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Nat Genet. 2018 Jul;50(7):928-936. doi: 10.1038/s41588-018-0142-8. Epub 2018 Jun 11.

Association analyses of more than 140,000 men identify 63 new prostate cancer susceptibility loci.

Schumacher FR1,2, Al Olama AA3,4, Berndt SI5, Benlloch S6,7, Ahmed M7, Saunders EJ7, Dadaev T7, Leongamornlert D7, Anokian E7, Cieza-Borrella C7, Goh C7, Brook MN7, Sheng X8, Fachal L9,10, Dennis J6, Tyrer J6, Muir K11,12, Lophatananon A11,12, Stevens VL13, Gapstur SM13, Carter BD13, Tangen CM14, Goodman PJ14, Thompson IM Jr15, Batra J16,17, Chambers S18,19, Moya L16,17, Clements J16,17, Horvath L20,21, Tilley W22, Risbridger GP23,24, Gronberg H25, Aly M26,27, Nordström T25,28, Pharoah P6,10, Pashayan N10,29, Schleutker J30,31, Tammela TLJ32, Sipeky C30, Auvinen A33, Albanes D5, Weinstein S5, Wolk A34,35, Håkansson N34, West CML36, Dunning AM10, Burnet N37, Mucci LA38, Giovannucci E38, Andriole GL39, Cussenot O40,41, Cancel-Tassin G40,41, Koutros S5, Beane Freeman LE5, Sorensen KD42,43, Orntoft TF42,43, Borre M43,44, Maehle L45, Grindedal EM45, Neal DE46,47,48, Donovan JL49, Hamdy FC48, Martin RM49, Travis RC50, Key TJ50, Hamilton RJ51, Fleshner NE51, Finelli A52, Ingles SA8, Stern MC8, Rosenstein BS53,54, Kerns SL55, Ostrer H56, Lu YJ57, Zhang HW58, Feng N59, Mao X57, Guo X60, Wang G61, Sun Z62, Giles GG63,64, Southey MC65, MacInnis RJ63,64, FitzGerald LM63,66, Kibel AS67, Drake BF39, Vega A9, Gómez-Caamaño A68, Szulkin R69,70, Eklund M25, Kogevinas M71,72,73,74, Llorca J72,75, Castaño-Vinyals G71,72,73,74, Penney KL76, Stampfer M76, Park JY77, Sellers TA77, Lin HY78, Stanford JL79,80, Cybulski C81, Wokolorczyk D81, Lubinski J81, Ostrander EA82, Geybels MS79, Nordestgaard BG83,84, Nielsen SF83,84, Weischer M84, Bisbjerg R85, Røder MA86, Iversen P86, Brenner H87,88,89, Cuk K87, Holleczek B90, Maier C91, Luedeke M91, Schnoeller T92, Kim J93, Logothetis CJ93, John EM94,95, Teixeira MR96,97, Paulo P96, Cardoso M96, Neuhausen SL98, Steele L98, Ding YC98, De Ruyck K99, De Meerleer G99, Ost P100, Razack A101, Lim J101, Teo SH102, Lin DW79,103, Newcomb LF79,103, Lessel D104, Gamulin M105, Kulis T106, Kaneva R107, Usmani N108,109, Singhal S108,109, Slavov C110, Mitev V107, Parliament M108,109, Claessens F111, Joniau S112, Van den Broeck T111,112, Larkin S113, Townsend PA114, Aukim-Hastie C115, Gago-Dominguez M116,117, Castelao JE118, Martinez ME119, Roobol MJ120, Jenster G120, van Schaik RHN121, Menegaux F122, Truong T122, Koudou YA122, Xu J123, Khaw KT124, Cannon-Albright L125,126, Pandha H115, Michael A115, Thibodeau SN127, McDonnell SK128, Schaid DJ128, Lindstrom S80, Turman C129, Ma J76, Hunter DJ129, Riboli E130, Siddiq A131, Canzian F132, Kolonel LN133, Le Marchand L133, Hoover RN5, Machiela MJ5, Cui Z134, Kraft P129, Amos CI135,136,137, Conti DV8, Easton DF6,10, Wiklund F25, Chanock SJ5, Henderson BE8, Kote-Jarai Z7, Haiman CA8, Eeles RA138,139; Profile Study; Australian Prostate Cancer BioResource (APCB); IMPACT Study; Canary PASS Investigators; Breast and Prostate Cancer Cohort Consortium (BPC3); PRACTICAL (Prostate Cancer Association Group to Investigate Cancer-Associated Alterations in the Genome) Consortium; Cancer of the Prostate in Sweden (CAPS); Prostate Cancer Genome-wide Association Study of Uncommon Susceptibility Loci (PEGASUS); Genetic Associations and Mechanisms in Oncology (GAME-ON)/Elucidating Loci Involved in Prostate Cancer Susceptibility (ELLIPSE) Consortium.

