Letter | Published:

Identification of 23 new prostate cancer susceptibility loci using the iCOGS custom genotyping array

Nature Genetics volume 45, pages 385391 (2013) | Download Citation

Abstract

Prostate cancer is the most frequently diagnosed cancer in males in developed countries. To identify common prostate cancer susceptibility alleles, we genotyped 211,155 SNPs on a custom Illumina array (iCOGS) in blood DNA from 25,074 prostate cancer cases and 24,272 controls from the international PRACTICAL Consortium. Twenty-three new prostate cancer susceptibility loci were identified at genome-wide significance (P < 5 × 10−8). More than 70 prostate cancer susceptibility loci, explaining 30% of the familial risk for this disease, have now been identified. On the basis of combined risks conferred by the new and previously known risk loci, the top 1% of the risk distribution has a 4.7-fold higher risk than the average of the population being profiled. These results will facilitate population risk stratification for clinical studies.

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Acknowledgements

Acknowledgments are detailed in the Supplementary Note.

Author information

Author notes

    • Sara Benlloch
    • , Edward J Saunders
    • , Daniel A Leongamornlert
    • , Malgorzata Tymrakiewicz
    • , Maya Ghoussaini
    • , Craig Luccarini
    • , Joe Dennis
    • , Sarah Jugurnauth-Little
    • , Tokhir Dadaev
    • , David E Neal
    • , Freddie C Hamdy
    • , Jenny L Donovan
    • , Ken Muir
    • , Graham G Giles
    • , Gianluca Severi
    • , Fredrik Wiklund
    • , Henrik Gronberg
    • , Christopher A Haiman
    • , Fredrick Schumacher
    • , Brian E Henderson
    • , Loic Le Marchand
    • , Sara Lindstrom
    • , Peter Kraft
    • , David J Hunter
    • , Susan Gapstur
    • , Stephen J Chanock
    • , Sonja I Berndt
    • , Demetrius Albanes
    • , Gerald Andriole
    • , Johanna Schleutker
    • , Maren Weischer
    • , Federico Canzian
    • , Elio Riboli
    • , Tim J Key
    • , Ruth C Travis
    • , Daniele Campa
    • , Sue A Ingles
    • , Esther M John
    • , Richard B Hayes
    • , Paul D P Pharoah
    • , Nora Pashayan
    • , Kay-Tee Khaw
    • , Janet L Stanford
    • , Elaine A Ostrander
    • , Lisa B Signorello
    • , Stephen N Thibodeau
    • , Dan Schaid
    • , Christiane Maier
    • , Walther Vogel
    • , Adam S Kibel
    • , Cezary Cybulski
    • , Jan Lubinski
    • , Lisa Cannon-Albright
    • , Hermann Brenner
    • , Jong Y Park
    • , Radka Kaneva
    • , Jyotsna Batra
    • , Amanda B Spurdle
    • , Judith A Clements
    •  & Manuel R Teixeira

    These authors contributed equally to this work.

    • Rosalind A Eeles
    • , Ali Amin Al Olama
    • , Zsofia Kote-Jarai
    •  & Douglas F Easton

    These authors jointly directed this work.

Affiliations

  1. The Institute of Cancer Research, Sutton, UK.

    • Rosalind A Eeles
    • , Edward J Saunders
    • , Daniel A Leongamornlert
    • , Malgorzata Tymrakiewicz
    • , Sarah Jugurnauth-Little
    • , Tokhir Dadaev
    • , Koveela Govindasami
    • , Michelle Guy
    • , Rosemary A Wilkinson
    • , Emma J Sawyer
    • , Angela Morgan
    • , David P Dearnaley
    • , Alan Horwich
    • , Robert A Huddart
    • , Vincent S Khoo
    • , Christopher C Parker
    • , Colin S Cooper
    •  & Zsofia Kote-Jarai
  2. Royal Marsden National Health Service (NHS) Foundation Trust, London and Sutton, UK.

    • Rosalind A Eeles
    • , David P Dearnaley
    • , Alan Horwich
    • , Robert A Huddart
    • , Vincent S Khoo
    • , Christopher C Parker
    • , Nicholas J Van As
    • , Christopher J Woodhouse
    • , Alan Thompson
    • , Tim Dudderidge
    •  & Chris Ogden
  3. Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Cambridge, UK.

