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Additional SNPs improve risk stratification of a polygenic hazard score for prostate cancer

Karunamuni RA 1 , Huynh-Le MP 2 , Fan CC 3 , Thompson W 4 , Eeles RA 5 , Kote-Jarai Z 5 Show all authors , Muir K 6 , Lophatananon A 6 , UKGPCS collaborators , Schleutker J 7 , Pashayan N 8 , Batra J 9 , APCB BioResource (Australian Prostate Cancer BioResource) , Grönberg H 10 , Walsh EI 11 , Turner EL 11 , Lane A 11 , Martin RM 11 , Neal DE 12 , Donovan JL 13 , Hamdy FC 12 , Nordestgaard BG 14 , Tangen CM 15 , MacInnis RJ 16 , Wolk A 17 , Albanes D 18 , Haiman CA 19 , Travis RC 20 , Stanford JL 21 , Mucci LA 22 , West CML 23 , Nielsen SF 14 , Kibel AS 24 , Wiklund F 10 , Cussenot O 25 , Berndt SI 18 , Koutros S 18 , Sørensen KD 26 , Cybulski C 27 , Grindedal EM 28 , Park JY 29 , Ingles SA 30 , Maier C 31 , Hamilton RJ 32 , Rosenstein BS 33 , Vega A 34 , IMPACT Study Steering Committee and Collaborators , Kogevinas M 35 , Penney KL 36 , Teixeira MR 37 , Brenner H 38 , John EM 39 , Kaneva R 40 , Logothetis CJ 41 , Neuhausen SL 42 , Razack A 43 , Newcomb LF 21 , Canary PASS Investigators , Gamulin M 44 , Usmani N 45 , Claessens F 46 , Gago-Dominguez M 47 , Townsend PA 48 , Roobol MJ 49 , Zheng W 50 , Profile Study Steering Committee , Mills IG 51 , Andreassen OA 52 , Dale AM 53 , Seibert TM 54 , PRACTICAL Consortium