Author information

1
Department of Population and Quantitative Health Sciences, Case Western Reserve University, Cleveland, OH, USA. frs2@case.edu.
2
Seidman Cancer Center, University Hospitals, Cleveland, OH, USA. frs2@case.edu.
3
Department of Public Health and Primary Care, Centre for Cancer Genetic Epidemiology, University of Cambridge, Strangeways Research Laboratory, Cambridge, UK. aa461@medschl.cam.ac.uk.
4
Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK. aa461@medschl.cam.ac.uk.
5
Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, Bethesda, MD, USA.
6
Department of Public Health and Primary Care, Centre for Cancer Genetic Epidemiology, University of Cambridge, Strangeways Research Laboratory, Cambridge, UK.
7
Institute of Cancer Research, London, UK.
8
Department of Preventive Medicine, Keck School of Medicine, University of Southern California/Norris Comprehensive Cancer Center, Los Angeles, CA, USA.
9
Fundación Pública Galega de Medicina Xenómica-SERGAS, Grupo de Medicina Xenómica, CIBERER, IDIS, Santiago de Compostela, Spain.
10
Department of Oncology, Centre for Cancer Genetic Epidemiology, Strangeways Laboratory, University of Cambridge, Cambridge, UK.
11
Division of Population Health, Health Services Research and Primary Care, University of Manchester, Manchester, UK.
12
Warwick Medical School, University of Warwick, Coventry, UK.
13
Epidemiology Research Program, American Cancer Society, Atlanta, GA, USA.
14
SWOG Statistical Center, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
15
CHRISTUS Santa Rosa Hospital-Medical Center, San Antonio, TX, USA.
16
Institute of Health and Biomedical Innovation and School of Biomedical Sciences, Queensland University of Technology, Brisbane, Queensland, Australia.
17
Australian Prostate Cancer Research Centre-Qld, Translational Research Institute, Brisbane, Queensland, Australia.
18
Menzies Health Institute of Queensland, Griffith University, Nathan, Queensland, Australia.
19
Cancer Council Queensland, Fortitude Valley, Queensland, Australia.
20
Chris O'Brien Lifehouse (COBLH), Camperdown, New South Wales, Australia.
21
Garvan Institute of Medical Research, Sydney, New South Wales, Australia.
22
Dame Roma Mitchell Cancer Research Centre, University of Adelaide, Adelaide, South Australia, Australia.
23
Monash Biomedicine Discovery Institute Cancer Program, Prostate Cancer Research Program, Department of Anatomy and Developmental Biology, Monash University, Victoria, Australia.
24
Cancer Research Division, Peter MacCallum Cancer Centre, Melbourne, Australia.
25
Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
26
Department of Urology, Karolinska University Hospital, Stockholm, Sweden.
27
Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.
28
Department of Clinical Sciences at Danderyds Hospital, Karolinska Institutet, Stockholm, Sweden.