    • Ali Amin Al Olama
    • , Sara Benlloch
    • , Maya Ghoussaini
    • , Craig Luccarini
    • , Joe Dennis
    • , Paul D P Pharoah
    • , Nora Pashayan
    • , Ed Dicks
    • , Andrew Lee
    • , Alison M Dunning
    • , Caroline Baynes
    • , Don Conroy
    • , Melanie J Maranian
    • , Shahana Ahmed
    • , Antonis C Antoniou
    •  & Douglas F Easton
  4. Surgical Oncology (Uro-Oncology: S4), University of Cambridge, Addenbrooke's Hospital, Cambridge, UK.

    • David E Neal
  5. Cancer Research UK Cambridge Research Institute, Li Ka Shing Centre, Cambridge, UK.

    • David E Neal
  6. Nuffield Department of Surgical Sciences, University of Oxford, Oxford, UK.

    • Freddie C Hamdy
  7. Faculty of Medical Science, University of Oxford, John Radcliffe Hospital, Oxford, UK.

    • Freddie C Hamdy
  8. School of Social and Community Medicine, University of Bristol, Bristol, UK.

    • Jenny L Donovan
  9. Warwick Medical School, University of Warwick, Coventry, UK.

    • Ken Muir
    •  & Artitaya Lophatananon
  10. Institute of Population Health, University of Manchester, Manchester, UK.

    • Ken Muir
  11. Cancer Epidemiology Centre, The Cancer Council Victoria, Carlton, Victoria, Australia.

    • Graham G Giles
    • , Gianluca Severi
    •  & Dallas R English
  12. Centre for Molecular, Environmental, Genetic and Analytic Epidemiology, The University of Melbourne, Melbourne, Victoria, Australia.

    • Graham G Giles
    • , Gianluca Severi
    • , John L Hopper
    •  & Dallas R English
  13. Department of Medical Epidemiology and Biostatistics, Karolinska Institute, Stockholm, Sweden.

    • Fredrik Wiklund
    • , Henrik Gronberg
    •  & Markus Aly
  14. Department of Preventive Medicine, Keck School of Medicine, University of Southern California/Norris Comprehensive Cancer Center, Los Angeles, California, USA.

    • Christopher A Haiman
    • , Fredrick Schumacher
    • , Brian E Henderson
    • , Sue A Ingles
    • , Mariana C Stern
    • , Roman Corral
    • , Amit D Joshi
    •  & Ahva Shahabi
  15. University of Hawaii Cancer Center, Honolulu, Hawaii, USA.

    • Loic Le Marchand
  16. Program in Molecular and Genetic Epidemiology, Department of Epidemiology, Harvard School of Pubic Health, Boston, Massachusetts, USA.

    • Sara Lindstrom
    • , Peter Kraft
    •  & David J Hunter
  17. Epidemiology Research Program, American Cancer Society, Atlanta, Georgia, USA.

    • Susan Gapstur
    • , W Ryan Diver
    •  & Mia M Gaudet
  18. Division of Cancer Epidemiology and Genetics, National Cancer Institute, US National Institutes of Health (NIH), Bethesda, Maryland, USA.

    • Stephen J Chanock
    • , Sonja I Berndt
    •  & Meredith Yeager
  19. Nutritional Epidemiology Branch, National Cancer Institute, US NIH, Bethesda, Maryland, USA.

    • Demetrius Albanes
  20. Division of Urologic Surgery, Washington University School of Medicine, St. Louis, Missouri, USA.

    • Gerald Andriole
    • , Bettina Drake
    •  & Graham Colditz
  21. Institute of Biomedical Technology (BioMediTech), University of Tampere and FimLab Laboratories, Tampere, Finland.

    • Johanna Schleutker
    •  & Tiina Wahlfors
  22. Department of Medical Biochemistry and Genetics, University of Turku, Turku, Finland.

    • Johanna Schleutker
  23. Department of Clinical Biochemistry, Herlev Hospital, Copenhagen University Hospital, Herlev, Denmark.

    • Maren Weischer
    • , Børge G Nordestgaard
    • , Sune F Nielsen
    •  & Stig E Bojesen
  24. Genomic Epidemiology Group, German Cancer Research Center (DKFZ), Heidelberg, Germany.

    • Federico Canzian
    •  & Daniele Campa
  25. Department of Epidemiology & Biostatistics, School of Public Health, Imperial College London, London, UK.

    • Elio Riboli
  26. Cancer Epidemiology Unit, Nuffield Department of Clinical Medicine, University of Oxford, Oxford, UK.

    • Tim J Key
    •  & Ruth C Travis
  27. Cancer Prevention Institute of California, Fremont, California, USA.

    • Esther M John
  28. Stanford Cancer Institute, Stanford University School of Medicine, Stanford, California, USA.

    • Esther M John
  29. Department of Health Research & Policy, Division of Epidemiology, Stanford University School of Medicine, Stanford, California, USA.

