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Nat Commun. 2018 Nov 5;9(1):4616. doi: 10.1038/s41467-018-06863-1.

Germline variation at 8q24 and prostate cancer risk in men of European ancestry.

Collaborators (227)

Henderson BE, Stern MC, Thwaites A, Guy M, Whitmore I, Morgan A, Fisher C, Hazel S, Livni N, Cook M, Fachal L, Weinstein S, Beane Freeman LE, Hoover RN, Machiela MJ, Lophatananon A, Carter BD, Goodman P, Moya L, Srinivasan S, Kedda MA, Yeadon T, Eckert A, Eklund M, Cavalli-Bjoerkman C, Dunning AM, Sipeky C, Hakansson N, Elliott R, Ranu H, Giovannucci E, Turman C, Hunter DJ, Cussenot O, Orntoft TF, Lane A, Lewis SJ, Davis M, Key TJ, Brown P, Kulkarni GS, Zlotta AR, Fleshner NE, Finelli A, Mao X, Marzec J, MacInnis RJ, Milne R, Hopper JL, Aguado M, Bustamante M, Castaño-Vinyals G, Gracia-Lavedan E, Cecchini L, Stampfer M, Ma J, Sellers TA, Geybels MS, Park H, Zachariah B, Kolb S, Wokolorczyk D, Jan Lubinski, Kluzniak W, Nielsen SF, Weisher M, Cuk K, Vogel W, Luedeke M, Logothetis CJ, Paulo P, Cardoso M, Maia S, Silva MP, Steele L, Ding YC, De Meerleer G, De Langhe S, Thierens H, Lim J, Tan MH, Ong AT, Lin DW, Kachakova D, Mitkova A, Mitev V, Parliament M, Jenster G, Bangma C, Schroder FH, Truong T, Koudou YA, Michael A, Kierzek A, Karlsson A, Broms M, Wu H, Aukim-Hastie C, Tillmans L, Riska S, McDonnell SK, Dearnaley D, Spurdle A, Gardiner R, Hayes V, Butler L, Taylor R, Papargiris M, Saunders P, Kujala P, Talala K, Taari K, Bentzen S, Hicks B, Vogt A, Hutchinson A, Cox A, George A, Toi A, Evans A, van der Kwast TH, Imai T, Saito S, Zhao SC, Ren G, Zhang Y, Yu Y, Wu Y, Wu J, Zhou B, Pedersen J, Lobato-Busto R, Ruiz-Dominguez JM, Mengual L, Alcaraz A, Pow-Sang J, Herkommer K, Vlahova A, Dikov T, Christova S, Carracedo A, Tretarre B, Rebillard X, Mulot C, Jan Adolfsson, Stattin P, Johansson JE, Martin RM, Thompson IM Jr, Chambers S, Aitken J, Horvath L, Haynes AM, Tilley W, Risbridger G, Aly M, Nordström T, Pharoah P, Tammela TLJ, Murtola T, Auvinen A, Burnet N, Barnett G, Andriole G, Klim A, Drake BF, Borre M, Kerns S, Ostrer H, Zhang HW, Cao G, Lin J, Ling J, Li M, Feng N, Li J, He W, Guo X, Sun Z, Wang G, Guo J, Southey MC, FitzGerald LM, Marsden G, Gómez-Caamaño A, Carballo A, Peleteiro P, Calvo P, Szulkin R, Llorca J, Dierssen-Sotos T, Gomez-Acebo I, Lin HY, Ostrander EA, Bisbjerg R, Klarskov P, Røder MA, Iversen P, Holleczek B, Stegmaier C, Schnoeller T, Bohnert P, John EM, Ost P, Teo SH, Gamulin M, Kulis T, Kastelan Z, Slavov C, Popov E, Van den Broeck T, Joniau S, Larkin S, Castelao JE, Martinez ME, van Schaik RHN, Xu J, Lindström S, Riboli E, Berry C, Siddiq A, Canzian F, Kolonel LN, Le Marchand L, Freedman M, Cenee S, Sanchez M.

