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Nat Commun. 2016 Apr 7;7:10979. doi: 10.1038/ncomms10979.

Atlas of prostate cancer heritability in European and African-American men pinpoints tissue-specific regulation.

Gusev A1,2, Shi H3, Kichaev G3, Pomerantz M4, Li F5,6, Long HW4,5, Ingles SA7, Kittles RA8, Strom SS9, Rybicki BA10, Nemesure B11, Isaacs WB12, Zheng W13, Pettaway CA14, Yeboah ED15,16, Tettey Y15,16, Biritwum RB15,16, Adjei AA15,16, Tay E15,16, Truelove A17, Niwa S17, Chokkalingam AP18, John EM19,20, Murphy AB21, Signorello LB1,22, Carpten J23, Leske MC11, Wu SY11, Hennis AJ11,24, Neslund-Dudas C10, Hsing AW19,20, Chu L19,20, Goodman PJ25, Klein EA26, Witte JS27,28, Casey G7, Kaggwa S29, Cook MB30, Stram DO7, Blot WJ13,22, Eeles RA31,32, Easton D33, Kote-Jarai Z31, Al Olama AA33, Benlloch S33, Muir K34,35, Giles GG36,37, Southey MC38, Fitzgerald LM36, Gronberg H39, Wiklund F39, Aly M39,40, Henderson BE41, Schleutker J42,43, Wahlfors T43, Tammela TL44, Nordestgaard BG45,46, Key TJ47, Travis RC47, Neal DE48,49, Donovan JL50, Hamdy FC51,52, Pharoah P53, Pashayan N53,54, Khaw KT55, Stanford JL56,57, Thibodeau SN58, McDonnell SK58, Schaid DJ58, Maier C59, Vogel W59, Luedeke M60, Herkommer K61, Kibel AS62, Cybulski C63, Wokolorczyk D63, Kluzniak W63, Cannon-Albright L64,65, Teerlink C64,65, Brenner H66,67, Dieffenbach AK66,67, Arndt V66, Park JY68, Sellers TA68, Lin HY69, Slavov C70, Kaneva R71, Mitev V71, Batra J72, Spurdle A73, Clements JA72, Teixeira MR74,75, Pandha H76, Michael A76, Paulo P74, Maia S74, Kierzek A76; PRACTICAL consortium, Conti DV77, Albanes D78, Berg C79, Berndt SI30, Campa D80, Crawford ED81, Diver WR82, Gapstur SM82, Gaziano JM1,83,84, Giovannucci E1,85, Hoover R30, Hunter DJ1, Johansson M86,87, Kraft P1,88, Le Marchand L89, Lindström S1,88, Navarro C90,91, Overvad K79, Riboli E92, Siddiq A93, Stevens VL82, Trichopoulos D1,94,95, Vineis P96,97, Yeager M30, Trynka G98,99, Raychaudhuri S2,98,100, Schumacher FR77, Price AL1,2, Freedman ML2,4,5, Haiman CA77, Pasaniuc B3,101,102.

