Prostate cancer risk stratification improvement across multiple ancestries with new polygenic hazard score

Minh-Phuong Huynh-Le^{1

2

3}, Roshan Karunamuni^{2

3}, Chun Chieh Fan³, Lui Asona², Wesley K Thompson^{4

5}, Maria Elena Martinez⁶, Rosalind A Eeles^{7

8}, Zsofia Kote-Jarai⁷, Kenneth R Muir⁹, Artitaya Lophatananon⁹, Johanna Schleutker^{10

11}, Nora Pashayan^{12

13}, Jyotsna Batra^{14

15}, Henrik Grönberg¹⁶, David E Neal^{17

18

19}, Børge G Nordestgaard^{20

21}, Catherine M Tangen²², Robert J MacInnis^{23

24}, Alicja Wolk²⁵, Demetrius Albanes²⁶, Christopher A Haiman²⁷, Ruth C Travis²⁸, William J Blot^{29

30}, Janet L Stanford^{31

32}, Lorelei A Mucci³³, Catharine M L West³⁴, Sune F Nielsen^{20

21}, Adam S Kibel³⁵, Olivier Cussenot^{36

37}, Sonja I Berndt²⁶, Stella Koutros²⁶, Karina Dalsgaard Sørensen^{38

39}, Cezary Cybulski⁴⁰, Eli Marie Grindedal⁴¹, Florence Menegaux⁴², Jong Y Park⁴³, Sue A Ingles⁴⁴, Christiane Maier⁴⁵, Robert J Hamilton^{46

47}, Barry S Rosenstein⁴⁸, Yong-Jie Lu⁴⁹, Stephen Watya⁵⁰, Ana Vega^{51

52

53}, Manolis Kogevinas^{54

55

56}, Fredrik Wiklund¹⁶, Kathryn L Penney⁵⁷, Chad D Huff⁵⁸, Manuel R Teixeira^{59

60

61}, Luc Multigner⁶², Robin J Leach⁶³, Hermann Brenner^{64

65

66}, Esther M John⁶⁷, Radka Kaneva⁶⁸, Christopher J Logothetis⁶⁹, Susan L Neuhausen⁷⁰, Kim De Ruyck⁷¹, Piet Ost⁷², Azad Razack⁷³, Lisa F Newcomb^{31

74}, Jay H Fowke⁷⁵, Marija Gamulin⁷⁶, Aswin Abraham⁷⁷, Frank Claessens⁷⁸, Jose Esteban Castelao⁷⁹, Paul A Townsend^{80

81}, Dana C Crawford⁸², Gyorgy Petrovics^{83

84}, Ron H N van Schaik⁸⁵, Marie-Élise Parent^{86

87}, Jennifer J Hu⁸⁸, Wei Zheng²⁹; UKGPCS collaborators; APCB (Australian Prostate Cancer BioResource); NC-LA PCaP Investigators; IMPACT Study Steering Committee and Collaborators; Canary PASS Investigators; Profile Study Steering Committee; PRACTICAL Consortium; Ian G Mills⁸⁹, Ole A Andreassen⁹⁰, Anders M Dale^{3

