. 2016 Apr 7:7:10979.

doi: 10.1038/ncomms10979.

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

Alexander Gusev^{1

2}, Huwenbo Shi³, Gleb Kichaev³, Mark Pomerantz⁴, Fugen Li^{5

6}, Henry W Long^{4

5}, Sue A Ingles⁷, Rick A Kittles⁸, Sara S Strom⁹, Benjamin A Rybicki¹⁰, Barbara Nemesure¹¹, William B Isaacs¹², Wei Zheng¹³, Curtis A Pettaway¹⁴, Edward D Yeboah^{15

16}, Yao Tettey^{15

16}, Richard B Biritwum^{15

16}, Andrew A Adjei^{15

16}, Evelyn Tay^{15

16}, Ann Truelove¹⁷, Shelley Niwa¹⁷, Anand P Chokkalingam¹⁸, Esther M John^{19

20}, Adam B Murphy²¹, Lisa B Signorello^{1

22}, John Carpten²³, M Cristina Leske¹¹, Suh-Yuh Wu¹¹, Anslem J M Hennis^{11

24}, Christine Neslund-Dudas¹⁰, Ann W Hsing^{19

20}, Lisa Chu^{19

20}, Phyllis J Goodman²⁵, Eric A Klein²⁶, John S Witte^{27

28}, Graham Casey⁷, Sam Kaggwa²⁹, Michael B Cook³⁰, Daniel O Stram⁷, William J Blot^{13

22}, Rosalind A Eeles^{31

32}, Douglas Easton³³, Zsofia Kote-Jarai³¹, Ali Amin Al Olama³³, Sara Benlloch³³, Kenneth Muir^{34

35}, Graham G Giles^{36

37}, Melissa C Southey³⁸, Liesel M Fitzgerald³⁶, Henrik Gronberg³⁹, Fredrik Wiklund³⁹, Markus Aly^{39

40}, Brian E Henderson⁴¹, Johanna Schleutker^{42

43}, Tiina Wahlfors⁴³, Teuvo L J Tammela⁴⁴, Børge G Nordestgaard^{45

46}, Tim J Key⁴⁷, Ruth C Travis⁴⁷, David E Neal^{48

49}, Jenny L Donovan⁵⁰, Freddie C Hamdy^{51

52}, Paul Pharoah⁵³, Nora Pashayan^{53

54}, Kay-Tee Khaw⁵⁵, Janet L Stanford^{56

57}, Stephen N Thibodeau⁵⁸, Shannon K McDonnell⁵⁸, Daniel J Schaid⁵⁸, Christiane Maier⁵⁹, Walther Vogel⁵⁹, Manuel Luedeke⁶⁰, Kathleen Herkommer⁶¹, Adam S Kibel⁶², Cezary Cybulski⁶³, Dominika Wokolorczyk⁶³, Wojciech Kluzniak⁶³, Lisa Cannon-Albright^{64

65}, Craig Teerlink^{64

65}, Hermann Brenner^{66

67}, Aida K Dieffenbach^{66

67}, Volker Arndt⁶⁶, Jong Y Park⁶⁸, Thomas A Sellers⁶⁸, Hui-Yi Lin⁶⁹, Chavdar Slavov⁷⁰, Radka Kaneva⁷¹, Vanio Mitev⁷¹, Jyotsna Batra⁷², Amanda Spurdle⁷³, Judith A Clements⁷², Manuel R Teixeira^{74

75}, Hardev Pandha⁷⁶, Agnieszka Michael⁷⁶, Paula Paulo⁷⁴, Sofia Maia⁷⁴, Andrzej Kierzek⁷⁶; PRACTICAL consortium; David V Conti⁷⁷, Demetrius Albanes⁷⁸, Christine Berg⁷⁹, Sonja I Berndt³⁰, Daniele Campa⁸⁰, E David Crawford⁸¹, W Ryan Diver⁸², Susan M Gapstur⁸², J Michael Gaziano^{1

83

84}, Edward Giovannucci^{1

85}, Robert Hoover³⁰, David J Hunter¹, Mattias Johansson^{86

87}, Peter Kraft^{1

88}, Loic Le Marchand⁸⁹, Sara Lindström^{1

88}, Carmen Navarro^{90

91}, Kim Overvad⁷⁹, Elio Riboli⁹², Afshan Siddiq⁹³, Victoria L Stevens⁸², Dimitrios Trichopoulos^{1

