canada
  • 24 Epidemiology and Biostatistics Unit, Centre Armand-Frappier Santé Biotechnologie, Institut national de la recherche scientifique, Laval, QC, Canada
  • 25 Division of Public Health Sciences, Fred Hutchinson Cancer Center, Seattle, WA, USA
  • 26 Division of Nutritional Epidemiology, Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden
  • 27 Department of Molecular Medicine, Aarhus University Hospital, Aarhus N, Denmark
  • 28 Division of Epidemiology, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA
  • 29 University of Ghana Medical School, Accra, Ghana
  • 30 Centre for Biomarkers and Biotherapeutics, Barts Cancer Institute, Queen Mary University of London, John Vane Science Centre, London, UK
  • 31 Department of Quantitative Health Sciences, Mayo Clinic, Rochester, MN, USA
  • 32 Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA
  • 33 Division of Cancer Sciences, University of Manchester, Manchester Academic Health Science Centre, Radiotherapy Related Research, The Christie Hospital NHS Foundation Trust, Manchester, UK
  • 34 Humangenetik Tuebingen, Tuebingen, Germany
  • 35 Division of Urologic Surgery, Brigham and Womens Hospital, Boston, MA, USA
  • 36 CeRePP, Tenon Hospital, Paris, France
  • 37 "Exposome and Heredity", CESP (UMR 1018), Faculté de Médecine, Université Paris-Saclay, Inserm, Gustave Roussy, Villejuif, France
  • 38 Department of Epidemiology & Population Health, Stanford University School of Medicine, Stanford, CA, USA
  • 39 Department of Medical Genetics, Oslo University Hospital, Oslo, Norway
  • 40 Clinical Gerontology Unit, University of Cambridge, Cambridge, UK
  • 41 Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
  • 42 Fundación Pública Galega Medicina Xenómica, Santiago De Compostela, Spain
  • 43 Department of Radiation Oncology and Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA
  • 44 Department of Genetics, Portuguese Oncology Institute of Porto (IPO-Porto), Porto, Portugal
  • 45 ISGlobal, Barcelona, Spain
  • 46 Division of Epidemiology, Department of Internal Medicine, University of Utah School of Medicine, Salt Lake City, Utah, USA
  • 47 Department of Epidemiology, The University of Texas M. D. Anderson Cancer Center, Houston, TX, USA
  • 48 Univ Rennes, Inserm, EHESP, Irset (Institut de recherche en santé, environnement et travail), Rennes, France
  • 49 Molecular Medicine Center, Department of Medical Chemistry and Biochemistry, Medical University of Sofia, Sofia, Bulgaria
  • 50 Department of Urology, Cancer Therapy and Research Center, University of Texas Health Science Center at San Antonio, San Antonio Texas, USA
  • 51 Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany
  • 52 Department of Medicine and Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA, USA
  • 53 Division of Health Equities, Department of Population Sciences, City of Hope, Duarte, CA, USA
  • 54 Department of Urology, Northwestern University, Chicago, IL, USA
  • 55 The University of Texas M. D. Anderson Cancer Center, Department of Genitourinary Medical Oncology, Houston, TX, USA
  • 56 Department of Population Sciences, Beckman Research Institute of the City of Hope, Duarte, CA, USA
  • 57 James Buchanan Brady Urological Institute, Johns Hopkins Hospital and Medical Institution, Baltimore, MD, USA
  • 58 Department of Family, Population and Preventive Medicine, Stony Brook University, Stony Brook, NY, USA
  • 59 Department of Translational Genomics, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
  • 60 Faculty of Health and Medical Sciences, The University of Surrey, Guildford, Surrey, UK
  • 61 Ghent University, Faculty of Medicine and Health Sciences, Basic Medical Sciences, Gent, Belgium
  • 62 Program for Personalized Cancer Care and Department of Surgery, NorthShore University HealthSystem, Evanston, IL, USA
  • 63 Department of Surgery, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia
  • 64 Cancer Research Malaysia (CRM), Outpatient Centre, Subang Jaya Medical Centre, Subang Jaya, Selangor, Malaysia
  • 65 Division of Epidemiology, Department of Preventive Medicine, The University of Tennessee Health Science Center, TN, USA
  • 66 Department of Public Health Sciences, Henry Ford Hospital, Detroit, MI, USA
  • 67 Department of Oncology, University Hospital Centre Zagreb, University of Zagreb School of Medicine, Zagreb, Croatia
  • 68 Department of Oncology, Cross Cancer Institute, University of Alberta, Edmonton, Alberta, Canada
  • 69 Molecular Endocrinology Laboratory, Department of Cellular and Molecular Medicine, Leuven, Belgium
  • 70 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
  • 71 Genetic Oncology Unit, CHUVI Hospital, Complexo Hospitalario Universitario de Vigo, Instituto de Investigación Biomédica Galicia Sur (IISGS), Vigo (Pontevedra), Spain
  • 72 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, UK
  • 73 Case Western Reserve University, Department of Population and Quantitative Health Sciences, Cleveland Institute for Computational Biology, Cleveland, OH, USA
  • 74 Center for Prostate Disease Research, Uniformed Services University, Bethesda, MD, USA
  • 75 Center for Public Health Genomics, Department of Public Health Sciences, University of Virginia, Charlottesville, VA, USA
  • 76 109 Department of Urology, Erasmus University Medical Center, Cancer Institute, Rotterdam, The Netherlands
  • 77 The University of Miami School of Medicine, Sylvester Comprehensive Cancer Center, Miami, FL, USA
  • 78 Division of Research, Kaiser Permanente, Northern California, Oakland, CA, USA
  • 79 Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Strangeways Research Laboratory, Cambridge, UK
  • 80 Department of Epidemiology and Population Health, Department of Biomedical Data Science, Stanford Cancer Institute, Stanford, CA, USA
  • 81 The Institute of Cancer Research, Sutton, London, UK
  • 82 School of Public Health, Makerere University College of Health Sciences, Kampala Uganda
  • 83 VA Boston Healthcare System, Boston, MA, USA
  • 84 VA Connecticut Healthcare System, West Haven, CT, USA
medRxiv, 2023 May 15.
PMID: 37292833 DOI: 10.1101/2023.05.12.23289860

Abstract

Genome-wide polygenic risk scores (GW-PRS) have been reported to have better predictive ability than PRS 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 GWAS and fine-mapping studies (PRS 269 ). GW-PRS models were trained using a large and diverse prostate cancer GWAS of 107,247 cases and 127,006 controls used to develop the multi-ancestry PRS 269 . 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 OR 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. However, compared to the GW-PRS, in African and European ancestry men, the PRS 269 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 OR (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 data. This investigation suggests that current GW-PRS approaches may not improve the ability to predict prostate cancer risk compared to the multi-ancestry PRS 269 constructed with fine-mapping.

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

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