90

91}, Tyler M Seibert^{92

93

94

95

96}

Affiliations

¹ Radiation Oncology, George Washington University, Washington, DC, USA.
² Department of Radiation Medicine and Applied Sciences, University of California San Diego, La Jolla, CA, USA.
³ Center for Multimodal Imaging and Genetics, University of California San Diego, La Jolla, CA, USA.
⁴ Division of Biostatistics and Halicioğlu Data Science Institute, University of California San Diego, La Jolla, CA, USA.
⁵ Department of Family Medicine and Public Health, University of California San Diego, La Jolla, CA, USA.
⁶ University of California San Diego, Moores Cancer Center, Herbert Wertheim School of Public Health and Human Longevity Science, University of California San Diego, La Jolla, CA, 92093-0012, USA.
⁷ The Institute of Cancer Research, London, SM2 5NG, UK.
⁸ Royal Marsden NHS Foundation Trust, London, SW3 6JJ, UK.
⁹ Division of Population Health, Health Services Research and Primary Care, University of Manchester, Oxford Road, Manchester, M13 9PL, UK.
¹⁰ Institute of Biomedicine, University of Turku, Turku, Finland.
¹¹ Department of Medical Genetics, Genomics, Laboratory Division, Turku University Hospital, PO Box 52, 20521, Turku, Finland.
¹² Department of Applied Health Research, University College London, London, WC1E 7HB, UK.
¹³ Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Strangeways Laboratory, Worts Causeway, Cambridge, CB1 8RN, UK.
¹⁴ Australian Prostate Cancer Research Centre-Qld, Institute of Health and Biomedical Innovation and School of Biomedical Sciences, Queensland University of Technology, Brisbane, QLD, 4059, Australia.
¹⁵ Translational Research Institute, Brisbane, QLD, 4102, Australia.
¹⁶ Department of Medical Epidemiology and Biostatistics, Karolinska Institute, SE-171 77, Stockholm, Sweden.
¹⁷ Nuffield Department of Surgical Sciences, University of Oxford, Room 6603, Level 6, John Radcliffe Hospital, Headley Way, Headington, Oxford, OX3 9DU, UK.
¹⁸ University of Cambridge, Department of Oncology, Box 279, Addenbrooke's Hospital, Hills Road, Cambridge, CB2 0QQ, UK.
¹⁹ Cancer Research UK, Cambridge Research Institute, Li Ka Shing Centre, Cambridge, CB2 0RE, UK.
²⁰ Faculty of Health and Medical Sciences, University of Copenhagen, 2200, Copenhagen, Denmark.
²¹ Department of Clinical Biochemistry, Herlev and Gentofte Hospital, Copenhagen University Hospital, Herlev, 2200, Copenhagen, Denmark.
²² SWOG Statistical Center, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
²³ Cancer Epidemiology Division, Cancer Council Victoria, 615 St Kilda Road, Melbourne, VIC, 3004, Australia.
²⁴ Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Grattan Street, Parkville, VIC, 3010, Australia.
²⁵ Department of Surgical Sciences, Uppsala University, 75185, Uppsala, Sweden.
²⁶ Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, Bethesda, MD, 20892, USA.
²⁷ Center for Genetic Epidemiology, Department of Preventive Medicine, Keck School of Medicine, University of Southern California/Norris Comprehensive Cancer Center, Los Angeles, CA, 90015, USA.
²⁸ Cancer Epidemiology Unit, Nuffield Department of Population Health, University of Oxford, Oxford, OX3 7LF, UK.
²⁹ Division of Epidemiology, Department of Medicine, Vanderbilt University Medical Center, 2525 West End Avenue, Suite 800, Nashville, TN, 37232, USA.
³⁰ International Epidemiology Institute, Rockville, MD, 20850, USA.
³¹ Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA, 98109-1024, USA.
³² Department of Epidemiology, School of Public Health, University of Washington, Seattle, WA, 98195, USA.
