Article | Published:

Breast cancer risk variants at 6q25 display different phenotype associations and regulate ESR1, RMND1 and CCDC170

Nature Genetics volume 48, pages 374386 (2016) | Download Citation

Abstract

We analyzed 3,872 common genetic variants across the ESR1 locus (encoding estrogen receptor α) in 118,816 subjects from three international consortia. We found evidence for at least five independent causal variants, each associated with different phenotype sets, including estrogen receptor (ER+ or ER) and human ERBB2 (HER2+ or HER2) tumor subtypes, mammographic density and tumor grade. The best candidate causal variants for ER tumors lie in four separate enhancer elements, and their risk alleles reduce expression of ESR1, RMND1 and CCDC170, whereas the risk alleles of the strongest candidates for the remaining independent causal variant disrupt a silencer element and putatively increase ESR1 and RMND1 expression.

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Acknowledgements

We thank all the individuals who took part in these studies and all the researchers, clinicians, technicians and administrative staff who have enabled this work to be carried out. This study would not have been possible without the contributions of the following: A. Berchuck (OCAC), R.A. Eeles, A.A. Al Olama, Z. Kote-Jarai and S. Benlloch (PRACTICAL), C. Luccarini and the staff of the Centre for Genetic Epidemiology Laboratory, the staff of the CNIO genotyping unit, D.C. Tessier, F. Bacot, D. Vincent, S. LaBoissière, F. Robidoux and the staff of the McGill University and Génome Québec Innovation Centre, S.F. Nielsen, B.G. Nordestgaard and the staff of the Copenhagen DNA laboratory, and J.M. Cunningham, S.A. Windebank, C.A. Hilker, J. Meyer and the staff of the Mayo Clinic Genotyping Core Facility. Normal human tissues from the Susan G. Komen for the Cure Tissue Bank at the Indiana University Simon Cancer Center (Indianapolis) were used in this study. We thank the contributors, including Indiana University who collected samples used in this study, as well as the donors and their families, whose help and participation made this work possible. We also acknowledge National Institute for Health Research (NIHR) support to the Royal Marsden Biomedical Research Centre. Funding for the iCOGS infrastructure came from the European Community's Seventh Framework Programme under grant agreement 223175 (HEALTH-F2-2009-223175) (COGS), Cancer Research UK (C1287/A10118, C1287/A10710, C12292/A11174, C1281/A12014, C5047/A8384, C5047/A15007, C5047/A10692 and C8197/A16565), the US National Institutes of Health (NIH; CA128978, CA192393, CA116167, CA176785 and an NIH Specialized Program of Research Excellence (SPORE) in Breast Cancer (CA116201)) and Post-Cancer GWAS initiative (1U19 CA148537, 1U19 CA148065 and 1U19 CA148112, the GAME-ON initiative), the US Department of Defense (W81XWH-10-1-0341), the Canadian Institutes of Health Research (CIHR) for the CIHR Team in Familial Risks of Breast Cancer, the Komen Foundation for the Cure, the Breast Cancer Research Foundation and the Ovarian Cancer Research Fund. Full acknowledgments are given in the Supplementary Note.

Author information

Author notes

    • Alison M Dunning
    • , Kyriaki Michailidou
    • , Karoline B Kuchenbaecker
    • , Deborah Thompson
    • , Juliet D French
    • , Jonathan Beesley
    •  & Catherine S Healey

    These authors contributed equally to this work.

    • Antonis C Antoniou
    • , Douglas F Easton
    •  & Stacey L Edwards

    These authors jointly supervised this work.

Affiliations

  1. Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Cambridge, UK.

    • Alison M Dunning
    • , Catherine S Healey
    • , Siddhartha Kar
    • , Ed Dicks
    • , Maya Ghoussaini
    • , Barbara J Perkins
    • , Mitul Shah
    • , Paul D P Pharoah
    •  & Douglas F Easton
  2. Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.

