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.
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.
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.
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.
Prostate cancer and prostatic diseases. 2022 Feb 12 [Epub ahead of print]
Minh-Phuong Huynh-Le, Roshan Karunamuni, Chun Chieh Fan, Lui Asona, Wesley K Thompson, Maria Elena Martinez, Rosalind A Eeles, Zsofia Kote-Jarai, Kenneth R Muir, Artitaya Lophatananon, Johanna Schleutker, Nora Pashayan, Jyotsna Batra, Henrik Grönberg, David E Neal, Børge G Nordestgaard, Catherine M Tangen, Robert J MacInnis, Alicja Wolk, Demetrius Albanes, Christopher A Haiman, Ruth C Travis, William J Blot, Janet L Stanford, Lorelei A Mucci, Catharine M L West, Sune F Nielsen, Adam S Kibel, Olivier Cussenot, Sonja I Berndt, Stella Koutros, Karina Dalsgaard Sørensen, Cezary Cybulski, Eli Marie Grindedal, Florence Menegaux, Jong Y Park, Sue A Ingles, Christiane Maier, Robert J Hamilton, Barry S Rosenstein, Yong-Jie Lu, Stephen Watya, Ana Vega, Manolis Kogevinas, Fredrik Wiklund, Kathryn L Penney, Chad D Huff, Manuel R Teixeira, Luc Multigner, Robin J Leach, Hermann Brenner, Esther M John, Radka Kaneva, Christopher J Logothetis, Susan L Neuhausen, Kim De Ruyck, Piet Ost, Azad Razack, Lisa F Newcomb, Jay H Fowke, Marija Gamulin, Aswin Abraham, Frank Claessens, Jose Esteban Castelao, Paul A Townsend, Dana C Crawford, Gyorgy Petrovics, Ron H N van Schaik, Marie-Élise Parent, Jennifer J Hu, Wei Zheng, 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 Mills, Ole A Andreassen, Anders M Dale, Tyler M Seibert
Radiation Oncology, George Washington University, Washington, DC, USA., Department of Radiation Medicine and Applied Sciences, University of California San Diego, La Jolla, CA, USA., Center for Multimodal Imaging and Genetics, University of California San Diego, La Jolla, CA, USA., Division of Biostatistics and Halicioğlu Data Science Institute, University of California San Diego, La Jolla, CA, USA., 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., The Institute of Cancer Research, London, SM2 5NG, UK., Division of Population Health, Health Services Research and Primary Care, University of Manchester, Oxford Road, Manchester, M13 9PL, UK., Institute of Biomedicine, University of Turku, Turku, Finland., Department of Applied Health Research, University College London, London, WC1E 7HB, UK., 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., Department of Medical Epidemiology and Biostatistics, Karolinska Institute, SE-171 77, Stockholm, Sweden., Nuffield Department of Surgical Sciences, University of Oxford, Room 6603, Level 6, John Radcliffe Hospital, Headley Way, Headington, Oxford, OX3 9DU, UK., Faculty of Health and Medical Sciences, University of Copenhagen, 2200, Copenhagen, Denmark., SWOG Statistical Center, Fred Hutchinson Cancer Research Center, Seattle, WA, USA., Cancer Epidemiology Division, Cancer Council Victoria, 615 St Kilda Road, Melbourne, VIC, 3004, Australia., Department of Surgical Sciences, Uppsala University, 75185, Uppsala, Sweden., Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, Bethesda, MD, 20892, USA., 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., Cancer Epidemiology Unit, Nuffield Department of Population Health, University of Oxford, Oxford, OX3 7LF, UK., Division of Epidemiology, Department of Medicine, Vanderbilt University Medical Center, 2525 West End Avenue, Suite 800, Nashville, TN, 37232, USA., Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA, 98109-1024, USA., Department of Epidemiology, Harvard T. H. Chan School of Public Health, Boston, MA, 02115, USA., 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., Division of Urologic Surgery, Brigham and Womens Hospital, 75 Francis Street, Boston, MA, 02115, USA., Sorbonne Universite, GRC n°5, AP-HP, Tenon Hospital, 4 rue de la Chine, F-45020, Paris, France., Department of Molecular Medicine, Aarhus University Hospital, Palle Juul-Jensen Boulevard 99, 8200, Aarhus N, Denmark., International Hereditary Cancer Center, Department of Genetics and Pathology, Pomeranian Medical University, 