29
Department of Applied Health Research, University College London, London, UK.
30
Institute of Biomedicine, University of Turku, Turku, Finland.
31
Tyks Microbiology and Genetics, Department of Medical Genetics, Turku University Hospital, Turku, Finland.
32
Department of Urology, Tampere University Hospital and Faculty of Medicine and Life Sciences, University of Tampere, Tampere, Finland.
33
Department of Epidemiology, School of Health Sciences, University of Tampere, Tampere, Finland.
34
Division of Nutritional Epidemiology, Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.
35
Department of Surgical Sciences, Uppsala University, Uppsala, Sweden.
36
Division of Cancer Sciences, Manchester Cancer Research Centre, Manchester Academic Health Science Centre and Christie NHS Foundation Trust, University of Manchester, Manchester, UK.
37
Department of Oncology, Oncology Centre, Cambridge University Hospitals NHS Foundation Trust, University of Cambridge, Cambridge, UK.
38
Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
39
Washington University School of Medicine, St. Louis, MO, USA.
40
UPMC Sorbonne Universités, GRC no. 5 ONCOTYPE-URO, Tenon Hospital, Paris, France.
41
CeRePP, Tenon Hospital, Paris, France.
42
Department of Molecular Medicine, Aarhus University Hospital, Aarhus, Denmark.
43
Department of Clinical Medicine, Aarhus University, Aarhus, Denmark.
44
Department of Urology, Aarhus University Hospital, Aarhus, Denmark.
45
Department of Medical Genetics, Oslo University Hospital, Oslo, Norway.
46
Department of Oncology, Addenbrooke's Hospital, University of Cambridge, Cambridge, UK.
47
Cancer Research UK, Cambridge Research Institute, Cambridge, UK.
48
Nuffield Department of Surgical Sciences, University of Oxford, Oxford, UK, Faculty of Medical Science, John Radcliffe Hospital, University of Oxford, Oxford, UK.
49
School of Social and Community Medicine, University of Bristol, Bristol, UK.
50
Cancer Epidemiology Unit, Nuffield Department of Population Health, University of Oxford, Oxford, UK.
51
Department of Surgical Oncology, Princess Margaret Cancer Centre, Toronto, Ontario, Canada.
52
Division of Urology, Princess Margaret Cancer Centre, Toronto, Ontario, Canada.
53
Department of Radiation Oncology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
54
Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
55
Department of Radiation Oncology, University of Rochester Medical Center, Rochester, NY, USA.
56
Department of Pathology, Albert Einstein College of Medicine, Bronx, NY, USA.
57
Centre for Molecular Oncology, Barts Cancer Institute, Queen Mary University of London, London, UK.
58
Second Military Medical University, Shanghai, China.
59
Wuxi Second Hospital, Nanjing Medical University, Wuxi, China.
60
Department of Urology, First Affiliated Hospital, Chongqing Medical University, Chongqing, China.
61
Department of Urology, Zhongshan Hospital, Fudan University Medical College, Shanghai, China.
62
People's Hospital of Liaoning Province, People's Hospital of China Medical University, Shenyang, China.
63
Cancer Epidemiology and Intelligence Division, Cancer Council Victoria, Melbourne, Victoria, Australia.
64
Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, University of Melbourne, Melbourne, Australia.
65
Precision Medicine, School of Clinical Sciences at Monash Health, Monash University, Clayton, Victoria, Australia.
66
Menzies Institute for Medical Research, University of Tasmania, Hobart, Tasmania, Australia.
67
Division of Urologic Surgery, Brigham and Womens Hospital, Boston, MA, USA.
68
Department of Radiation Oncology, Complexo Hospitalario Universitario de Santiago, SERGAS, Santiago de Compostela, Spain.
69
Division of Family Medicine, Department of Neurobiology, Care Science and Society, Karolinska, Institutet, Huddinge, Sweden.
70
Scandinavian Development Services, Danderyd, Sweden.