    • Kyriaki Michailidou
    • , Karoline B Kuchenbaecker
    • , Deborah Thompson
    • , Karen A Pooley
    • , Daniel Barrowdale
    • , Manjeet K Bolla
    • , Joe Dennis
    • , Qin Wang
    • , Lesley McGuffog
    • , Andrew Lee
    • , Debra Frost
    • , Steve Ellis
    • , Paul D P Pharoah
    • , Antonis C Antoniou
    •  & Douglas F Easton
  3. Cancer Division, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.

    • Juliet D French
    • , Jonathan Beesley
    • , Kristine M Hillman
    • , Susanne Kaufmann
    • , Haran Sivakumaran
    • , Mahdi Moradi Marjaneh
    • , Jason S Lee
    • , Sue Healey
    • , Georgia Chenevix-Trench
    •  & Stacey L Edwards
  4. Breast Cancer Research, Breakthrough Breast Cancer Research Centre, London, UK.

    • Elena Lopez-Knowles
    • , Monika Jarosz
    • , Suzie Drury
    •  & Mitch Dowsett
  5. Academic Biochemistry, Royal Marsden Hospital, London, UK.

    • Elena Lopez-Knowles
    • , Margaret Hills
    • , Monika Jarosz
    • , Suzie Drury
    •  & Mitch Dowsett
  6. Department of Genetics, Stanford University School of Medicine, Stanford, California, USA.

    • Nicholas A Sinnott-Armstrong
  7. Computer Science and Artificial Intelligence Laboratory, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.

    • Richard C Sallari
  8. Netherlands Cancer Institute, Antoni van Leeuwenhoek Hospital, Amsterdam, the Netherlands.

    • Sander Canisius
    • , Annegien Broeks
    •  & Marjanka K Schmidt
  9. Centre for Epidemiology and Biostatistics, School of Population and Global Health, University of Melbourne, Melbourne, Victoria, Australia.

    • John L Hopper
    • , Graham G Giles
    • , Roger L Milne
    •  & Carmel Apicella
  10. Department of Pathology, University of Melbourne, Melbourne, Victoria, Australia.

    • Melissa C Southey
  11. Division of Health Sciences, Warwick Medical School, Warwick University, Coventry, UK.

    • Artitaya Lophatananon
    •  & Kenneth Muir
  12. Institute of Population Health, University of Manchester, Manchester, UK.

    • Kenneth Muir
  13. Department of Gynecology and Obstetrics, University Hospital Erlangen, Friedrich Alexander University Erlangen-Nuremberg, Comprehensive Cancer Center Erlangen-Nuremberg Metropolitan Region, Erlangen, Germany.

    • Matthias W Beckmann
    •  & Peter A Fasching
  14. Department of Medicine, Division of Hematology and Oncology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California, USA.

    • Peter A Fasching
  15. Department of Non-Communicable Disease Epidemiology, London School of Hygiene and Tropical Medicine, London, UK.

    • Isabel dos-Santos-Silva
    •  & Julian Peto
  16. Research Oncology, Division of Cancer Studies, King's College London, Guy's Hospital, London, UK.

    • Elinor J Sawyer
  17. Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.

    • Ian Tomlinson
  18. Oxford Biomedical Research Centre, University of Oxford, Oxford, UK.

    • Ian Tomlinson
  19. Division of Molecular Genetic Epidemiology, German Cancer Research Center, Heidelberg, Germany.

    • Barbara Burwinkel
  20. Molecular Epidemiology Group, German Cancer Research Center, Heidelberg, Germany.

    • Barbara Burwinkel
  21. National Center for Tumor Diseases, University of Heidelberg, Heidelberg, Germany.

    • Frederik Marme
  22. Department of Obstetrics and Gynecology, University of Heidelberg, Heidelberg, Germany.

    • Frederik Marme
  23. Environmental Epidemiology of Cancer, Center for Research in Epidemiology and Population Health, INSERM, Villejuif, France.

    • Pascal Guénel
    •  & Thérèse Truong
  24. University Paris–Sud, Villejuif, France.

    • Pascal Guénel
    •  & Thérèse Truong
  25. Copenhagen General Population Study, Herlev Hospital, Copenhagen University Hospital, Herlev, Denmark.

