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Fine-mapping of prostate cancer susceptibility loci in a large meta-analysis identifies candidate causal variants

Dadaev T 1 , Saunders EJ 1 , Newcombe PJ 2 , Anokian E 1 , Leongamornlert DA 1 , Brook MN 1 Show all authors , Cieza-Borrella C 1 , Mijuskovic M 1 , Wakerell S 1 , Olama AAA 3 , Schumacher FR 4 , Berndt SI 5 , Benlloch S 1 , Ahmed M 1 , Goh C 1 , Sheng X 6 , Zhang Z 6 , Muir K 7 , Govindasami K 1 , Lophatananon A 7 , Stevens VL 8 , Gapstur SM 8 , Carter BD 8 , Tangen CM 9 , Goodman P 9 , Thompson IM 10 , Batra J 11 , Chambers S 12 , Moya L 11 , Clements J 11 , Horvath L 13 , Tilley W 14 , Risbridger G 15 , Gronberg H 16 , Aly M 16 , Nordström T 16 , Pharoah P 3 , Pashayan N 17 , Schleutker J 18 , Tammela TLJ 19 , Sipeky C 18 , Auvinen A 20 , Albanes D 5 , Weinstein S 5 , Wolk A 21 , Hakansson N 21 , West C 22 , Dunning AM 17 , Burnet N 23 , Mucci L 24 , Giovannucci E 24 , Andriole G 25 , Cussenot O 26 , Cancel-Tassin G 26 , Koutros S 5 , Freeman LEB 5 , Sorensen KD 27 , Orntoft TF 27 , Borre M 28 , Maehle L 29 , Grindedal EM 29 , Neal DE 30 , Donovan JL 31 , Hamdy FC 32 , Martin RM 31 , Travis RC 33 , Key TJ 33 , Hamilton RJ 34 , Fleshner NE 34 , Finelli A 34 , Ingles SA 6 , Stern MC 6 , Rosenstein B 35 , Kerns S 36 , Ostrer H 37 , Lu YJ 38 , Zhang HW 39 , Feng N 40 , Mao X 38 , Guo X 41 , Wang G 42 , Sun Z 43 , Giles GG 44 , Southey MC 45 , MacInnis RJ 44 , FitzGerald LM 46 , Kibel AS 47 , Drake BF 25 , Vega A 48 , Gómez-Caamaño A 49 , Fachal L 3 , Szulkin R 50 , Eklund M 16 , Kogevinas M 51 , Llorca J 52 , Castaño-Vinyals G 51 , Penney KL 53 , Stampfer M 53 , Park JY 54 , Sellers TA 54 , Lin HY 55 , Stanford JL 56 , Cybulski C 57 , Wokolorczyk D 57 , Lubinski J 57 , Ostrander EA 58 , Geybels MS 56 , Nordestgaard BG 59 , Nielsen SF 59 , Weisher M 60 , Bisbjerg R 61 , Røder MA 62 , Iversen P 59 , Brenner H 63 , Cuk K 63 , Holleczek B 64 , Maier C 65 , Luedeke M 65 , Schnoeller T 66 , Kim J 67 , Logothetis CJ 67 , John EM 68 , Teixeira MR 69 , Paulo P 69 , Cardoso M 69 , Neuhausen SL 70 , Steele L 70 , Ding YC 70 , De Ruyck K 71 , De Meerleer G 71 , Ost P 72 , Razack A 73 , Lim J 73 , Teo SH 74 , Lin DW 56 , Newcomb LF 56 , Lessel D 75 , Gamulin M 76 , Kulis T 77 , Kaneva R 78 , Usmani N 79 , Slavov C 80 , Mitev V 78 , Parliament M 79 , Singhal S 79 , Claessens F 81 , Joniau S 82 , Van den Broeck T 81 , Larkin S 83 , Townsend PA 84 , Aukim-Hastie C 85 , Gago-Dominguez M 86 , Castelao JE 87 , Martinez ME 88 , Roobol MJ 89 , Jenster G 89 , van Schaik RHN 90 , Menegaux F 91 , Truong T 91 , Koudou YA 91 , Xu J 92 , Khaw KT 93 , Cannon-Albright L 94 , Pandha H 85 , Michael A 85 , Kierzek A 85 , Thibodeau SN 95 , McDonnell SK 96 , Schaid DJ 96 , Lindstrom S 97 , Turman C 98 , Ma J 53 , Hunter DJ 98 , Riboli E 99 , Siddiq A 100 , Canzian F 101 , Kolonel LN 102 , Le Marchand L 102 , Hoover RN 5 , Machiela MJ 5 , Kraft P 98 , PRACTICAL (Prostate Cancer Association Group to Investigate Cancer-Associated Alterations in the Genome) Consortium , Freedman M 103 , Wiklund F 16 , Chanock S 5 , Henderson BE 6 , Easton DF 3 , Haiman CA 6 , Eeles RA 1 , Conti DV 6 , Kote-Jarai Z 104