Author information

1
Department of Preventive Medicine, Keck School of Medicine, University of Southern California/Norris Comprehensive Cancer Center, Los Angeles, CA, 90033, USA.
2
The Institute of Cancer Research, London, SW7 3RP, 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 Clinical Neurosciences, University of Cambridge, Cambridge, CB2 0QQ, UK.
5
Department of Population and Quantitative Health Sciences, Case Western Reserve University, Cleveland, OH, 44106-7219, USA.
6
Seidman Cancer Center, University Hospitals, Cleveland, OH, 44106, USA.
7
Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, Bethesda, MD, 20892, USA.
8
Institute of Population Health, University of Manchester, Manchester, M13 9PL, UK.
9
Warwick Medical School, University of Warwick, Coventry, CV4 7AL, UK.
10
Epidemiology Research Program, American Cancer Society, 250 Williams Street, Atlanta, GA, 30303, USA.
11
SWOG Statistical Center, Fred Hutchinson Cancer Research Center, Seattle, WA, 98109, USA.
12
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.
13
Translational Research Institute, Brisbane, QLD, 4102, Australia.
14
Department of Medical Epidemiology and Biostatistics, Karolinska Institute, SE-171 77, Stockholm, Sweden.
15
Centre for Cancer Genetic Epidemiology, Department of Oncology, Strangeways Research Laboratory, University of Cambridge, Cambridge, CB1 8RN, UK.
16
Department of Applied Health Research, University College London, London, WC1E 7HB, UK.
17
Department of Medical Biochemistry and Genetics, Institute of Biomedicine, University of Turku, FI-20014, Turku, Finland.
18
Tyks Microbiology and Genetics, Department of Medical Genetics, Turku University Hospital, 20521, Turku, Finland.
19
BioMediTech, University of Tampere, 33520, Tampere, Finland.
20
Division of Nutritional Epidemiology, Institute of Environmental Medicine, Karolinska Institutet, SE-171 77, Stockholm, Sweden.
21
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.
22
Department of Epidemiology, Harvard School of Public Health, Boston, MA, 02115, USA.
23
Program in Genetic Epidemiology and Statistical Genetics, Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, 02115, USA.
24
GRC N°5 ONCOTYPE-URO, UPMC Univ Paris 06, Tenon Hospital, F-75020, Paris, France.
25
CeRePP, Tenon Hospital, F-75020, Paris, France.
26
Department of Molecular Medicine, Aarhus University Hospital, 8200, Aarhus N, Denmark.
27
Department of Clinical Medicine, Aarhus University, 8200, Aarhus N, Denmark.
28
Department of Medical Genetics, Oslo University Hospital, 0424, Oslo, Norway.
29
Department of Epidemiology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA.
30
Department of Oncology, Addenbrooke's Hospital, University of Cambridge, Cambridge, CB2 0QQ, UK.
31
Cancer Research UK Cambridge Research Institute, Li Ka Shing Centre, Cambridge, CB2 0RE, UK.
32
Nuffield Department of Surgical Sciences, University of Oxford, Oxford, OX1 2JD, UK.
33
School of Social and Community Medicine, University of Bristol, Canynge Hall, 39 Whatley Road, Bristol, BS8 2PS, UK.
34
Cancer Epidemiology, Nuffield Department of Population Health, University of Oxford, Oxford, OX3 7LF, UK.
35
Department of Surgical Oncology, Princess Margaret Cancer Centre, Toronto, ON, M5G 2M9, Canada.
36
Department of Radiation Oncology, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA.
37
Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, 10029-5674, USA.
38
Centre for Molecular Oncology, John Vane Science Centre, Barts Cancer Institute, Queen Mary University of London, London, EC1M 6BQ, UK.
39
Cancer Epidemiology & Intelligence Division, Cancer Council Victoria, Melbourne, VIC, 3004, Australia.
40
Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, VIC, 3010, Australia.
41
Division of Urologic Surgery, Brigham and Womens Hospital, Boston, MA, 02115, USA.
42
Fundación Pública Galega de Medicina Xenómica-SERGAS, Grupo de Medicina Xenómica, CIBERER, IDIS, 15706, Santiago de Compostela, Spain.
43
Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina, Columbia, SC, 29208, USA.
44
Centre for Research in Environmental Epidemiology (CREAL), Barcelona Institute for Global Health (ISGlobal), 08003, Barcelona, Spain.
45
CIBER Epidemiología y Salud Pública (CIBERESP), 28029, Madrid, Spain.
46
IMIM (Hospital del Mar Research Institute), 08003, Barcelona, Spain.
47
Universitat Pompeu Fabra (UPF), 08002, Barcelona, Spain.
48
Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital/Harvard Medical School, Boston, MA, 02184, USA.
49
Department of Cancer Epidemiology, Moffitt Cancer Center, Tampa, FL, 33612, USA.
50
Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA, 98109-1024, USA.
51
Department of Epidemiology, School of Public Health, University of Washington, Seattle, WA, 98195, USA.
52
International Hereditary Cancer Center, Department of Genetics and Pathology, Pomeranian Medical University, 70-115, Szczecin, Poland.
53
Faculty of Health and Medical Sciences, University of Copenhagen, 2200, Copenhagen, Denmark.
54
Department of Clinical Biochemistry, Herlev and Gentofte Hospital, Copenhagen University Hospital, Herlev, 2200, Copenhagen, Denmark.
55
Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), D-69120, Heidelberg, Germany.
56
German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), D-69120, Heidelberg, Germany.
57
Division of Preventive Oncology, German Cancer Research Center (DKFZ) and National Center for Tumor Diseases (NCT), 69120, Heidelberg, Germany.
58
Institute for Human Genetics, University Hospital Ulm, 89075, Ulm, Germany.
59
Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA.
60
Department of Genetics, Portuguese Oncology Institute of Porto, 4200-072, Porto, Portugal.
61
Biomedical Sciences Institute (ICBAS), University of Porto, 4050-313, Porto, Portugal.
62
Department of Population Sciences, Beckman Research Institute of the City of Hope, Duarte, CA, 91010, USA.
63
Ghent University, Faculty of Medicine and Health Sciences, Basic Medical Sciences, B-9000, Gent, Belgium.
64
Department of Surgery, Faculty of Medicine, University of Malaya, 50603, Kuala Lumpur, Malaysia.
65
Department of Urology, University of Washington, Seattle, WA, 98195, USA.
66
Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, D-20246, Hamburg, Germany.
67
Molecular Medicine Center, Department of Medical Chemistry and Biochemistry, Medical University of Sofia, 1431, Sofia, Bulgaria.
68
Department of Oncology, Cross Cancer Institute, University of Alberta, Edmonton, AB, T6G 1Z2, Canada.
69
Division of Radiation Oncology, Cross Cancer Institute, University of Alberta, Edmonton, AB, T6G 1Z2, Canada.
70
Molecular Endocrinology Laboratory, Department of Cellular and Molecular Medicine, KU Leuven, BE-3000, Leuven, Belgium.
71
Manchester Cancer Research Centre, Faculty of Biology Medicine and Health, Manchester Academic Health Science Centre, NIHR Manchester Biomedical Research Centre, Health Innovation Manchester, University of Manchester, Manchester, M13 9WL, UK.
72
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.
73
Moores Cancer Center, University of California San Diego, La Jolla, CA, 92037, USA.
74
Department of Urology, Erasmus University Medical Center, 3015 CE, Rotterdam, The Netherlands.
75
Cancer and Environment Group, Center for Research in Epidemiology and Population Health (CESP), INSERM, University Paris-Sud, University Paris-Saclay, 94807, Villejuif Cédex, France.
76
Clinical Gerontology Unit, University of Cambridge, Cambridge, CB2 2QQ, UK.
77
Division of Genetic Epidemiology, Department of Medicine, University of Utah School of Medicine, Salt Lake City, UT, 84112, USA.
78
George E. Wahlen Department of Veterans Affairs Medical Center, Salt Lake City, UT, 84148, USA.
79
The University of Surrey, Guildford, Surrey, GU2 7XH, UK.
80
Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, 55905, USA.
81
Division of Biomedical Statistics and Informatics, Mayo Clinic, Rochester, MN, 55905, USA.
82
Royal Marsden NHS Foundation Trust, London, SW3 6JJ, UK.
83
Department of Preventive Medicine, Keck School of Medicine, University of Southern California/Norris Comprehensive Cancer Center, Los Angeles, CA, 90033, USA. Christopher.Haiman@med.usc.edu.

Abstract

Chromosome 8q24 is a susceptibility locus for multiple cancers, including prostate cancer. Here we combine genetic data across the 8q24 susceptibility region from 71,535 prostate cancer cases and 52,935 controls of European ancestry to define the overall contribution of germline variation at 8q24 to prostate cancer risk. We identify 12 independent risk signals for prostate cancer (p < 4.28 × 10-15), including three risk variants that have yet to be reported. From a polygenic risk score (PRS) model, derived to assess the cumulative effect of risk variants at 8q24, men in the top 1% of the PRS have a 4-fold (95%CI = 3.62-4.40) greater risk compared to the population average. These 12 variants account for ~25% of what can be currently explained of the familial risk of prostate cancer by known genetic risk factors. These findings highlight the overwhelming contribution of germline variation at 8q24 on prostate cancer risk which has implications for population risk stratification.

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