    • Stig E Bojesen
  26. Department of Clinical Biochemistry, Herlev Hospital, Copenhagen University Hospital, Herlev, Denmark.

    • Stig E Bojesen
  27. Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.

    • Stig E Bojesen
  28. Department of Breast Surgery, Herlev Hospital, Copenhagen University Hospital, Herlev, Denmark.

    • Henrik Flyger
  29. Human Cancer Genetics Program, Spanish National Cancer Centre (CNIO), Madrid, Spain.

    • Anna González-Neira
  30. Servicio de Cirugía General y Especialidades, Hospital Monte Naranco, Oviedo, Spain.

    • Jose I A Perez
  31. Department of Epidemiology, University of California–Irvine, Irvine, California, USA.

    • Hoda Anton-Culver
  32. Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California, USA.

    • Lee Eunjung
    • , Chiu-chen Tseng
    • , Anna H Wu
    • , Christopher A Haiman
    • , Brian E Henderson
    •  & Simon A Gayther
  33. Division of Clinical Epidemiology and Aging Research, German Cancer Research Center, Heidelberg, Germany.

    • Volker Arndt
    •  & Hermann Brenner
  34. German Cancer Consortium, German Cancer Research Center, Heidelberg, Germany.

    • Hermann Brenner
    •  & Hiltrud Brauch
  35. Department of Gynaecology and Obstetrics, Technical University of Munich, Munich, Germany.

    • Alfons Meindl
  36. Division of Molecular Gyneco-Oncology, Department of Gynaecology and Obstetrics, University Hospital of Cologne, Cologne, Germany.

    • Rita K Schmutzler
  37. Centre of Familial Breast and Ovarian Cancer, University Hospital of Cologne, Cologne, Germany.

    • Rita K Schmutzler
  38. Center for Integrated Oncology, University Hospital, Cologne, Germany.

    • Rita K Schmutzler
  39. Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart, Germany.

    • Hiltrud Brauch
  40. University of Tübingen, Tübingen, Germany.

    • Hiltrud Brauch
  41. Molecular Genetics of Breast Cancer, German Cancer Research Center, Heidelberg, Germany.

    • Ute Hamann
    • , Maria Kabisch
    • , Diana Torres
    •  & Muhammad Usman Rashid
  42. Department of Clinical Genetics, Helsinki University Central Hospital, Helsinki, Finland.

    • Kristiina Aittomäki
  43. Department of Oncology, Helsinki University Central Hospital, University of Helsinki, Helsinki, Finland.

    • Carl Blomqvist
  44. Division of Epidemiology and Prevention, Aichi Cancer Center Research Institute, Aichi, Japan.

    • Hidemi Ito
  45. Division of Molecular Medicine, Aichi Cancer Center Research Institute, Nagoya, Japan.

    • Keitaro Matsuo
  46. Radiation Oncology Research Unit, Hannover Medical School, Hannover, Germany.

    • Natasha Bogdanova
  47. Gynaecology Research Unit, Hannover Medical School, Hannover, Germany.

    • Thilo Dörk
  48. Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.

    • Annika Lindblom
  49. Department of Oncology-Pathology, Karolinska University Hospital, Stockholm, Sweden.

    • Sara Margolin
    •  & Anna von Wachenfeldt
  50. Cancer Center, Kuopio University Hospital, Kuopio, Finland.

    • Veli-Matti Kosma
    •  & Arto Mannermaa
  51. Institute of Clinical Medicine, Pathology and Forensic Medicine, University of Eastern Finland, Kuopio, Finland.

    • Veli-Matti Kosma
    •  & Arto Mannermaa
  52. Imaging Center, Department of Clinical Pathology, Kuopio University Hospital, Kuopio, Finland.

    • Veli-Matti Kosma
    •  & Arto Mannermaa
  53. Vesalius Research Center, Leuven, Belgium.

    • Diether Lambrechts
  54. Laboratory for Translational Genetics, Department of Oncology, University of Leuven, Leuven, Belgium.