Affiliations 

  • 1 The Institute of Cancer Research, London, SW7 3RP, UK
  • 2 MRC Biostatistics Unit, University of Cambridge, Robinson Way, Cambridge, CB2 0SR, UK
  • 3 Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, Strangeways Research Laboratory, University of Cambridge, Cambridge, CB1 8RN, UK
  • 4 Department of Population and Quantitative Health Sciences, Case Western Reserve University, Cleveland, OH, 44106-7219, USA
  • 5 Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, Bethesda, MD, 20892, USA
  • 6 Department of Preventive Medicine, Keck School of Medicine, University of Southern California/Norris Comprehensive Cancer Center, Los Angeles, CA, 90015, USA
  • 7 Institute of Population Health, University of Manchester, Manchester, M13 9PL, UK
  • 8 Epidemiology Research Program, American Cancer Society, 250 Williams Street, Atlanta, GA, 30303, USA
  • 9 SWOG Statistical Center, Fred Hutchinson Cancer Research Center, Seattle, WA, 98109, USA
  • 10 CHRISTUS Santa Rosa Hospital - Medical Center, San Antonio, TX, 78229, USA
  • 11 Australian Prostate Cancer Research Centre-Qld, Institute of Health and Biomedical Innovation and School of Biomedical Science, Queensland University of Technology, Brisbane, QLD, 4059, Australia
  • 12 Menzies Health Institute Queensland, Griffith University, Gold Coast, QLD, 4222, Australia
  • 13 Chris O'Brien Lifehouse (COBLH), Camperdown, Sydney, NSW, 2010, Australia
  • 14 Dame Roma Mitchell Cancer Research Centre, University of Adelaide, Adelaide, SA, 5005, Australia
  • 15 Department of Anatomy and Developmental Biology, Biomedicine Discovery Institute, Monash University, Melbourne, VIC, 3800, Australia
  • 16 Department of Medical Epidemiology and Biostatistics, Karolinska Institute, SE-171 77, Stockholm, Sweden
  • 17 Centre for Cancer Genetic Epidemiology, Department of Oncology, Strangeways Laboratory, University of Cambridge, Cambridge, CB1 8RN, UK
  • 18 Institute of Biomedicine, University of Turku, FI-20014, Turku, Finland
  • 19 Department of Urology, Tampere University Hospital, University of Tampere, Kalevantie 4, FI-33014, Tampere, Finland
  • 20 Department of Epidemiology, School of Health Sciences, University of Tampere, FI-33014, Tampere, Finland
  • 21 Division of Nutritional Epidemiology, Institute of Environmental Medicine, Karolinska Institutet, SE-171 77, Stockholm, Sweden
  • 22 Division of Cancer Sciences, Manchester Academic Health Science Centre, Radiotherapy Related Research, Manchester NIHR Biomedical Research Centre, The Christie Hospital NHS Foundation Trust, University of Manchester, Manchester, M13 9PL, UK
  • 23 University of Cambridge Department of Oncology, Oncology Centre, Cambridge University Hospitals NHS Foundation Trust, Cambridge, CB1 8RN, UK
  • 24 Department of Epidemiology, Harvard School of Public Health, Boston, MA, 02115, USA
  • 25 Washington University School of Medicine, St. Louis, MO, 63110, USA
  • 26 GRC N°5 ONCOTYPE-URO, UPMC Univ Paris 06, Tenon Hospital, F-75020, Paris, France
  • 27 Department of Molecular Medicine, Aarhus University Hospital, 8200, Aarhus N, Denmark
  • 28 Department of Clinical Medicine, Aarhus University, 8200, Aarhus N, Denmark
  • 29 Department of Medical Genetics, Oslo University Hospital, 0424, Oslo, Norway
  • 30 Department of Oncology, Addenbrooke's Hospital, University of Cambridge, Cambridge, CB2 0QQ, UK
  • 31 School of Social and Community Medicine, University of Bristol, Canynge Hall, 39 Whatley Road, Bristol, BS8 2PS, UK
  • 32 Nuffield Department of Surgical Sciences, University of Oxford, Oxford, OX1 2JD, UK
  • 33 Cancer Epidemiology, Nuffield Department of Population Health, University of Oxford, Oxford, OX3 7LF, UK
  • 34 Department of Surgical Oncology, Princess Margaret Cancer Centre, Toronto, ON, M5G 2M9, Canada
  • 35 Department of Radiation Oncology, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA
  • 36 Department of Radiation Oncology, University of Rochester Medical Center, Rochester, NY, 14620, USA
  • 37 Professor of Pathology and Pediatrics, Albert Einstein College of Medicine, Bronx, NY, 10461, USA
  • 38 Centre for Molecular Oncology, Barts Cancer Institute, John Vane Science Centre, Queen Mary University of London, London, EC1M 6BQ, UK