94

95}, Paolo Vineis^{96

97}, Meredith Yeager³⁰, Gosia Trynka^{98

99}, Soumya Raychaudhuri^{2

98

100}, Frederick R Schumacher⁷⁷, Alkes L Price^{1

2}, Matthew L Freedman^{2

4

5}, Christopher A Haiman⁷⁷, Bogdan Pasaniuc^{3

101

102}

Collaborators, Affiliations

Collaborators

PRACTICAL consortium:
Margaret Cook, Michelle Guy, Koveela Govindasami, Daniel Leongamornlert, Emma J Sawyer, Rosemary Wilkinson, Edward J Saunders, Malgorzata Tymrakiewicz, Tokhir Dadaev, Angela Morgan, Cyril Fisher, Steve Hazel, Naomi Livni, Artitaya Lophatananon, John Pedersen, John L Hopper, Jan Adolfson, Paer Stattin, Jan-Erik Johansson, Carin Cavalli-Bjoerkman, Ami Karlsson, Michael Broms, Anssi Auvinen, Paula Kujala, Liisa Maeaettaenen, Teemu Murtola, Kimmo Taari, Maren Weischer, Sune F Nielsen, Peter Klarskov, Andreas Roder, Peter Iversen, Hans Wallinder, Sven Gustafsson, Angela Cox, Paul Brown, Anne George, Gemma Marsden, Athene Lane, Michael Davis, Wei Zheng, Lisa B Signorello, William J Blot, Lori Tillmans, Shaun Riska, Liang Wang, Antje Rinckleb, Jan Lubiski, Christa Stegmaier, Julio Pow-Sang, Hyun Park, Selina Radlein, Maria Rincon, James Haley, Babu Zachariah, Darina Kachakova, Elenko Popov, Atanaska Mitkova, Aleksandrina Vlahova, Tihomir Dikov, Svetlana Christova, Peter Heathcote, Glenn Wood, Greg Malone, Pamela Saunders, Allison Eckert, Trina Yeadon, Kris Kerr, Angus Collins, Megan Turner, Srilakshmi Srinivasan, Mary-Anne Kedda, Kimberly Alexander, Tracy Omara, Huihai Wu, Rui Henrique, Pedro Pinto, Joana Santos, Joao Barros-Silva

Affiliations

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.

PMID: 27052111
PMCID: PMC4829663
DOI: 10.1038/ncomms10979

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

Alexander Gusev et al. Nat Commun. 2016.

. 2016 Apr 7:7:10979.

doi: 10.1038/ncomms10979.

Authors

Collaborators

PRACTICAL consortium:
Margaret Cook, Michelle Guy, Koveela Govindasami, Daniel Leongamornlert, Emma J Sawyer, Rosemary Wilkinson, Edward J Saunders, Malgorzata Tymrakiewicz, Tokhir Dadaev, Angela Morgan, Cyril Fisher, Steve Hazel, Naomi Livni, Artitaya Lophatananon, John Pedersen, John L Hopper, Jan Adolfson, Paer Stattin, Jan-Erik Johansson, Carin Cavalli-Bjoerkman, Ami Karlsson, Michael Broms, Anssi Auvinen, Paula Kujala, Liisa Maeaettaenen, Teemu Murtola, Kimmo Taari, Maren Weischer, Sune F Nielsen, Peter Klarskov, Andreas Roder, Peter Iversen, Hans Wallinder, Sven Gustafsson, Angela Cox, Paul Brown, Anne George, Gemma Marsden, Athene Lane, Michael Davis, Wei Zheng, Lisa B Signorello, William J Blot, Lori Tillmans, Shaun Riska, Liang Wang, Antje Rinckleb, Jan Lubiski, Christa Stegmaier, Julio Pow-Sang, Hyun Park, Selina Radlein, Maria Rincon, James Haley, Babu Zachariah, Darina Kachakova, Elenko Popov, Atanaska Mitkova, Aleksandrina Vlahova, Tihomir Dikov, Svetlana Christova, Peter Heathcote, Glenn Wood, Greg Malone, Pamela Saunders, Allison Eckert, Trina Yeadon, Kris Kerr, Angus Collins, Megan Turner, Srilakshmi Srinivasan, Mary-Anne Kedda, Kimberly Alexander, Tracy Omara, Huihai Wu, Rui Henrique, Pedro Pinto, Joana Santos, Joao Barros-Silva

Affiliations

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.

PMID: 27052111
PMCID: PMC4829663
DOI: 10.1038/ncomms10979

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.