    • Diether Lambrechts
  55. Multidisciplinary Breast Center, Department of General Medical Oncology, University Hospitals Leuven, Leuven, Belgium.

    • Hans Wildiers
  56. Division of Cancer Epidemiology, German Cancer Research Center, Heidelberg, Germany.

    • Jenny Chang-Claude
    •  & Anja Rudolph
  57. University Cancer Center Hamburg (UCCH), University Medical Center Hamburg-Eppendorf, Hamburg, Germany.

    • Jenny Chang-Claude
  58. IFOM, Fondazione Istituto FIRC di Oncologia Molecolare, Milan, Italy.

    • Paolo Peterlongo
  59. Unit of Molecular Basis of Genetic Risk and Genetic Testing, Department of Preventive and Predictive Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.

    • Paolo Radice
  60. Department of Health Sciences Research, Mayo Clinic, Rochester, Minnesota, USA.

    • Janet E Olson
    • , Noralane Lindor
    • , Fergus J Couch
    • , Christopher Scott
    •  & Celine Vachon
  61. Cancer Epidemiology Centre, Cancer Council Victoria, Melbourne, Victoria, Australia.

    • Graham G Giles
    •  & Roger L Milne
  62. Department of Medicine, McGill University, Montreal, Quebec, Canada.

    • Mark S Goldberg
  63. Division of Clinical Epidemiology, Royal Victoria Hospital, McGill University, Montreal, Quebec, Canada.

    • Mark S Goldberg
  64. Cancer Research Initiatives Foundation, Sime Darby Medical Centre, Subang Jaya, Malaysia.

    • Soo H Teo
    •  & Sook-Yee Yoon
  65. Breast Cancer Research Unit, University Malaya Cancer Research Institute, University Malaya Medical Centre, Kuala Lumpur, Malaysia.

    • Soo H Teo
    •  & Cheng Har Yip
  66. Department of Genetics, Institute for Cancer Research, Oslo University Hospital, Radiumhospitalet, Oslo, Norway.

    • Silje Nord
    • , Anne-Lise Borresen-Dale
    • , Vessela Kristensen
    • , Åslaug Helland
    •  & Vilde Haakensen
  67. Institute of Clinical Medicine, University of Oslo, Oslo, Norway.

    • Anne-Lise Borresen-Dale
    •  & Vessela Kristensen
  68. Department of Clinical Molecular Biology, Oslo University Hospital, University of Oslo, Oslo, Norway.

    • Vessela Kristensen
  69. Division of Epidemiology, Department of Medicine, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, Tennessee, USA.

    • Jirong Long
    • , Wei Zheng
    • , Xiao-Ou Shu
    • , William Blot
    •  & Qiuyin Cai
  70. Laboratory of Cancer Genetics and Tumor Biology, Department of Clinical Chemistry and Biocenter Oulu, University of Oulu, NordLab Oulu University Hospital, Oulu, Finland.

    • Katri Pylkäs
    •  & Robert Winqvist
  71. Laboratory of Cancer Genetics and Tumor Biology, Northern Finland Laboratory Centre NordLab, Oulu, Finland.

    • Katri Pylkäs
    •  & Robert Winqvist
  72. Lunenfeld-Tanenbaum Research Institute of Mount Sinai Hospital, Toronto, Ontario, Canada.

    • Irene L Andrulis
    •  & Gord Glendon
  73. Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada.

    • Irene L Andrulis
  74. Prosserman Centre for Health Research, Lunenfeld-Tanenbaum Research Institute of Mount Sinai Hospital, Toronto, Ontario, Canada.

    • Julia A Knight
  75. Division of Epidemiology, Dalla Lana School of Public Health, University of Toronto, Toronto, Ontario, Canada.

    • Julia A Knight
  76. Department of Pathology, Leiden University Medical Center, Leiden, the Netherlands.

    • Peter Devilee
  77. Department of Human Genetics, Leiden University Medical Center, Leiden, the Netherlands.

    • Peter Devilee
  78. Department of Medical Oncology, Erasmus University Medical Center, Rotterdam, the Netherlands.