  • 39 Second Military Medical University, Shanghai, 200433, P. R. China
  • 40 Wuxi Second Hospital, Nanjing Medical University, Wuxi, Jiangzhu, 214003, China
  • 41 Department of Urology, The First Affiliated Hospital, Chongqing Medical University, Chongqing, 200032, China
  • 42 Department of Urology, Zhongshan Hospital, Fudan University Medical College, Shanghai, 200032, China
  • 43 The People's Hospital of Liaoning Province and The People's Hospital of China Medical University, Shenyang, 110001, China
  • 44 Cancer Epidemiology & Intelligence Division, Cancer Council Victoria, Melbourne, VIC, 3004, Australia
  • 45 Precision Medicine, School and Clinical Sciences at Monash Health, Monash University, Clayton, VIC, 3168, Australia
  • 46 Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, VIC, 3010, Australia
  • 47 Division of Urologic Surgery, Brigham and Womens Hospital, Boston, MA, 02115, USA
  • 48 Fundación Pública Galega de Medicina Xenómica-SERGAS, Grupo de Medicina Xenómica, CIBERER, IDIS, Santiago de Compostela, 15706, Spain
  • 49 Department of Radiation Oncology, Complexo Hospitalario Universitario de Santiago, SERGAS, 15706, Santiago de Compostela, Spain
  • 50 Division of Family Medicine, Department of Neurobiology, Care Science and Society, Karolinska Institutet, Huddinge, SE-171 77, Stockholm, Sweden
  • 51 Centre for Research in Environmental Epidemiology (CREAL), Barcelona Institute for Global Health (ISGlobal), 08003, Barcelona, Spain
  • 52 CIBER Epidemiología y Salud Pública (CIBERESP), 28029, Madrid, Spain
  • 53 Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital/Harvard Medical School, Boston, MA, 02184, USA
  • 54 Department of Cancer Epidemiology, Moffitt Cancer Center, Tampa, FL, 33612, USA
  • 55 School of Public Health, Louisiana State University Health Sciences Center, New Orleans, LA, 70112, USA
  • 56 Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA, 98109-1024, USA
  • 57 International Hereditary Cancer Center, Department of Genetics and Pathology, Pomeranian Medical University, 70-115, Szczecin, Poland
  • 58 National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, 20892, USA
  • 59 Faculty of Health and Medical Sciences, University of Copenhagen, 2200, Copenhagen, Denmark
  • 60 Department of Clinical Biochemistry, Herlev and Gentofte Hospital, Copenhagen University Hospital, Herlev, 2200, Copenhagen, Denmark
  • 61 Department of Urology, Herlev and Gentofte Hospital, Copenhagen University Hospital, Herlev, 2200, Copenhagen, Denmark
  • 62 Copenhagen Prostate Cancer Center, Department of Urology, Rigshospitalet, Copenhagen University Hospital, DK-2730, Herlev, Denmark
  • 63 Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), D-69120, Heidelberg, Germany
  • 64 Saarland Cancer Registry, 66119, Saarbrücken, Germany
  • 65 Institute for Human Genetics, University Hospital Ulm, 89075, Ulm, Germany
  • 66 Department of Urology, University Hospital Ulm, 89075, Ulm, Germany
  • 67 Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA
  • 68 Cancer Prevention Institute of California, Fremont, CA, 94538, USA
  • 69 Department of Genetics, Portuguese Oncology Institute of Porto, 4200-072, Porto, Portugal
  • 70 Department of Population Sciences, Beckman Research Institute of the City of Hope, Duarte, CA, 91010, USA
  • 71 Ghent University, Faculty of Medicine and Health Sciences, Basic Medical Sciences, B-9000, Gent, Belgium
  • 72 Department of Radiotherapy, Ghent University Hospital, B-9000, Gent, Belgium
  • 73 Department of Surgery, Faculty of Medicine, University of Malaya, 50603, Kuala Lumpur, Malaysia
  • 74 Cancer Research Malaysia (CRM), Outpatient Centre, Subang Jaya Medical Centre, 47500, Subang Jaya, Selangor, Malaysia
  • 75 Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, D-20246, Hamburg, Germany
  • 76 Division of Medical Oncology, Urogenital Unit, Department of Oncology at the University Hospital Centre Zagreb, Šalata 2, 10000, Zagreb, Croatia
  • 77 Department of Urology, University Hospital Center Zagreb, University of Zagreb School of Medicine, Šalata 2, 10000, Zagreb, Croatia
  • 78 Molecular Medicine Center, Department of Medical Chemistry and Biochemistry, Medical University of Sofia, 1431, Sofia, Bulgaria