³³ Department of Epidemiology, Harvard T. H. Chan School of Public Health, Boston, MA, 02115, USA.
³⁴ Division of Cancer Sciences, University of Manchester, Manchester Academic Health Science Centre, Radiotherapy Related Research, The Christie Hospital NHS Foundation Trust, Manchester, M13 9PL, UK.
³⁵ Division of Urologic Surgery, Brigham and Womens Hospital, 75 Francis Street, Boston, MA, 02115, USA.
³⁶ Sorbonne Universite, GRC n°5, AP-HP, Tenon Hospital, 4 rue de la Chine, F-45020, Paris, France.
³⁷ CeRePP, Tenon Hospital, F-75020, Paris, France.
³⁸ Department of Molecular Medicine, Aarhus University Hospital, Palle Juul-Jensen Boulevard 99, 8200, Aarhus N, Denmark.
³⁹ Department of Clinical Medicine, Aarhus University, DK, 8200, Aarhus N, Denmark.
⁴⁰ International Hereditary Cancer Center, Department of Genetics and Pathology, Pomeranian Medical University, 70-115, Szczecin, Poland.
⁴¹ Department of Medical Genetics, Oslo University Hospital, 0424, Oslo, Norway.
⁴² Exposome and Heredity, CESP (UMR 1018), Faculté de Médecine, Université Paris-Saclay, Inserm, Gustave Roussy, Villejuif, France.
⁴³ Department of Cancer Epidemiology, Moffitt Cancer Center, 12902 Magnolia Drive, Tampa, FL, 33612, USA.
⁴⁴ Department of Preventive Medicine, Keck School of Medicine, University of Southern California/Norris Comprehensive Cancer Center, Los Angeles, CA, 90015, USA.
⁴⁵ Humangenetik Tuebingen, Paul-Ehrlich-Str 23, D-72076, Tuebingen, Germany.
⁴⁶ Dept. of Surgical Oncology, Princess Margaret Cancer Centre, Toronto, ON, M5G 2M9, Canada.
⁴⁷ Dept. of Surgery (Urology), University of Toronto, Toronto, Canada.
⁴⁸ Department of Radiation Oncology and Department of Genetics and Genomic Sciences, Box 1236, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY, 10029, USA.
⁴⁹ Centre for Cancer Biomarker and Biotherapeutics, Barts Cancer Institute, Queen Mary University of London, John Vane Science Centre, Charterhouse Square, London, EC1M 6BQ, UK.
⁵⁰ Uro Care, Kampala, Uganda.
⁵¹ Fundación Pública Galega Medicina Xenómica, Santiago de Compostela, 15706, Spain.
⁵² Instituto de Investigación Sanitaria de Santiago de Compostela, Santiago De Compostela, 15706, Spain.
⁵³ Centro de Investigación en Red de Enfermedades Raras (CIBERER), Santiago De Compostela, Spain.
⁵⁴ ISGlobal, Barcelona, Spain.
⁵⁵ IMIM (Hospital del Mar Medical Research Institute), Barcelona, Spain.
⁵⁶ Universitat Pompeu Fabra (UPF), Barcelona, Spain.
⁵⁷ Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital/Harvard Medical School, Boston, MA, 02115, USA.
⁵⁸ Department of Epidemiology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX, 77030, USA.
⁵⁹ Department of Genetics, Portuguese Oncology Institute of Porto (IPO-Porto), 4200-072, Porto, Portugal.
⁶⁰ Biomedical Sciences Institute (ICBAS), University of Porto, 4050-313, Porto, Portugal.
⁶¹ Cancer Genetics Group, IPO-Porto Research Center (CI-IPOP), Portuguese Oncology Institute of Porto (IPO-Porto), 4200-072, Porto, Portugal.
⁶² Univ Rennes, Inserm, EHESP, Irset (Institut de recherche en santé, environnement et travail) - UMR_S 1085, Rennes, France.
⁶³ Department of Cell Systems and Anatomy, Mays Cancer Center, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA.
⁶⁴ Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), D-69120, Heidelberg, Germany.
⁶⁵ German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), D-69120, Heidelberg, Germany.
⁶⁶ Division of Preventive Oncology, German Cancer Research Center (DKFZ) and National Center for Tumor Diseases (NCT), Im Neuenheimer Feld 460, 69120, Heidelberg, Germany.