    • Caroline Seynaeve
    •  & Antoinette Hollestelle
  79. Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, Maryland, USA.

    • Jonine Figueroa
    •  & Mark E Sherman
  80. Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.

    • Kamila Czene
    • , Hatef Darabi
    • , Keith Humphreys
    •  & Per Hall
  81. Department of Clinical Genetics, Erasmus University Medical Center, Rotterdam, the Netherlands.

    • Ans M W van den Ouweland
  82. Department of Epidemiology, Shanghai Cancer Institute, Shanghai, China.

    • Yu-Tang Gao
  83. Sheffield Cancer Research, Department of Oncology, University of Sheffield, Sheffield, UK.

    • Angela Cox
  84. Academic Unit of Pathology, Department of Neuroscience, University of Sheffield, Sheffield, UK.

    • Simon S Cross
  85. International Epidemiology Institute, Rockville, Maryland, USA.

    • William Blot
  86. Department of Preventive Medicine, Seoul National University College of Medicine, Seoul, Korea.

    • Ji-Yeob Choi
    • , Daehee Kang
    •  & Sue Kyung Park
  87. Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, Korea.

    • Ji-Yeob Choi
    • , Daehee Kang
    •  & Sue Kyung Park
  88. Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea.

    • Daehee Kang
    •  & Sue Kyung Park
  89. Department of Haematology-Oncology, National University Health System, Singapore.

    • Soo Chin Lee
  90. Cancer Science Institute of Singapore, National University of Singapore, Singapore.

    • Soo Chin Lee
  91. Saw Swee Hock School of Public Health, National University of Singapore, Singapore.

    • Mikael Hartman
  92. Department of Surgery, National University Health System, Singapore.

    • Mikael Hartman
  93. Institute of Human Genetics, Pontificia Universidad Javerianar, Bogota, Colombia.

    • Diana Torres
  94. Department of Genetics and Pathology, Pomeranian Medical University, Szczecin, Poland.

    • Anna Jakubowska
    • , Jan Lubinski
    • , Jacek Gronwald
    •  & Tomasz Huzarski
  95. International Agency for Research on Cancer, Lyon, France.

    • Paul Brennan
  96. National Cancer Institute, Bangkok, Thailand.

    • Suleeporn Sangrajrang
  97. Roswell Park Cancer Institute, Buffalo, New York, USA.

    • Christine B Ambrosone
  98. Department of Molecular Virology, Immunology and Medical Genetics, Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio, USA.

    • Amanda E Toland
  99. School of Public Health, China Medical University, Taichung, Taiwan.

    • Chen-Yang Shen
  100. Taiwan Biobank, Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan.

    • Chen-Yang Shen
    •  & Pei-Ei Wu
  101. Division of Cancer Studies, Breakthrough Breast Cancer Research Centre, Institute of Cancer Research, London, UK.

    • Nick Orr
    •  & Montserrat García-Closas
  102. Division of Genetics and Epidemiology, Institute of Cancer Research, London, UK.

    • Anthony Swerdlow
    •  & Montserrat García-Closas
  103. Division of Breast Cancer Research, Institute of Cancer Research, London, UK.

    • Anthony Swerdlow
  104. Centre for Epidemiology and Biostatistics, University of Melbourne, Melbourne, Victoria, Australia.

    • Miroslav Kapuscinski
  105. Department of Epidemiology, Cancer Prevention Institute of California, Fremont, California, USA.

    • Esther M John
  106. Department of Epidemiology, Mailman School of Public Health, Columbia University, New York, New York, USA.

    • Mary Beth Terry
  107. Department of Clinical Genetics, Fox Chase Cancer Center, Philadelphia, Pennsylvania, USA.

    • Mary B Daly
  108. Department of Dermatology, Huntsman Cancer Institute, University of Utah School of Medicine, Salt Lake City, Utah, USA.

    • David E Goldgar
  109. Department of Medicine, Huntsman Cancer Institute, University of Utah School of Medicine, Salt Lake City, Utah, USA.

    • Saundra S Buys
  110. State Research Institute Centre for Innovative Medicine, Vilnius, Lithuania.