Author information

1
Program in Genetic Epidemiology and Statistical Genetics, Harvard T.H. Chan School of Public Health, Boston, Massachusetts 02115, USA.
2
Broad Institute of Harvard and MIT, Cambridge, Massachusetts 02142, USA.
3
Bioinformatics Interdepartmental Program, University of California Los Angeles, Los Angeles, California 90095, USA.
4
Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts 02115, USA.
5
Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, Massachusetts 02115, USA.
6
Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, Massachusetts 02115, USA.
7
Department of Preventative Medicine, Keck School of Medicine, University of Southern California/Norris Comprehensive Cancer Center, Los Angeles, California 90033, USA.
8
University of Arizona College of Medicine and University of Arizona Cancer Center, Tucson, Arizona 85721, USA.
9
Department of Epidemiology, University of Texas M.D. Anderson Cancer Center, Houston, Texas 77030, USA.
10
Department of Public Health Sciences, Henry Ford Hospital, Detroit, Michigan 48202, USA.
11
Department of Preventive Medicine, Stony Brook University, Stony Brook, New York 11794, USA.
12
James Buchanan Brady Urological Institute, Johns Hopkins Hospital and Medical Institution, Baltimore, Maryland 21205, USA.
13
Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt University School of Medicine, Nashville, Tennessee 37232, USA.
14
Department of Urology, University of Texas M.D. Anderson Cancer Center, Houston, Texas 77030, USA.
15
Korle Bu Teaching Hospital, Accra, Ghana.
16
University of Ghana Medical School, Accra, Ghana.
17
Westat, Rockville, Maryland 20850, USA.
18
School of Public Health, University of California, Berkeley, California 94720, USA.
19
Cancer Prevention Institute of California, Fremont, California 94538, USA.
20
Stanford University School of Medicine and Stanford Cancer Institute, Palo Alto, California 94305, USA.
21
Department of Urology, Northwestern University, Chicago, Illinois 60611, USA.
22
International Epidemiology Institute, Rockville, Maryland 20850, USA.
23
The Translational Genomics Research Institute, Phoenix, Arizona 85004, USA.
24
Chronic Disease Research Centre and Faculty of Medical Sciences, University of the West Indies, Bridgetown, Barbados.
25
SWOG Statistical Center, Fred Hutchinson Cancer Research Center, Seattle, Washington 98109, USA.
26
Glickman Urological &Kidney Institute, Cleveland Clinic, Cleveland, Ohio 44195, USA.
27
Department of Epidemiology and Biostatistics, University of California, San Francisco, San Francisco, California 94118, USA.
28
Institute for Human Genetics, University of California, San Francisco, San Francisco, California 94118, USA.
29
Department of Surgery, Makerere University College of Health Sciences, Kampala 94118, Uganda.
30
Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland 20892, USA.
31
The Institute of Cancer Research, Sutton SM2 5NG, UK.
32
Royal Marsden National Health Service (NHS) Foundation Trust, London and Sutton, UK.
33
Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Strangeways Laboratory, Worts Causeway, Cambridge CB1 8RN, UK.
34
Institute of Population Health, University of Manchester, Manchester M13 9PL, UK.
35
Warwick Medical School, University of Warwick, Coventry CV4 7AL, UK.
36
Cancer Epidemiology Centre, The Cancer Council Victoria, 615 St Kilda Road, Melbourne, Victoria 3004, Australia.
37
Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Victoria 3004, Australia.
38
Genetic Epidemiology Laboratory, Department of Pathology, The University of Melbourne, Grattan Street, Parkville, Victoria 3010, Australia.
39
Department of Medical Epidemiology and Biostatistics, Karolinska Institute, Stockholm 171 77, Sweden.
40
Department of Clinical Sciences at Danderyds Hospital, Stockholm 171 77, Sweden.
41
Department of Preventive Medicine, Keck School of Medicine, University of Southern California/Norris Comprehensive Cancer Center, Los Angeles, California 90007, USA.
42
Department of Medical Biochemistry and Genetics Institute of Biomedicine Kiinamyllynkatu 10, University of Turku, Turku FI-20014, Finland.
43
BioMediTech, University of Tampere and FimLab Laboratories, Tampere 33200, Finland.
44
Department of Urology, Tampere University Hospital and Medical School, University of Tampere, Tampere 33200, Finland.
45
Department of Clinical Biochemistry, Herlev Hospital, Copenhagen University Hospital, Herlev Ringvej 75, Herlev DK-2730, Denmark.
46
Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen 1165, Densmark.
47
Cancer Epidemiology, Nuffield Department of Population Health; University of Oxford, Oxford OX3 7LF, UK.
48
University of Cambridge, Department of Oncology, Addenbrooke's Hospital, Box 279, Hills Road, Cambridge CB2 0QQ.
49
Cancer Research UK Cambridge Research Institute, Li Ka Shing Centre, Cambridge, UK.
50
School of Social and Community Medicine, University of Bristol, Canynge Hall, 39 Whatley Road, Bristol BS8 2PS, UK.
51
Department of Public Health, Section for Epidemiology, Aarhus University, Aarhus OX1 3PN, Denmark.
52
Faculty of Medical Science, University of Oxford, John Radcliffe Hospital, Oxford OX1 3PN, UK.
53
Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Strangeways Laboratory, Worts Causeway, Cambridge CB1 8RN, UK.
54
University College London, Department of Applied Health Research, 1-19 Torrington Place, London WC1E 7HB, UK.
55
Clinical Gerontology Unit, University of Cambridge, Cambridge CB1 8RN, UK.
56
Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington 98109-1024, USA.
57
Department of Epidemiology, School of Public Health, University of Washington, Seattle, Washington 98109, USA.