⁶⁷ Departments of Epidemiology & Population Health and of Medicine, Division of Oncology, Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA, 94304, USA.
⁶⁸ Molecular Medicine Center, Department of Medical Chemistry and Biochemistry, Medical University of Sofia, Sofia, 2 Zdrave Str., 1431, Sofia, Bulgaria.
⁶⁹ The University of Texas M. D. Anderson Cancer Center, Department of Genitourinary Medical Oncology, 1515 Holcombe Blvd., Houston, TX, 77030, USA.
⁷⁰ Department of Population Sciences, Beckman Research Institute of the City of Hope, 1500 East Duarte Road, Duarte, CA, 91010, USA.
⁷¹ Ghent University, Faculty of Medicine and Health Sciences, Basic Medical Sciences, Proeftuinstraat 86, B-9000, Gent, Belgium.
⁷² Ghent University Hospital, Department of Radiotherapy, De Pintelaan 185, B-9000, Gent, Belgium.
⁷³ Department of Surgery, Faculty of Medicine, University of Malaya, 50603, Kuala Lumpur, Malaysia.
⁷⁴ Department of Urology, University of Washington, 1959 NE Pacific Street, Box 356510, Seattle, WA, 98195, USA.
⁷⁵ Division of Epidemiology, Department of Preventive Medicine, University of Tennessee Health Science Center, Memphis, TN, 38163, USA.
⁷⁶ Department of Oncology, University Hospital Centre Zagreb, University of Zagreb, School of Medicine, 10 000, Zagreb, Croatia.
⁷⁷ Department of Oncology, Cross Cancer Institute, University of Alberta, 11560 University Avenue, Edmonton, AB, T6G 1Z2, Canada.
⁷⁸ Molecular Endocrinology Laboratory, Department of Cellular and Molecular Medicine, KU Leuven, BE-3000, Belgium.
⁷⁹ Genetic Oncology Unit, CHUVI Hospital, Complexo Hospitalario Universitario de Vigo, Instituto de Investigación Biomédica Galicia Sur (IISGS), 36204, Vigo (Pontevedra), Spain.
⁸⁰ 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, M13 9WL, UK.
⁸¹ The University of Surrey, Guildford, Surrey, GU2 7XH, UK.
⁸² Case Western Reserve University, Department of Population and Quantitative Health Sciences, Cleveland Institute for Computational Biology, 2103 Cornell Road, Wolstein Research Building, Suite 2527, Cleveland, OH, 44106, USA.
⁸³ Uniformed Services University, 4301 Jones Bridge Rd, Bethesda, MD, 20814, USA.
⁸⁴ Center for Prostate Disease Research, 6720A Rockledge Drive, Suite 300, Bethesda, MD, 20817, USA.
⁸⁵ Department of Clinical Chemistry, Erasmus University Medical Center, 3015 CE, Rotterdam, The Netherlands.
⁸⁶ Epidemiology and Biostatistics Unit, Centre Armand-Frappier Santé Biotechnologie, Institut national de la recherche scientifique, 531 Boul. des Prairies, Laval, QC, H7V 1B7, Canada.
⁸⁷ Department of Social and Preventive Medicine, School of Public Health, University of Montreal, Montreal, QC, Canada.
⁸⁸ The University of Miami School of Medicine, Sylvester Comprehensive Cancer Center, 1120 NW 14th Street, CRB 1511, Miami, FL, 33136, USA.
⁸⁹ Nuffield Department of Surgical Sciences, University of Oxford, Oxford, UK.
⁹⁰ NORMENT, KG Jebsen Centre, Oslo University Hospital and University of Oslo, Oslo, Norway.
⁹¹ Department of Radiology, University of California San Diego, La Jolla, CA, USA.
⁹² Department of Radiation Medicine and Applied Sciences, University of California San Diego, La Jolla, CA, USA. tseibert@ucsd.edu.
⁹³ Center for Multimodal Imaging and Genetics, University of California San Diego, La Jolla, CA, USA. tseibert@ucsd.edu.
⁹⁴ NORMENT, KG Jebsen Centre, Oslo University Hospital and University of Oslo, Oslo, Norway. tseibert@ucsd.edu.
⁹⁵ Department of Radiology, University of California San Diego, La Jolla, CA, USA. tseibert@ucsd.edu.
⁹⁶ Department of Bioengineering, University of California San Diego, La Jolla, CA, USA. tseibert@ucsd.edu.