71
ISGlobal, Centre for Research in Environmental Epidemiology (CREAL), Barcelona, Spain.
72
CIBER Epidemiología y Salud Pública (CIBERESP), Madrid, Spain.
73
IMIM (Hospital del Mar Research Institute), Barcelona, Spain.
74
Universitat Pompeu Fabra (UPF), Barcelona, Spain.
75
University of Cantabria-IDIVAL, Santander, Spain.
76
Department of Medicine, Channing Division of Network Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
77
Department of Cancer Epidemiology, Moffitt Cancer Center, Tampa, FL, USA.
78
Biostatistics Program, School of Public Health, Louisiana State University Health Sciences Center, New Orleans, LA, USA.
79
Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
80
Department of Epidemiology, School of Public Health, University of Washington, Seattle, WA, USA.
81
International Hereditary Cancer Center, Department of Genetics and Pathology, Pomeranian Medical University, Szczecin, Poland.
82
National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA.
83
Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
84
Department of Clinical Biochemistry, Herlev and Gentofte Hospital, Copenhagen University Hospital, Herlev, Denmark.
85
Department of Urology, Herlev and Gentofte Hospital, Copenhagen University Hospital, Herlev, Denmark.
86
Copenhagen Prostate Cancer Center, Department of Urology, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark.
87
Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany.
88
German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany.
89
Division of Preventive Oncology, German Cancer Research Center (DKFZ) and National Center for Tumor Diseases (NCT), Heidelberg, Germany.
90
Saarland Cancer Registry, Saarbrücken, Germany.
91
Institute for Human Genetics, University Hospital Ulm, Ulm, Germany.
92
Department of Urology, University Hospital Ulm, Ulm, Germany.
93
Department of Genitourinary Medical Oncology, University of Texas-MD Anderson Cancer Center, Houston, TX, USA.
94
Cancer Prevention Institute of California, Fremont, CA, USA.
95
Department of Health Research & Policy (Epidemiology) and Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA, USA.
96
Department of Genetics, Portuguese Oncology Institute of Porto, Porto, Portugal.
97
Biomedical Sciences Institute (ICBAS), University of Porto, Porto, Portugal.
98
Department of Population Sciences, Beckman Research Institute of the City of Hope, Duarte, CA, USA.
99
Faculty of Medicine and Health Sciences, Basic Medical Sciences, Ghent University, Ghent, Belgium.
100
Department of Radiotherapy, Ghent University Hospital, Ghent, Belgium.
101
Department of Surgery, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia.
102
Cancer Research Malaysia (CRM), Outpatient Centre, Subang Jaya Medical Centre, Selangor, Malaysia.
103
Department of Urology, University of Washington, Seattle, WA, USA.
104
Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
105
Department of Oncology, Division of Medical Oncology, Urogenital Unit, University Hospital Centre Zagreb, Zagreb, Croatia.
106
Department of Urology, University Hospital Center Zagreb, University of Zagreb School of Medicine, Zagreb, Croatia.
107
Molecular Medicine Center, Department of Medical Chemistry and Biochemistry, Medical University of Sofia, Sofia, Bulgaria.
108
Department of Oncology, Cross Cancer Institute, University of Alberta, Edmonton, Alberta, Canada.
109
Division of Radiation Oncology, Cross Cancer Institute, Edmonton, Alberta, Canada.
110
Department of Urology and Alexandrovska University Hospital, Medical University of Sofia, Sofia, Bulgaria.
111
Molecular Endocrinology Laboratory, Department of Cellular and Molecular Medicine, KU Leuven, Leuven, Belgium.
112
Department of Urology, University Hospitals Leuven, Leuven, Belgium.
113
University of Southampton, Southampton General Hospital, Southampton, UK.
114
Division of Cancer Sciences, Manchester Cancer Research Centre, Faculty of Biology, Medicine and Health, Manchester Academic Health Science Center, NIHR Manchester Biomedical Research Centre, Health Innovation Manchester, University of Manchester, Manchester, UK.