58
Mayo Clinic, Rochester, Minnesota 55905, USA.
59
Institute of Human Genetics, University Hospital Ulm, 89081 Ulm, Germany.
60
Department of Urology, University Hospital Ulm, 89081 Ulm, Germany.
61
Department of Urology, Klinikum rechts der Isar der Technischen Universitaet Muenchen, 81675 Munich, Germany.
62
Division of Urologic Surgery, Brigham and Womens Hospital, Dana-Farber Cancer Institute, 75 Francis Street, Boston, Massachusetts 02115, USA.
63
International Hereditary Cancer Center, Department of Genetics and Pathology, Pomeranian Medical University, Szczecin, Poland.
64
Division of Genetic Epidemiology, Department of Medicine, University of Utah School of Medicine, Salt Lake City, Utah 84132, USA.
65
George E. Wahlen Department of Veterans Affairs Medical Center, Salt Lake City, Utah 84132, USA.
66
Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg 69120, Germany.
67
German Cancer Consortium (DKTK), Heidelberg 69120, Germany.
68
Department of Cancer Epidemiology, Moffitt Cancer Center, 12902 Magnolia Drive, Tampa, Florida 33612, USA.
69
Biostatistics Program, Moffitt Cancer Center, 12902 Magnolia Drive, Tampa, Florida 33612, USA.
70
Department of Urology and Alexandrovska University Hospital, Medical University, Sofia 1431, Bulgaria.
71
Department of Medical Chemistry and Biochemistry, Molecular Medicine Center, Medical University, Sofia, 2 Zdrave Str., Sofia 1431, Bulgaria.
72
Australian Prostate Cancer Research Centre-Qld, Institute of Health and Biomedical Innovation and School of Biomedical Science, Queensland University of Technology, Brisbane, Queensland 4000, Australia.
73
Molecular Cancer Epidemiology Laboratory, Queensland Institute of Medical Research, Brisbane, Queensland 4000, Australia.
74
Department of Genetics, Portuguese Oncology Institute, Porto 4200, Portugal.
75
Biomedical Sciences Institute (ICBAS), University of Porto, Porto 4200, Portugal.
76
The University of Surrey, Guildford, Surrey GU2 7XH, UK.
77
Department of Preventive Medicine, Norris Cancer Center, University of Southern California Keck School of Medicine, Los Angeles, California 90033, USA.
78
Nutritional Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, US National Institute of Health, Bethesda, Maryland 20892, USA.
79
Department of Radiation Oncology and Molecular Radiation Sciences, Johns Hopkins Medicine, Baltimore, Maryland 21287, USA.
80
Genomic Epidemiology Group, German Cancer Research Center (DKFZ), 69121 Heidelberg, Germany.
81
Urologic Oncology, University of Colorado at Denver Health Sciences Center, Denver, Colorado 80230, USA.
82
Epidemiology Research Program, American Cancer Society, Atlanta, Georgia 30303, USA.
83
Department of Medicine, Harvard Medical School, Boston, Massachusetts 02115, USA.
84
Division of Aging, Brigham and Women's Hospital, Boston, Massachusetts 02115, USA.
85
Department of Nutrition, Harvard School of Public Health, Boston, Massachusetts 02115, USA.
86
International Agency for Research on Cancer, Lyon 69008, France.
87
Department of Surgical and Perioperative Sciences, Urology and Andrology, Umeå University, Umeå 907 36, Sweden.
88
Department of Biostatistics, Harvard School of Public Health, Boston, Massachusetts 02115, USA.
89
Epidemiology Program, University of Hawaii Cancer Center, Honolulu, Hawaii 96813, USA.
90
Department of Epidemiology, Regional Health Authority, Murcia 30009, Spain.
91
CIBER Epidemiología y Salud Pública (CIBERESP), Barcelona 28029, Spain.
92
Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London SW7 2AZ, UK.
93
Department of Genomics of Common Disease, School of Public Health, Imperial College London, London SW7 2AZ, UK.
94
Bureau of Epidemiologic Research, Academy of Athens, Athens 106 79, Greece.
95
Hellenic Health Foundation, Athens 106 79, Greece.
96
HuGeF Foundation, Torino 10126, Italy.
97
School of Public Health, Imperial College London, London SW7 2AZ, UK.
98
Divisions of Genetics and Rheumatology, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA.
99
Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Cambridge CB10 1SA, UK.
100
Institute of Inflammation and Repair, University of Manchester, Manchester M13 9PT, UK.
101
Departments of Pathology and Laboratory Medicine, University of California Los Angeles, Los Angeles, California, USA.
102
Department of Human Genetics, University of California Los Angeles, Los Angeles, California 90095, USA.

Abstract

Although genome-wide association studies have identified over 100 risk loci that explain ∼33% of familial risk for prostate cancer (PrCa), their functional effects on risk remain largely unknown. Here we use genotype data from 59,089 men of European and African American ancestries combined with cell-type-specific epigenetic data to build a genomic atlas of single-nucleotide polymorphism (SNP) heritability in PrCa. We find significant differences in heritability between variants in prostate-relevant epigenetic marks defined in normal versus tumour tissue as well as between tissue and cell lines. The majority of SNP heritability lies in regions marked by H3k27 acetylation in prostate adenoc7arcinoma cell line (LNCaP) or by DNaseI hypersensitive sites in cancer cell lines. We find a high degree of similarity between European and African American ancestries suggesting a similar genetic architecture from common variation underlying PrCa risk. Our findings showcase the power of integrating functional annotation with genetic data to understand the genetic basis of PrCa.

PMID:
27052111
PMCID:
PMC4829663
DOI:
10.1038/ncomms10979
[Indexed for MEDLINE]
Free PMC Article

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