PMID: 35152271
PMCID: PMC9372232
DOI: 10.1038/s41391-022-00497-7

Prostate cancer risk stratification improvement across multiple ancestries with new polygenic hazard score

Minh-Phuong Huynh-Le et al. Prostate Cancer Prostatic Dis. 2022 Apr.

. 2022 Apr;25(4):755-761.

doi: 10.1038/s41391-022-00497-7. Epub 2022 Feb 12.

Authors

Affiliations

¹ Radiation Oncology, George Washington University, Washington, DC, USA.
² Department of Radiation Medicine and Applied Sciences, University of California San Diego, La Jolla, CA, USA.
³ Center for Multimodal Imaging and Genetics, University of California San Diego, La Jolla, CA, USA.
⁴ Division of Biostatistics and Halicioğlu Data Science Institute, University of California San Diego, La Jolla, CA, USA.
⁵ Department of Family Medicine and Public Health, University of California San Diego, La Jolla, CA, USA.
⁶ University of California San Diego, Moores Cancer Center, Herbert Wertheim School of Public Health and Human Longevity Science, University of California San Diego, La Jolla, CA, 92093-0012, USA.
⁷ The Institute of Cancer Research, London, SM2 5NG, UK.
⁸ Royal Marsden NHS Foundation Trust, London, SW3 6JJ, UK.
⁹ Division of Population Health, Health Services Research and Primary Care, University of Manchester, Oxford Road, Manchester, M13 9PL, UK.
¹⁰ Institute of Biomedicine, University of Turku, Turku, Finland.
¹¹ Department of Medical Genetics, Genomics, Laboratory Division, Turku University Hospital, PO Box 52, 20521, Turku, Finland.
¹² Department of Applied Health Research, University College London, London, WC1E 7HB, UK.
¹³ Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Strangeways Laboratory, Worts Causeway, Cambridge, CB1 8RN, UK.
¹⁴ Australian Prostate Cancer Research Centre-Qld, Institute of Health and Biomedical Innovation and School of Biomedical Sciences, Queensland University of Technology, Brisbane, QLD, 4059, Australia.
¹⁵ Translational Research Institute, Brisbane, QLD, 4102, Australia.
¹⁶ Department of Medical Epidemiology and Biostatistics, Karolinska Institute, SE-171 77, Stockholm, Sweden.
¹⁷ Nuffield Department of Surgical Sciences, University of Oxford, Room 6603, Level 6, John Radcliffe Hospital, Headley Way, Headington, Oxford, OX3 9DU, UK.
¹⁸ University of Cambridge, Department of Oncology, Box 279, Addenbrooke's Hospital, Hills Road, Cambridge, CB2 0QQ, UK.
¹⁹ Cancer Research UK, Cambridge Research Institute, Li Ka Shing Centre, Cambridge, CB2 0RE, UK.
²⁰ Faculty of Health and Medical Sciences, University of Copenhagen, 2200, Copenhagen, Denmark.
²¹ Department of Clinical Biochemistry, Herlev and Gentofte Hospital, Copenhagen University Hospital, Herlev, 2200, Copenhagen, Denmark.
²² SWOG Statistical Center, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
²³ Cancer Epidemiology Division, Cancer Council Victoria, 615 St Kilda Road, Melbourne, VIC, 3004, Australia.
²⁴ Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Grattan Street, Parkville, VIC, 3010, Australia.
²⁵ Department of Surgical Sciences, Uppsala University, 75185, Uppsala, Sweden.
²⁶ Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, Bethesda, MD, 20892, USA.
²⁷ Center for Genetic Epidemiology, Department of Preventive Medicine, Keck School of Medicine, University of Southern California/Norris Comprehensive Cancer Center, Los Angeles, CA, 90015, USA.
²⁸ Cancer Epidemiology Unit, Nuffield Department of Population Health, University of Oxford, Oxford, OX3 7LF, UK.
²⁹ Division of Epidemiology, Department of Medicine, Vanderbilt University Medical Center, 2525 West End Avenue, Suite 800, Nashville, TN, 37232, USA.
³⁰ International Epidemiology Institute, Rockville, MD, 20850, USA.
