Thumbnail Image
Publication

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

Huynh-Le, M. P.
; 
Karunamuni, R.
; 
Fan, C. C.
; 
Asona, L.
; 
Thompson, W. K.
; 
Martinez, M. E.
; 
Eeles, R. A.
; 
Kote-Jarai, Z.
; 
Muir, K. R.
; 
Lophatananon, A.
... show 10 more
Citations
Altmetric:
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.
Authors
Huynh-Le, M. P.
Karunamuni, R.
Fan, C. C.
Asona, L.
Thompson, W. K.
Martinez, M. E.
Eeles, R. A.
Kote-Jarai, Z.
Muir, K. R.
Lophatananon, A.
Schleutker, J.
Pashayan, N.
Batra, J.
Grönberg, H.
Neal, D. E.
Nordestgaard, B. G.
Tangen, C. M.
MacInnis, R. J.
Wolk, A.
Albanes, D.
Haiman, C. A.
Travis, R. C.
Blot, W. J.
Stanford, J. L.
Mucci, L. A.
West, Catharine M L
Nielsen, S. F.
Kibel, A. S.
Cussenot, O.
Berndt, S. I.
Koutros, S.
Sørensen, K. D.
Cybulski, C.
Grindedal, E. M.
Menegaux, F.
Park, J. Y.
Ingles, S. A.
Maier, C.
Hamilton, R. J.
Rosenstein, B. S.
Lu, Y. J.
Watya, S.
Vega, A.
Kogevinas, M.
Wiklund, F.
Penney, K. L.
Huff, C. D.
Teixeira, M. R.
Multigner, L.
Leach, R. J.
Brenner, H.
John, E. M.
Kaneva, R.
Logothetis, C. J.
Neuhausen, S. L.
De Ruyck, K.
Ost, P.
Razack, A.
Newcomb, L. F.
Fowke, J. H.
Gamulin, M.
Abraham, A.
Claessens, F.
Castelao, J. E.
Townsend, Paul A
Crawford, D. C.
Petrovics, G.
van Schaik, R. H. N.
Parent, M.
Hu, J. J.
Zheng, W.
Mills, I. G.
Andreassen, O. A.
Dale, A. M.
Seibert, T. M.
Affiliation
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. Department of Family Medicine and Public Health, 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. Royal Marsden NHS Foundation Trust, London, SW3 6JJ, 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 Medical Genetics, Genomics, Laboratory Division, Turku University Hospital, PO Box 52, 20521, Turku, Finland. Department of Applied Health Research, University College London, London, WC1E 7HB, UK. Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Strangeways Laboratory, Worts Causeway, Cambridge, CB1 8RN, 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. Translational Research Institute, Brisbane, QLD, 4102, 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. University of Cambridge, Department of Oncology, Box 279, Addenbrooke's Hospital, Hills Road, Cambridge, CB2 0QQ, UK. Cancer Research UK, Cambridge Research Institute, Li Ka Shing Centre, Cambridge, CB2 0RE, UK. Faculty of Health and Medical Sciences, University of Copenhagen, 2200, Copenhagen, Denmark. Department of Clinical Biochemistry, Herlev and Gentofte Hospital, Copenhagen University Hospital, Herlev, 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. Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Grattan Street, Parkville, VIC, 3010, 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. International Epidemiology Institute, Rockville, MD, 20850, USA. Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA, 98109-1024, USA. Department of Epidemiology, School of Public Health, University of Washington, Seattle, WA, 98195, 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. CeRePP, Tenon Hospital, F-75020, Paris, France. Department of Molecular Medicine, Aarhus University Hospital, Palle Juul-Jensen Boulevard 99, 8200, Aarhus N, Denmark. Department of Clinical Medicine, Aarhus University, DK, 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. Dept. of Surgery (Urology), University of Toronto, Toronto, 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. Instituto de Investigación Sanitaria de Santiago de Compostela, Santiago De Compostela, 15706, Spain. Centro de Investigación en Red de Enfermedades Raras (CIBERER), Santiago De Compostela, Spain. ISGlobal, Barcelona, Spain. IMIM (Hospital del Mar Medical Research Institute), Barcelona, Spain. Universitat Pompeu Fabra (UPF), 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. Biomedical Sciences Institute (ICBAS), University of Porto, 4050-313, Porto, Portugal. Cancer Genetics Group, IPO-Porto Research Center (CI-IPOP), 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. German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), D-69120, Heidelberg, Germany. Division of Preventive Oncology, German Cancer Research Center (DKFZ) and National Center for Tumor Diseases (NCT), Im Neuenheimer Feld 460, 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. Department of Urology, University of Washington, 1959 NE Pacific Street, Box 356510, Seattle, WA, 98195, USA. 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. The University of Surrey, Guildford, Surrey, GU2 7XH, 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. Center for Prostate Disease Research, 6720A Rockledge Drive, Suite 300, Bethesda, MD, 20817, 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. Department of Social and Preventive Medicine, School of Public Health, University of Montreal, Montreal, QC, 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 Radiology, University of California San Diego, La Jolla, CA, USA. Department of Radiation Medicine and Applied Sciences, University of California San Diego, La Jolla, CA, USA. tseibert@ucsd.edu. Center for Multimodal Imaging and Genetics, University of California San Diego, La Jolla, CA, USA. tseibert@ucsd.edu. NORMENT, KG Jebsen Centre, Oslo University Hospital and University of Oslo, Oslo, Norway. tseibert@ucsd.edu. Department of Radiology, University of California San Diego, La Jolla, CA, USA. tseibert@ucsd.edu. Department of Bioengineering, University of California San Diego, La Jolla, CA, USA. tseibert@ucsd.edu.
Description
Date
2022
Publisher
Collections
All Christie Publications
Show all metadata
Files
Thumbnail Image
Identified with Open Access button
Adobe PDF, 2.14 MB
Keywords
Type
Article
Citation
Huynh-Le M-P, Karunamuni R, Fan CC, Asona L, Thompson WK, Martinez ME, et al. Prostate cancer risk stratification improvement across multiple ancestries with new polygenic hazard score [Internet]. Prostate Cancer and Prostatic Diseases. Springer Science and Business Media LLC; 2022.
Journal Title
Journal ISSN
Volume Title
URI
http://hdl.handle.net/10541/625123
Embedded videos