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Figures

**Figure 1. Functional partitioning for variants within ARBS for PrCa.**
Bars graphs detailing %SNP heritability estimates from two models of PrCa relevant functional annotations. (a) Joint comparison of variants within 5 kb of tumour-only and normal-only regions in the ARBS in prostate tissue (P=2.1 × 10⁻¹⁹ for difference by Z-test). (b) Estimates from ARBS in prostate tissue (no longer using a 5 kb flank) and ARBS in LNCaP cell lines (P=4.4 × 10⁻⁷ for difference). The null is labelled by the dashed lines. Error bars show analytical standard error of estimate.

formula image — **Figure 1. Functional partitioning for variants within ARBS for PrCa.**
Bars graphs detailing %SNP heritability estimates from two models of PrCa relevant functional annotations. (a) Joint comparison of variants within 5 kb of tumour-only and normal-only regions in the ARBS in prostate tissue (P=2.1 × 10⁻¹⁹ for difference by Z-test). (b) Estimates from ARBS in prostate tissue (no longer using a 5 kb flank) and ARBS in LNCaP cell lines (P=4.4 × 10⁻⁷ for difference). The null is labelled by the dashed lines. Error bars show analytical standard error of estimate.

**Figure 2. Functional partitioning of heritability across six main epigenetic classes.**
Each point corresponds to an estimate of % SNP heritability (y axis) from SNPs within a cell-type-specific functional annotation versus annotation size (%SNPs, x axis). Overall, 544 annotations were tested, and red points indicate significant deviations from the null of equal to %SNPs after accounting for all tests. The two most significant annotations in each class are shown with triangle/cross, respectively, and labelled in bottom right (see Supplementary Data for all annotations).

**Figure 3. Pairwise analysis of DHS marks in three prostate cell types.**
Joint model from all pairs of DHS marks shown for: cancer cell line (LNCAP); normal prostate epithelial (PREC); and immortalized prostate epithelial (RWPE1). Circle size corresponds to % SNPs, with % SNP heritability and significance labelled. P value was computed for difference between and %SNP, with bold representing significance after correcting for nine tests. The observed trend is LNCAP>PREC>RWPE1: (a) in LNCaP DHS was nominally significantly higher than PrEC (P=0.01); and in LNCaP and PrEC was significantly higher than RWPE1 (b,c; P=1.5 × 10⁻⁹, P=1.2 × 10⁻⁵, respectively). All P values computed by Z-test using estimate and analytical standard error.

**Figure 4. Comparison of enhancers and super enhancers across 49 cell types.**
Each bar represents the %SNP heritability / %SNP for enhancers (left) and super enhancers (right) from a given cell type tested marginally. Red indicates significant difference from 1.0 (no enrichment) after accounting for 49 tests. Enhancer LNCAP is most significant, with other cancers also appearing significant and non-cancer tissues least significant. Error bars show analytical s.e. of estimate.

**Figure 5. Partitioning of heritability across functional classes in prostate cancer.**
Visual representation of heritability enrichment in three studies a,b: iCOGS; c: AAPC; d: BPC3 (shown numerically in Table 1). Each subplot corresponds to an analysis of the listed joint model, with coloured slices representing the functional annotations evaluated. Volume of each interior (light coloured) pie-chart slice represents the %SNP for the functional annotation, which is equal to the expected under the null of no enrichment. Volume of each shaded pie-chart slice represents the actual inferred by the model. Slices extending outside/inside the middle pie correspond to enrichment/depletion in SNP heritability, as indicated by the dotted lines. Colour coding is consistent across all subpanels. * (**) denotes significant deviation at P<0.05 (P<0.05/15) of fraction of SNP heritability ( from null model of by Z-test; see Supplementary Table 6 for P values).

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References

1. Hjelmborg J. B. et al. The heritability of prostate cancer in the Nordic twin study of cancer. Cancer Epidemiol. Biomarkers Prev. 23, 2303–2310 (2014). - PMC - PubMed
1. Al Olama A. A. et al. A meta-analysis of 87,040 individuals identifies 23 new susceptibility loci for prostate cancer. Nat. Genet. 46, 1103–1109 (2014). - PMC - PubMed
1. Castro E. et al. Germline BRCA mutations are associated with higher risk of nodal involvement, distant metastasis, and poor survival outcomes in prostate cancer. J. Clin. Oncol. 31, 1748–1757 (2013). - PMC - PubMed
1. Eeles R. A. et al. Identification of 23 new prostate cancer susceptibility loci using the iCOGS custom genotyping array. Nat. Genet. 45, 385–391 (2013). - PMC - PubMed
1. Saunders E. J. et al. Fine-mapping the HOXB region detects common variants tagging a rare coding allele: evidence for synthetic association in prostate cancer. PLoS Genet. 10, e1004129 (2014). - PMC - PubMed

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

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

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