³¹ Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA, 98109-1024, USA.
³² Department of Epidemiology, School of Public Health, University of Washington, Seattle, WA, 98195, USA.
³³ Department of Epidemiology, Harvard T. H. Chan School of Public Health, Boston, MA, 02115, USA.
³⁴ Division of Cancer Sciences, University of Manchester, Manchester Academic Health Science Centre, Radiotherapy Related Research, The Christie Hospital NHS Foundation Trust, Manchester, M13 9PL, UK.
³⁵ Division of Urologic Surgery, Brigham and Womens Hospital, 75 Francis Street, Boston, MA, 02115, USA.
³⁶ Sorbonne Universite, GRC n°5, AP-HP, Tenon Hospital, 4 rue de la Chine, F-45020, Paris, France.
³⁷ CeRePP, Tenon Hospital, F-75020, Paris, France.
³⁸ Department of Molecular Medicine, Aarhus University Hospital, Palle Juul-Jensen Boulevard 99, 8200, Aarhus N, Denmark.
³⁹ Department of Clinical Medicine, Aarhus University, DK, 8200, Aarhus N, Denmark.
⁴⁰ International Hereditary Cancer Center, Department of Genetics and Pathology, Pomeranian Medical University, 70-115, Szczecin, Poland.
⁴¹ Department of Medical Genetics, Oslo University Hospital, 0424, Oslo, Norway.
⁴² Exposome and Heredity, CESP (UMR 1018), Faculté de Médecine, Université Paris-Saclay, Inserm, Gustave Roussy, Villejuif, France.
⁴³ Department of Cancer Epidemiology, Moffitt Cancer Center, 12902 Magnolia Drive, Tampa, FL, 33612, USA.
⁴⁴ Department of Preventive Medicine, Keck School of Medicine, University of Southern California/Norris Comprehensive Cancer Center, Los Angeles, CA, 90015, USA.
⁴⁵ Humangenetik Tuebingen, Paul-Ehrlich-Str 23, D-72076, Tuebingen, Germany.
⁴⁶ Dept. of Surgical Oncology, Princess Margaret Cancer Centre, Toronto, ON, M5G 2M9, Canada.
⁴⁷ Dept. of Surgery (Urology), University of Toronto, Toronto, Canada.
⁴⁸ Department of Radiation Oncology and Department of Genetics and Genomic Sciences, Box 1236, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY, 10029, USA.
⁴⁹ Centre for Cancer Biomarker and Biotherapeutics, Barts Cancer Institute, Queen Mary University of London, John Vane Science Centre, Charterhouse Square, London, EC1M 6BQ, UK.
⁵⁰ Uro Care, Kampala, Uganda.
⁵¹ Fundación Pública Galega Medicina Xenómica, Santiago de Compostela, 15706, Spain.
⁵² Instituto de Investigación Sanitaria de Santiago de Compostela, Santiago De Compostela, 15706, Spain.
⁵³ Centro de Investigación en Red de Enfermedades Raras (CIBERER), Santiago De Compostela, Spain.
⁵⁴ ISGlobal, Barcelona, Spain.
⁵⁵ IMIM (Hospital del Mar Medical Research Institute), Barcelona, Spain.
⁵⁶ Universitat Pompeu Fabra (UPF), Barcelona, Spain.
⁵⁷ Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital/Harvard Medical School, Boston, MA, 02115, USA.
⁵⁸ Department of Epidemiology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX, 77030, USA.
⁵⁹ Department of Genetics, Portuguese Oncology Institute of Porto (IPO-Porto), 4200-072, Porto, Portugal.
⁶⁰ Biomedical Sciences Institute (ICBAS), University of Porto, 4050-313, Porto, Portugal.
⁶¹ Cancer Genetics Group, IPO-Porto Research Center (CI-IPOP), Portuguese Oncology Institute of Porto (IPO-Porto), 4200-072, Porto, Portugal.
⁶² Univ Rennes, Inserm, EHESP, Irset (Institut de recherche en santé, environnement et travail) - UMR_S 1085, Rennes, France.
⁶³ Department of Cell Systems and Anatomy, Mays Cancer Center, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA.
⁶⁴ Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), D-69120, Heidelberg, Germany.
⁶⁵ German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), D-69120, Heidelberg, Germany.
⁶⁶ Division of Preventive Oncology, German Cancer Research Center (DKFZ) and National Center for Tumor Diseases (NCT), Im Neuenheimer Feld 460, 69120, Heidelberg, Germany.