Affiliations 

  • 1 Department of Radiation Medicine and Applied Sciences, University of California San Diego, La Jolla, CA, USA. [email protected]
  • 2 Radiation Oncology, George Washington University, Washington, DC, USA
  • 3 Center for Human Development, University of California San Diego, La Jolla, CA, USA
  • 4 Department of Family Medicine and Public Health, University of California, San Diego, La Jolla, CA, USA
  • 5 The Institute of Cancer Research, London, SM2 5NG, UK
  • 6 Division of Population Health, Health Services Research and Primary Care, University of Manchester, Oxford Road, Manchester, M13 9PL, UK
  • 7 Institute of Biomedicine, University of Turku, Turku, Finland
  • 8 Department of Applied Health Research, University College London, London, WC1E 7HB, UK
  • 9 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
  • 10 Department of Medical Epidemiology and Biostatistics, Karolinska Institute, SE-171 77, Stockholm, Sweden
  • 11 Bristol Medical School, Department of Population Health Sciences, University of Bristol, Bristol, UK
  • 12 Nuffield Department of Surgical Sciences, University of Oxford, Room 6603, Level 6, John Radcliffe Hospital, Headley Way, Headington, Oxford, OX3 9DU, UK
  • 13 School of Social and Community Medicine, University of Bristol, Bristol, UK
  • 14 Faculty of Health and Medical Sciences, University of Copenhagen, 2200, Copenhagen, Denmark
  • 15 SWOG Statistical Center, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
  • 16 Cancer Epidemiology Division, Cancer Council Victoria, 615 St Kilda Road, Melbourne, VIC, 3004, Australia
  • 17 Unit of Cardiovascular and Nutritional Epidemiology, Institute of Environmental Medicine, Karolinska Institutet, SE-171 77, Stockholm, Sweden
  • 18 Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, Bethesda, MD, 20892, USA
  • 19 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
  • 20 Cancer Epidemiology Unit, Nuffield Department of Population Health, University of Oxford, Oxford, OX3 7LF, UK
  • 21 Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA, 98109-1024, USA
  • 22 Department of Epidemiology, Harvard T. H. Chan School of Public Health, Boston, MA, 02115, USA
  • 23 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
  • 24 Division of Urologic Surgery, Brigham and Womens Hospital, 75 Francis Street, Boston, MA, 02115, USA
  • 25 Sorbonne Universite, GRC n°5, AP-HP, Tenon Hospital, 4 rue de la Chine, F-75020, Paris, France
  • 26 Department of Molecular Medicine, Aarhus University Hospital, Palle Juul-Jensen Boulevard 99, 8200, Aarhus, Denmark
  • 27 International Hereditary Cancer Center, Department of Genetics and Pathology, Pomeranian Medical University, 70-115, Szczecin, Poland
  • 28 Department of Medical Genetics, Oslo University Hospital, 0424, Oslo, Norway
  • 29 Department of Cancer Epidemiology, Moffitt Cancer Center, 12902 Magnolia Drive, Tampa, FL, 33612, USA
  • 30 Department of Preventive Medicine, Keck School of Medicine, University of Southern California/Norris Comprehensive Cancer Center, Los Angeles, CA, 90015, USA
  • 31 Humangenetik Tuebingen, Paul-Ehrlich-Str 23, D-72076, Tuebingen, Germany
  • 32 Dept. of Surgical Oncology, Princess Margaret Cancer Centre, Toronto, ON, M5G 2M9, Canada
  • 33 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
  • 34 Fundación Pública Galega Medicina Xenómica, Santiago de Compostela, 15706, Spain
  • 35 ISGlobal, Barcelona, Spain
  • 36 Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital/Harvard Medical School, Boston, MA, 02184, USA
  • 37 Department of Genetics, Portuguese Oncology Institute of Porto (IPO-Porto), 4200-072, Porto, Portugal
  • 38 Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), D-69120, Heidelberg, Germany
  • 39 Departments of Epidemiology & Population Health and of Medicine, Division of Oncology, Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA, 94304, USA
  • 40 Molecular Medicine Center, Department of Medical Chemistry and Biochemistry, Medical University of Sofia, Sofia, 2 Zdrave Str., 1431, Sofia, Bulgaria
  • 41 The University of Texas M. D. Anderson Cancer Center, Department of Genitourinary Medical Oncology, 1515 Holcombe Blvd., Houston, TX, 77030, USA
  • 42 Department of Population Sciences, Beckman Research Institute of the City of Hope, 1500 East Duarte Road, Duarte, CA, 91010, USA
  • 43 Department of Surgery, Faculty of Medicine, University of Malaya, 50603, Kuala Lumpur, Malaysia
  • 44 Division of Medical Oncology, Urogenital Unit, Department of Oncology, University Hospital Centre Zagreb, University of Zagreb, School of Medicine, 10000, Zagreb, Croatia
  • 45 Department of Oncology, Cross Cancer Institute, University of Alberta, 11560 University Avenue, Edmonton, AB, T6G 1Z2, Canada
  • 46 Molecular Endocrinology Laboratory, Department of Cellular and Molecular Medicine, KU, Leuven, BE-3000, Belgium
  • 47 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, 15706, Santiago de Compostela, Spain
  • 48 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, M13 9WL, Manchester, UK
  • 49 Department of Urology, Erasmus University Medical Center, 3015 CE, Rotterdam, The Netherlands
  • 50 Division of Epidemiology, Department of Medicine, Vanderbilt University Medical Center, 2525 West End Avenue, Suite 800, Nashville, TN, 37232, USA
  • 51 Center for Cancer Research and Cell Biology, Queen's University of Belfast, Belfast, UK
  • 52 NORMENT, KG Jebsen Centre, Oslo University Hospital and University of Oslo, Oslo, Norway
  • 53 Department of Radiology, University of California San Diego, La Jolla, CA, USA
  • 54 Department of Radiation Medicine and Applied Sciences, University of California San Diego, La Jolla, CA, USA. [email protected]
Prostate Cancer Prostatic Dis, 2021 Jun;24(2):532-541.
PMID: 33420416 DOI: 10.1038/s41391-020-00311-2

Abstract

BACKGROUND: Polygenic hazard scores (PHS) can identify individuals with increased risk of prostate cancer. We estimated the benefit of additional SNPs on performance of a previously validated PHS (PHS46).

MATERIALS AND METHOD: 180 SNPs, shown to be previously associated with prostate cancer, were used to develop a PHS model in men with European ancestry. A machine-learning approach, LASSO-regularized Cox regression, was used to select SNPs and to estimate their coefficients in the training set (75,596 men). Performance of the resulting model was evaluated in the testing/validation set (6,411 men) with two metrics: (1) hazard ratios (HRs) and (2) positive predictive value (PPV) of prostate-specific antigen (PSA) testing. HRs were estimated between individuals with PHS in the top 5% to those in the middle 40% (HR95/50), top 20% to bottom 20% (HR80/20), and bottom 20% to middle 40% (HR20/50). PPV was calculated for the top 20% (PPV80) and top 5% (PPV95) of PHS as the fraction of individuals with elevated PSA that were diagnosed with clinically significant prostate cancer on biopsy.

RESULTS: 166 SNPs had non-zero coefficients in the Cox model (PHS166). All HR metrics showed significant improvements for PHS166 compared to PHS46: HR95/50 increased from 3.72 to 5.09, HR80/20 increased from 6.12 to 9.45, and HR20/50 decreased from 0.41 to 0.34. By contrast, no significant differences were observed in PPV of PSA testing for clinically significant prostate cancer.

CONCLUSIONS: Incorporating 120 additional SNPs (PHS166 vs PHS46) significantly improved HRs for prostate cancer, while PPV of PSA testing remained the same.

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

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