70-115, Szczecin, Poland., Department of Medical Genetics, Oslo University Hospital, 0424, Oslo, Norway., Exposome and Heredity, CESP (UMR 1018), Faculté de Médecine, Université Paris-Saclay, Inserm, Gustave Roussy, Villejuif, France., Department of Cancer Epidemiology, Moffitt Cancer Center, 12902 Magnolia Drive, Tampa, FL, 33612, USA., Department of Preventive Medicine, Keck School of Medicine, University of Southern California/Norris Comprehensive Cancer Center, Los Angeles, CA, 90015, USA., Humangenetik Tuebingen, Paul-Ehrlich-Str 23, D-72076, Tuebingen, Germany., Dept. of Surgical Oncology, Princess Margaret Cancer Centre, Toronto, ON, M5G 2M9, Canada., 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., Centre for Cancer Biomarker and Biotherapeutics, Barts Cancer Institute, Queen Mary University of London, John Vane Science Centre, Charterhouse Square, London, EC1M 6BQ, UK., Uro Care, Kampala, Uganda., Fundación Pública Galega Medicina Xenómica, Santiago de Compostela, 15706, Spain., ISGlobal, Barcelona, Spain., Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital/Harvard Medical School, Boston, MA, 02115, USA., Department of Epidemiology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX, 77030, USA., Department of Genetics, Portuguese Oncology Institute of Porto (IPO-Porto), 4200-072, Porto, Portugal., Univ Rennes, Inserm, EHESP, Irset (Institut de recherche en santé, environnement et travail) - UMR_S 1085, Rennes, France., Department of Cell Systems and Anatomy, Mays Cancer Center, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA., Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), D-69120, Heidelberg, Germany., Departments of Epidemiology & Population Health and of Medicine, Division of Oncology, Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA, 94304, USA., Molecular Medicine Center, Department of Medical Chemistry and Biochemistry, Medical University of Sofia, Sofia, 2 Zdrave Str., 1431, Sofia, Bulgaria., The University of Texas M. D. Anderson Cancer Center, Department of Genitourinary Medical Oncology, 1515 Holcombe Blvd., Houston, TX, 77030, USA., Department of Population Sciences, Beckman Research Institute of the City of Hope, 1500 East Duarte Road, Duarte, CA, 91010, USA., Ghent University, Faculty of Medicine and Health Sciences, Basic Medical Sciences, Proeftuinstraat 86, B-9000, Gent, Belgium., Ghent University Hospital, Department of Radiotherapy, De Pintelaan 185, B-9000, Gent, Belgium., Department of Surgery, Faculty of Medicine, University of Malaya, 50603, Kuala Lumpur, Malaysia., Division of Epidemiology, Department of Preventive Medicine, University of Tennessee Health Science Center, Memphis, TN, 38163, USA., Department of Oncology, University Hospital Centre Zagreb, University of Zagreb, School of Medicine, 10 000, Zagreb, Croatia., Department of Oncology, Cross Cancer Institute, University of Alberta, 11560 University Avenue, Edmonton, AB, T6G 1Z2, Canada., Molecular Endocrinology Laboratory, Department of Cellular and Molecular Medicine, KU Leuven, BE-3000, Belgium., Genetic Oncology Unit, CHUVI Hospital, Complexo Hospitalario Universitario de Vigo, Instituto de Investigación Biomédica Galicia Sur (IISGS), 36204, Vigo (Pontevedra), Spain., 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., 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., Uniformed Services University, 4301 Jones Bridge Rd, Bethesda, MD, 20814, USA., Department of Clinical Chemistry, Erasmus University Medical Center, 3015 CE, Rotterdam, The Netherlands., Epidemiology and Biostatistics Unit, Centre Armand-Frappier Santé Biotechnologie, Institut national de la recherche scientifique, 531 Boul. des Prairies, Laval, QC, H7V 1B7, Canada., The University of Miami School of Medicine, Sylvester Comprehensive Cancer Center, 1120 NW 14th Street, CRB 1511, Miami, FL, 33136, USA., Nuffield Department of Surgical Sciences, University of Oxford, Oxford, UK., NORMENT, KG Jebsen Centre, Oslo University Hospital and University of Oslo, Oslo, Norway., Department of Radiation Medicine and Applied Sciences, University of California San Diego, La Jolla, CA, USA. .