⁶⁷ Departments of Epidemiology & Population Health and of Medicine, Division of Oncology, Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA, 94304, USA.
⁶⁸ Molecular Medicine Center, Department of Medical Chemistry and Biochemistry, Medical University of Sofia, Sofia, 2 Zdrave Str., 1431, Sofia, Bulgaria.
⁶⁹ The University of Texas M. D. Anderson Cancer Center, Department of Genitourinary Medical Oncology, 1515 Holcombe Blvd., Houston, TX, 77030, USA.
⁷⁰ Department of Population Sciences, Beckman Research Institute of the City of Hope, 1500 East Duarte Road, Duarte, CA, 91010, USA.
⁷¹ Ghent University, Faculty of Medicine and Health Sciences, Basic Medical Sciences, Proeftuinstraat 86, B-9000, Gent, Belgium.
⁷² Ghent University Hospital, Department of Radiotherapy, De Pintelaan 185, B-9000, Gent, Belgium.
⁷³ Department of Surgery, Faculty of Medicine, University of Malaya, 50603, Kuala Lumpur, Malaysia.
⁷⁴ Department of Urology, University of Washington, 1959 NE Pacific Street, Box 356510, Seattle, WA, 98195, USA.
⁷⁵ Division of Epidemiology, Department of Preventive Medicine, University of Tennessee Health Science Center, Memphis, TN, 38163, USA.
⁷⁶ Department of Oncology, University Hospital Centre Zagreb, University of Zagreb, School of Medicine, 10 000, Zagreb, Croatia.
⁷⁷ Department of Oncology, Cross Cancer Institute, University of Alberta, 11560 University Avenue, Edmonton, AB, T6G 1Z2, Canada.
⁷⁸ Molecular Endocrinology Laboratory, Department of Cellular and Molecular Medicine, KU Leuven, BE-3000, Belgium.
⁷⁹ Genetic Oncology Unit, CHUVI Hospital, Complexo Hospitalario Universitario de Vigo, Instituto de Investigación Biomédica Galicia Sur (IISGS), 36204, Vigo (Pontevedra), Spain.
⁸⁰ 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, M13 9WL, UK.
⁸¹ The University of Surrey, Guildford, Surrey, GU2 7XH, UK.
⁸² Case Western Reserve University, Department of Population and Quantitative Health Sciences, Cleveland Institute for Computational Biology, 2103 Cornell Road, Wolstein Research Building, Suite 2527, Cleveland, OH, 44106, USA.
⁸³ Uniformed Services University, 4301 Jones Bridge Rd, Bethesda, MD, 20814, USA.
⁸⁴ Center for Prostate Disease Research, 6720A Rockledge Drive, Suite 300, Bethesda, MD, 20817, USA.
⁸⁵ Department of Clinical Chemistry, Erasmus University Medical Center, 3015 CE, Rotterdam, The Netherlands.
⁸⁶ Epidemiology and Biostatistics Unit, Centre Armand-Frappier Santé Biotechnologie, Institut national de la recherche scientifique, 531 Boul. des Prairies, Laval, QC, H7V 1B7, Canada.
⁸⁷ Department of Social and Preventive Medicine, School of Public Health, University of Montreal, Montreal, QC, Canada.
⁸⁸ The University of Miami School of Medicine, Sylvester Comprehensive Cancer Center, 1120 NW 14th Street, CRB 1511, Miami, FL, 33136, USA.
⁸⁹ Nuffield Department of Surgical Sciences, University of Oxford, Oxford, UK.
⁹⁰ NORMENT, KG Jebsen Centre, Oslo University Hospital and University of Oslo, Oslo, Norway.
⁹¹ Department of Radiology, University of California San Diego, La Jolla, CA, USA.
⁹² Department of Radiation Medicine and Applied Sciences, University of California San Diego, La Jolla, CA, USA. tseibert@ucsd.edu.
⁹³ Center for Multimodal Imaging and Genetics, University of California San Diego, La Jolla, CA, USA. tseibert@ucsd.edu.
⁹⁴ NORMENT, KG Jebsen Centre, Oslo University Hospital and University of Oslo, Oslo, Norway. tseibert@ucsd.edu.
⁹⁵ Department of Radiology, University of California San Diego, La Jolla, CA, USA. tseibert@ucsd.edu.
⁹⁶ Department of Bioengineering, University of California San Diego, La Jolla, CA, USA. tseibert@ucsd.edu.