  • 79 Department of Oncology, Cross Cancer Institute, University of Alberta, Edmonton, AB, T6G 1Z2, Canada
  • 80 Department of Urology and Alexandrovska University Hospital, Medical University of Sofia, 1431, Sofia, Bulgaria
  • 81 Molecular Endocrinology Laboratory, Department of Cellular and Molecular Medicine, KU Leuven, BE-3000, Leuven, Belgium
  • 82 Department of Urology, University Hospitals Leuven, BE-3000, Leuven, Belgium
  • 83 Southampton General Hospital, The University of Southampton, Southampton, SO16 6YD, UK
  • 84 Manchester Cancer Research Centre, Faculty of Biology Medicine & Health, Manchester Academic Health Science Centre, NIHR Manchester Biomedical Research Centre, Health Innovation Manchester, University of Manchester, Manchester, M13 9WL, UK
  • 85 The University of Surrey, Guildford, Surrey, GU2 7XH, UK
  • 86 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
  • 87 Genetic Oncology Unit, CHUVI Hospital, Complexo Hospitalario Universitario de Vigo, Instituto de Investigación Biomédica Galicia Sur (IISGS), 36204, Vigo (Pontevedra), Spain
  • 88 Moores Cancer Center, Department of Family Medicine and Public Health, University of California San Diego, La Jolla, CA, 92093-0012, USA
  • 89 Department of Urology, Erasmus University Medical Center, 3015 CE, Rotterdam, The Netherlands
  • 90 Department of Clinical Chemistry, Erasmus University Medical Center, 3015 CE, Rotterdam, The Netherlands
  • 91 Cancer & Environment Group, Center for Research in Epidemiology and Population Health (CESP), INSERM, University Paris-Sud, University Paris-Saclay, 94807, Villejuif Cédex, France
  • 92 Program for Personalized Cancer Care, NorthShore University HealthSystem, Evanston, IL, 60201, USA
  • 93 Clinical Gerontology Unit, University of Cambridge, Cambridge, CB2 2QQ, UK
  • 94 Division of Genetic Epidemiology, Department of Medicine, University of Utah School of Medicine, Salt Lake City, UT, 84112, USA
  • 95 Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, 55905, USA
  • 96 Division of Biomedical Statistics & Informatics, Mayo Clinic, Rochester, MN, 55905, USA
  • 97 Department of Epidemiology, University of Washington, Seattle, WA, 98195, USA
  • 98 Program in Genetic Epidemiology and Statistical Genetics, Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, 02115, USA
  • 99 Department of Epidemiology and Biostatistics, School of Public Health, Imperial College, London, SW7 2AZ, UK
  • 100 Genomics England, Queen Mary University of London, Dawson Hall, Charterhouse Square, London, EC1M 6BQ, UK
  • 101 Genomic Epidemiology Group, German Cancer Research Center (DKFZ), D-69120, Heidelberg, Germany
  • 102 Epidemiology Program, University of Hawaii Cancer Center, Honolulu, HI, 96813, USA
  • 103 Dana-Farber Cancer Institute, Boston, MA, 02215, USA
  • 104 The Institute of Cancer Research, London, SW7 3RP, UK. zsofia.kote-jarai@icr.ac.uk
Nat Commun, 2018 06 11;9(1):2256.
PMID: 29892050 DOI: 10.1038/s41467-018-04109-8

Abstract

Prostate cancer is a polygenic disease with a large heritable component. A number of common, low-penetrance prostate cancer risk loci have been identified through GWAS. Here we apply the Bayesian multivariate variable selection algorithm JAM to fine-map 84 prostate cancer susceptibility loci, using summary data from a large European ancestry meta-analysis. We observe evidence for multiple independent signals at 12 regions and 99 risk signals overall. Only 15 original GWAS tag SNPs remain among the catalogue of candidate variants identified; the remainder are replaced by more likely candidates. Biological annotation of our credible set of variants indicates significant enrichment within promoter and enhancer elements, and transcription factor-binding sites, including AR, ERG and FOXA1. In 40 regions at least one variant is colocalised with an eQTL in prostate cancer tissue. The refined set of candidate variants substantially increase the proportion of familial relative risk explained by these known susceptibility regions, which highlights the importance of fine-mapping studies and has implications for clinical risk profiling.

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

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