    • Esther M John
  30. Department of Environmental Medicine, New York University (NYU) Langone Medical Center, Division of Epidemiology, NYU Cancer Institute, New York, New York, USA.

    • Richard B Hayes
  31. Clinical Gerontology Unit, University of Cambridge, Cambridge, UK.

    • Kay-Tee Khaw
  32. Fred Hutchinson Cancer Research Center, Division of Public Health Sciences, Seattle, Washington, USA.

    • Janet L Stanford
    • , Liesel M FitzGerald
    •  & Suzanne Kolb
  33. Department of Epidemiology, School of Public Health, University of Washington, Seattle, Washington, USA.

    • Janet L Stanford
  34. National Human Genome Research Institute, US NIH, Bethesda, Maryland, USA.

    • Elaine A Ostrander
    • , Erika M Kwon
    •  & Danielle M Karyadi
  35. International Epidemiology Institute, Rockville, Maryland, USA.

    • Lisa B Signorello
    •  & William J Blot
  36. Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Division of Epidemiology, Vanderbilt University School of Medicine, Nashville, Tennessee, USA.

    • Lisa B Signorello
    • , William J Blot
    • , Wei Zheng
    •  & Qiuyin Cai
  37. Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota, USA.

    • Stephen N Thibodeau
    •  & Shannon K McDonnell
  38. Division of Biomedical Statistics and Informatics, Department of Health Sciences Research, Mayo Clinic, Rochester, Minnesota, USA.

    • Dan Schaid
  39. Department of Urology, University Hospital Ulm, Ulm, Germany.

    • Christiane Maier
    •  & Antje E Rinckleb
  40. Institute of Human Genetics, University Hospital Ulm, Ulm, Germany.

    • Christiane Maier
    • , Walther Vogel
    •  & Antje E Rinckleb
  41. Division of Urologic Surgery, Brigham and Women's Hospital, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.

    • Adam S Kibel
  42. Department of Genetics and Pathology, International Hereditary Cancer Center, Pomeranian Medical University, Szczecin, Poland.

    • Cezary Cybulski
    • , Jan Lubinski
    •  & Dominika Wokolorczyk
  43. Division of Genetic Epidemiology, Department of Medicine, University of Utah School of Medicine, Salt Lake City, Utah, USA.

    • Lisa Cannon-Albright
    •  & Craig Teerlink
  44. George E. Wahlen Department of Veterans Affairs Medical Center, Salt Lake City, Utah, USA.

    • Lisa Cannon-Albright
    •  & Robert A Stephenson
  45. Division of Clinical Epidemiology and Aging Research, DKFZ, Heidelberg, Germany.

    • Hermann Brenner
    • , Heiko Muller
    •  & Dietrich Rothenbacher
  46. Division of Cancer Prevention and Control, H. Lee Moffitt Cancer Center, Tampa, Florida, USA.

    • Jong Y Park
    • , Thomas A Sellers
    •  & Hui-Yi Lin
  47. Department of Medical Chemistry and Biochemistry, Molecular Medicine Center, Medical University of Sofia, Sofia, Bulgaria.

    • Radka Kaneva
    •  & Vanio Mitev
  48. Australian Prostate Cancer Research Centre, Queensland Institute of Health and Biomedical Innovation and School of Biomedical Science, Queensland University of Technology, Brisbane, Queensland, Australia.

    • Jyotsna Batra
    • , Judith A Clements
    •  & Srilakshmi Srinivasan
  49. Molecular Cancer Epidemiology Laboratory, Queensland Institute of Medical Research, Brisbane, Queensland, Australia.

    • Amanda B Spurdle
    •  & Felicity Lose
  50. Department of Genetics, Portuguese Oncology Institute, Porto, Portugal.

    • Manuel R Teixeira
    • , Sofia Maia
    •  & Paula Paulo
  51. Abel Salazar Biomedical Sciences Institute (ICBAS), Porto University, Porto, Portugal.

    • Manuel R Teixeira
    • , Sofia Maia
    •  & Paula Paulo
  52. School of Biological Sciences, University of East Anglia, Norwich, UK.

    • Colin S Cooper
  53. Cancer Research UK/Yorkshire Cancer Research Sheffield Cancer Research Centre, University of Sheffield, Sheffield, UK.

    • Angela Cox
  54. Genetic Epidemiology Laboratory, Department of Pathology, The University of Melbourne, Parkville, Victoria, Australia.

    • Melissa C Southey
  55. Department of Clinical Sciences, Division of Urology, Danderyd Hospital, Karolinska Institute, Stockholm, Sweden.