PMID: 35152271
PMCID: PMC9372232
DOI: 10.1038/s41391-022-00497-7

Abstract

Background: Prostate cancer risk stratification using single-nucleotide polymorphisms (SNPs) demonstrates considerable promise in men of European, Asian, and African genetic ancestries, but there is still need for increased accuracy. We evaluated whether including additional SNPs in a prostate cancer polygenic hazard score (PHS) would improve associations with clinically significant prostate cancer in multi-ancestry datasets.

Methods: In total, 299 SNPs previously associated with prostate cancer were evaluated for inclusion in a new PHS, using a LASSO-regularized Cox proportional hazards model in a training dataset of 72,181 men from the PRACTICAL Consortium. The PHS model was evaluated in four testing datasets: African ancestry, Asian ancestry, and two of European Ancestry-the Cohort of Swedish Men (COSM) and the ProtecT study. Hazard ratios (HRs) were estimated to compare men with high versus low PHS for association with clinically significant, with any, and with fatal prostate cancer. The impact of genetic risk stratification on the positive predictive value (PPV) of PSA testing for clinically significant prostate cancer was also measured.

Results: The final model (PHS290) had 290 SNPs with non-zero coefficients. Comparing, for example, the highest and lowest quintiles of PHS290, the hazard ratios (HRs) for clinically significant prostate cancer were 13.73 [95% CI: 12.43-15.16] in ProtecT, 7.07 [6.58-7.60] in African ancestry, 10.31 [9.58-11.11] in Asian ancestry, and 11.18 [10.34-12.09] in COSM. Similar results were seen for association with any and fatal prostate cancer. Without PHS stratification, the PPV of PSA testing for clinically significant prostate cancer in ProtecT was 0.12 (0.11-0.14). For the top 20% and top 5% of PHS290, the PPV of PSA testing was 0.19 (0.15-0.22) and 0.26 (0.19-0.33), respectively.

Conclusions: We demonstrate better genetic risk stratification for clinically significant prostate cancer than prior versions of PHS in multi-ancestry datasets. This is promising for implementing precision-medicine approaches to prostate cancer screening decisions in diverse populations.

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Conflict of interest statement

All authors declare no support from any organization for the submitted work except as follows: AMD and TMS report a past research grant from the US Department of Defense. OAA reports research grants from K.G Jebsen Stiftelsen, Research Council of Norway, and South East Norway Health Authority. Authors declare no financial relationships with any organizations that might have an interest in the submitted work in the previous 3 years except as follows, with all of these relationships outside the present study: TMS reports honoraria from Multimodal Imaging Services Corporation, Varian Medical Systems, and WebMD; he has an equity interest in CorTechs Labs and also serves on its Scientific Advisory Board. 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. OAA reports speaker honoraria from Lundbeck. Authors declare no other relationships or activities that could appear to have influenced the submitted work except as follows: OAA has a patent application # U. S. 20150356243 pending; AMD also applied for this patent application and assigned it to UC San Diego. AMD has additional disclosures outside the present work: founder, equity holder, and advisory board member for CorTechs Labs, Inc.; founder and equity holder in HealthLytix, Inc., advisory board member of Human Longevity, Inc.; recipient of nonfinancial research support from General Electric Healthcare. OAA is a consultant for HealthLytix, Inc. Additional acknowledgments for the PRACTICAL consortium and contributing studies are described in the Supplementary Information.

Figures

Fig. 1. PPV performance in the ProtecT dataset for clinically significant prostate cancer, estimated using 3 approaches: standard (not using PHS), top 20% of PHS values (PPV80), and top 5% of PHS values (PPV95).
Error bars are 95% bootstrap confidence intervals.

**Fig. 2. Genetic-risk-adjusted cumulative incidence curves for PHS290.**
Curves are shown for the upper 5th (>95th) and upper 20th (>80th) percentile of PHS290 for clinically significant and non-clinically-significant prostate cancer. The reference curves represent the overall population average from the UK.

See this image and copyright information in PMC

References

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1. Huynh-Le M-P, Fan CC, Karunamuni R, Thompson WK, Martinez ME, Eeles RA, et al. Polygenic hazard score is associated with prostate cancer in multi-ethnic populations. Nat Commun. 2021;12:1236. doi: 10.1038/s41467-021-21287-0. - DOI - PMC - PubMed
1. Callender T, Emberton M, Morris S, Pharoah PDP, 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 Network Open. 2021;4:2037657. doi: 10.1001/jamanetworkopen.2020.37657. - DOI - PMC - PubMed
1. Callender T, Emberton M, Morris S, Eeles R, Kote-Jarai Z, Pharoah PDP, et al. Polygenic risk-tailored screening for prostate cancer: A benefit-harm and cost-effectiveness modelling study. PLoS Med. 2019;16:e1002998. doi: 10.1371/journal.pmed.1002998. - DOI - PMC - PubMed
1. Petrovski S, Goldstein DB. Unequal representation of genetic variation across ancestry groups creates healthcare inequality in the application of precision medicine. Genome Biol. 2016;17. 10.1186/s13059-016-1016-y. - PMC - PubMed

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Prostate cancer risk stratification improvement across multiple ancestries with new polygenic hazard score

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Prostate cancer risk stratification improvement across multiple ancestries with new polygenic hazard score

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