115
University of Surrey, Guildford, Surrey, UK.
116
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, Santiago de Compostela, Spain.
117
Moores Cancer Center, University of California San Diego, La Jolla, CA, USA.
118
Genetic Oncology Unit, CHUVI Hospital, Instituto de Investigación Biomédica Galicia Sur (IISGS), Complexo Hospitalario Universitario de Vigo, Vigo, Spain.
119
Department of Family Medicine and Public Health, Moores Cancer Center, University of California San Diego, La Jolla, CA, USA.
120
Department of Urology, Erasmus University Medical Center, Rotterdam, The Netherlands.
121
Department of Clinical Chemistry, Erasmus University Medical Center, Rotterdam, The Netherlands.
122
Cancer & Environment Group, Center for Research in Epidemiology and Population Health (CESP), INSERM, University Paris-Sud, University Paris-Saclay, Villejuif, France.
123
Program for Personalized Cancer Care, NorthShore University HealthSystem, Evanston, IL, USA.
124
Clinical Gerontology Unit, University of Cambridge, Cambridge, UK.
125
Division of Genetic Epidemiology, Department of Medicine, University of Utah School of Medicine, Salt Lake City, UT, USA.
126
George E. Wahlen Department of Veterans Affairs Medical Center, Salt Lake City, UT, USA.
127
Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA.
128
Division of Biomedical Statistics and Informatics, Mayo Clinic, Rochester, MN, USA.
129
Program in Genetic Epidemiology and Statistical Genetics, Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
130
Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, UK.
131
Genomics England, Queen Mary University of London, London, UK.
132
Genomic Epidemiology Group, German Cancer Research Center (DKFZ), Heidelberg, Germany.
133
Epidemiology Program, University of Hawaii Cancer Center, Honolulu, HI, USA.
134
Department of Population and Quantitative Health Sciences, Case Western Reserve University, Cleveland, OH, USA.
135
Department of Biomedical Data Science, Geisel School of Medicine at Dartmouth, Lebanon, NH, USA.
136
Department of Molecular and Systems Biology, Geisel School of Medicine at Dartmouth, Hanover, NH, USA.
137
Norris Cotton Cancer Center, Geisel School of Medicine at Dartmouth, Lebanon, NH, USA.
138
Institute of Cancer Research, London, UK. ros.eeles@icr.ac.uk.
139
Royal Marsden NHS Foundation Trust, London, UK. ros.eeles@icr.ac.uk.

Abstract

Genome-wide association studies (GWAS) and fine-mapping efforts to date have identified more than 100 prostate cancer (PrCa)-susceptibility loci. We meta-analyzed genotype data from a custom high-density array of 46,939 PrCa cases and 27,910 controls of European ancestry with previously genotyped data of 32,255 PrCa cases and 33,202 controls of European ancestry. Our analysis identified 62 novel loci associated (P < 5.0 × 10-8) with PrCa and one locus significantly associated with early-onset PrCa (≤55 years). Our findings include missense variants rs1800057 (odds ratio (OR) = 1.16; P = 8.2 × 10-9; G>C, p.Pro1054Arg) in ATM and rs2066827 (OR = 1.06; P = 2.3 × 10-9; T>G, p.Val109Gly) in CDKN1B. The combination of all loci captured 28.4% of the PrCa familial relative risk, and a polygenic risk score conferred an elevated PrCa risk for men in the ninetieth to ninety-ninth percentiles (relative risk = 2.69; 95% confidence interval (CI): 2.55-2.82) and first percentile (relative risk = 5.71; 95% CI: 5.04-6.48) risk stratum compared with the population average. These findings improve risk prediction, enhance fine-mapping, and provide insight into the underlying biology of PrCa1.

PMID:
29892016
DOI:
10.1038/s41588-018-0142-8

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