    • Markus Aly
  56. Regional Cancer Centre, Department of Clinical Science, Intervention and Technology (CLINTEC), Karolinska Institute, Stockholm, Sweden.

    • Jan Adolfsson
  57. Wake Forest University School of Medicine, Winston-Salem, North Carolina, USA.

    • Jiangfeng Xu
  58. Genomics Genotyping Laboratory, Center for Cancer Genomics, Wake Forest University Health Sciences, Winston-Salem, North Carolina, USA.

    • Siqun L Zheng
  59. Core Genotyping Facility, SAIC-Frederick, National Cancer Institute, US NIH, Gaithersburg, Maryland, USA.

    • Meredith Yeager
  60. Division of Cancer Epidemiology, DKFZ, Heidelberg, Germany.

    • Rudolf Kaaks
  61. Department of Urology, Tampere University Hospital and Medical School, University of Tampere, Tampere, Finland.

    • Teuvo L J Tammela
  62. Department of Epidemiology, School of Health Sciences, University of Tampere, Tampere, Finland.

    • Anssi Auvinen
  63. Department of Chronic Disease Prevention, National Institute for Health and Welfare, Helsinki, Finland.

    • Jarmo Virtamo
  64. Department of Urology, Herlev Hospital, Copenhagen University Hospital, Herlev, Denmark.

    • Peter Klarskov
  65. Department of Urology, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark.

    • M Andreas Røder
  66. Department of Genomics of Common Disease, School of Public Health, Imperial College London, London, UK.

    • Afshan Siddiq
  67. Huntsman Cancer Institute, Salt Lake City, Utah, USA.

    • Robert A Stephenson
  68. Department of Urology, Alexandrovska University Hospital, Medical University Sofia, Sofia, Bulgaria.

    • Chavdar Slavov
  69. Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.

    • Ethan Lange
  70. University of Michigan Comprehensive Cancer Center, Division of Hematology/Oncology, University of Michigan Medical School, Ann Arbor, Michigan, USA.

    • Kathleen A Cooney
  71. McGill University and Génome Québec Innovation Centre, Montreal, Quebec, Canada.

    • Daniel Vincent
    • , François Bacot
    •  & Daniel C Tessier

Consortia

  1. The COGS–Cancer Research UK GWAS–ELLIPSE (part of GAME-ON) Initiative

    A full list of members is provided in the Supplementary Note.

  2. The Australian Prostate Cancer Bioresource

    A full list of members is provided in the Supplementary Note.

  3. The UK Genetic Prostate Cancer Study Collaborators/British Association of Urological Surgeons' Section of Oncology

    A full list of members is provided in the Supplementary Note.

  4. The UK ProtecT (Prostate testing for cancer and Treatment) Study Collaborators

    A full list of members is provided in the Supplementary Note.

  5. The PRACTICAL (Prostate Cancer Association Group to Investigate Cancer-Associated Alterations in the Genome) Consortium

    A full list of members is provided in the Supplementary Note.

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  143. Search for Zsofia Kote-Jarai in:

  144. Search for Douglas F Easton in:

Contributions

R.A.E. and D.F.E. designed the study. R.A.E. is principal investigator of PRACTICAL. D.F.E. is Scientific Director of the COGS initiative. Z.K.-J. is co-investigator of PRACTICAL. R.A.E., D.F.E., Z.K.-J. and A.A.A.O. wrote the manuscript; the following named coauthors commented on the manuscript. A.A.A.O. and D.F.E. performed the statistical analyses; S.B. collated the data set. J.D. managed the database. Z.K.-J., E.J. Saunders, D.A.L. and M.T. coordinated sample collation and quality control for iCOGS PRACTICAL genotyping. S.J.-L. carried out pathway analysis and constructed regional plots, and T. Dadaev, K.G., M. Guy, R.A.W., E.J. Sawyer and A.M. managed the UKGPCS database and manifests for genotyping. C.L., A.M.D., C.B., D. Conroy, M.J.M., S.A., E.D., A. Lee, D.C.T., F.B. and D.V. carried out iCOGS PRACTICAL genotyping and set quality control standards. M. Ghoussaini selected the iCOGS PRACTICAL SNPs for fine-scale mapping. K.M. and A. Lophatananon collected some of the UKGPCS samples and controls. F.C.H., D.E.N. and J.L.D. are joint principal investigators of ProtecT. B.E.H. and L.L.M. are principal investigators of MEC; C.A.H. and F.S. are co-investigators. S.I.B. and D.A. are principal investigators of the PLCO study; G.A. is the principal investigator for the St. Louis screening center for PLCO; and S.J.C. and M.Y. led the genotyping for PLCO. S.G., R.B.H. and W.R.D. provided samples for PLCO. D.J.H. directs and P. Kraft coordinates data collection and management/analysis for HPFS. M.W. is the principal investigator of CPCS1 and CPCS2. B.G.N., S.F.N. S.E.B., P. Klarskov and M.A.R. have collected samples and data, and contributed to genotyping in this study. J.L.S. is principal investigator of the Fred Hutchinson–based study; E.A.O. collaborated on the study; L.M.F. and S.K. coordinated data collation; and E.M.K. and D.M.K. coordinated the preparation of samples. L.C.-A. is principal investigator of the Utah study; C.T. is the analyst; and R.A.S. is the surgeon. S.L. is a co-investigator of the BPC3 Consortium. H.G. is principal investigator of the CAPS and STHM1 study; J.A., M.A., F.W., S.L.Z. and J.X. have contributed to sample collection, clinical data retrieval, analyses and molecular work. S.A.I. is principal investigator of the USC study, and E.M.J. is principal investigator of SFPCS; M.C. Stem and R.C. led the genotyping of both studies. A.D.J. and A. Shahabi were both involved in genotype data production for the USC and SFPCS studies. A.S.K. is principal investigator of WUGS. B.D. and G.C. collected and collated clinical data and performed sample selection. M.R.T. is the principal investigator of the IPO-Porto study; S.M. and P.P. collected familial and molecular data on cases. L.B.S. and W.J.B. are the principal investigators of SCCS; L.B.S., W.J.B., W.Z. and Q.C. were responsible for the original collection of the samples. W.Z. and Q.C. coordinated sample retrieval, DNA extraction and genotyping. L.B.S. oversaw the assembly of the phenotype data. J.B. and J.A.C. are principal investigators of the Queensland study with input from A.B.S., F.L. and S.S. coordinated the data collation. K.A.C. and E.L. provided imputed data for genotyping in carriers of the mutation encoding the p.Gly84Glu alteration in the HOXB13 region. G.G.G., J.L.H., D.R.E. and G.S. are principal investigators of the Australian studies; M.C. Southey manages the molecular work. J.S. is principal investigator of the Tampere study; T.W. collected and collated clinical data and performed sample selection. T.L.J.T. coordinated sample collection. H.B. is principal investigator of the ESTHER study; D.R. and C.S. contributed to design and data collection; and H.M. is study coordinator. J.Y.P. is principal investigator of the Moffitt study; T.A.S. and H.-Y.L. are contributors to this study. R. Kaneva is principal investigator of the PCMUS study; C.S. provided the samples in the PCMUS study; V.M. oversaw the data collation. C.C. and J.L. are principal investigators of the Poland study; C.C. and D.W. collated the samples. C.M. and W.V. are principal investigators of the Ulm study; A.E.R. identified and collected clinical material, processed samples, undertook genotyping and/or collated data. E.R. is principal investigator of EPIC; F.C., R. Kaaks and D. Campa are investigators in Germany. T.J.K. is principal investigator of the EPIC-Oxford cohort and collected clinical material. R.C.T. collated data. K.-T.K. is principal investigator of the EPIC-Norfolk study. S.N.T. and D.S. are principal investigators of the Mayo Clinic study; S.K.M. coordinated data collation. M.M.G. provided samples for the ACS study. P.D.P.P. and N.P. provided samples for the East Anglia SEARCH study. C.S.C. gave advice about results and contributed to the manuscript. A.C.A. undertook risk prediction analysis for clinical application. D.P.D., A.H., R.A.H., V.S.K., C.C.P., N.J.V.A., C.J.W., A.T., T. Dudderidge, C.O., A.A., A.C., J.V. and A. Siddiq identified and collected clinical material. Other members of the UK Genetic Prostate Cancer Study Collaborators/British Association of Urological Surgeons' Section of Oncology, the UK ProtecT Study Collaborators and the PRACTICAL Consortium (membership lists provided in the Supplementary Note) collected clinical samples, assisted in genotyping and provided data management. Members of the COGS–Cancer Research UK GWAS–ELLIPSE (part of GAME-ON) Initiatives, the Australian Prostate Cancer Bioresource, the UK Genetic Prostate Cancer Study Collaborators/British Association of Urological Surgeons' Section of Oncology, the UK ProtecT Study Collaborators, the PRACTICAL Consortium and CSC collected clinical samples and/or assisted in genotyping and/or provided data management and/or discussion of the data.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Rosalind A Eeles.

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    Supplementary Text and Figures

    Supplementary Tables 1–8, Supplementary Figures 1–4 and Supplementary Note

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DOI

https://doi.org/10.1038/ng.2560

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