    • Ramunas Janavicius
  111. Latvian Biomedical Research and Study Centre, Riga, Latvia.

    • Laima Tihomirova
  112. Department of Medical Oncology, Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA.

    • Nadine Tung
  113. Department of Genetics, University of Pretoria, Pretoria, South Africa.

    • Cecilia M Dorfling
    •  & Elizabeth J van Rensburg
  114. Department of Population Sciences, Beckman Research Institute of City of Hope, Duarte, California, USA.

    • Susan L Neuhausen
  115. Department of Oncology, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark.

    • Bent Ejlertsen
  116. Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark.

    • Thomas V O Hansen
  117. Human Genetics Group, Spanish National Cancer Centre (CNIO), Madrid, Spain.

    • Ana Osorio
    •  & Javier Benitez
  118. Biomedical Network on Rare Diseases (CIBERER), Madrid, Spain.

    • Ana Osorio
    •  & Javier Benitez
  119. Human Genotyping (CEGEN) Unit, Human Cancer Genetics Program, Spanish National Cancer Research Centre (CNIO), Madrid, Spain.

    • Javier Benitez
  120. City of Hope Clinical Cancer Genomics Community Research Network, Duarte, California, USA.

    • Rachel Rando
  121. Clinical Cancer Genetics, City of Hope, Duarte, California, USA.

    • Jeffrey N Weitzel
  122. Division of Cancer Prevention and Genetics, Istituto Europeo di Oncologia, Milan, Italy.

    • Bernardo Bonanni
  123. Unit of Medical Genetics, Department of Preventive and Predictive Medicine, Fondazione Istituto di Ricovero e Cura a Carattere Scientifico, Istituto Nazionale Tumori, Milan, Italy.

    • Bernard Peissel
    •  & Siranoush Manoukian
  124. Unit of Medical Genetics, Department of Biomedical, Experimental and Clinical Sciences, University of Florence, Florence, Italy.

    • Laura Papi
  125. Department of Molecular Medicine, University La Sapienza, Rome, Italy.

    • Laura Ottini
  126. Molecular Diagnostics Laboratory, INRASTES (Institute of Nuclear and Radiological Sciences and Technology), National Centre for Scientific Research 'Demokritos', Aghia Paraskevi Attikis, Athens, Greece.

    • Irene Konstantopoulou
    •  & Paraskevi Apostolou
  127. Cancer Risk and Prevention Clinic, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.

    • Judy Garber
  128. Department of Basic Sciences, Shaukat Khanum Memorial Cancer Hospital and Research Centre, Lahore, Pakistan.

    • Muhammad Usman Rashid
  129. Clinical Genetics, Guy's and St. Thomas' National Health Service (NHS) Foundation Trust, London, UK.

    • Louise Izatt
  130. Department of Pathology and Laboratory Medicine, University of Kansas Medical Center, Kansas City, Kansas, USA.

    • Andrew K Godwin
  131. Department of Gynaecology and Obstetrics, University Hospital of Schleswig-Holstein, Campus Kiel, Christian Albrechts University Kiel, Kiel, Germany.

    • Norbert Arnold
  132. University Düsseldorf, Dusseldorf, Germany.

    • Dieter Niederacher
  133. Centre of Familial Breast and Ovarian Cancer, Department of Gynaecology and Obstetrics and Centre for Integrated Oncology, Center for Molecular Medicine Cologne, University Hospital of Cologne, Cologne, Germany.

    • Kerstin Rhiem
  134. Institute of Human Genetics, Münster, Germany.

    • Nadja Bogdanova-Markov
  135. INSERM U1052, CNRS UMR 5286, Université Lyon, Centre de Recherche en Cancérologie de Lyon, Lyon, France.

    • Charlotte Sagne
    • , Francesca Damiola
    • , Olga M Sinilnikova
    •  & Sylvie Mazoyer
  136. Institut Curie, Department of Tumour Biology, Paris, France.

    • Dominique Stoppa-Lyonnet
  137. Université Paris Descartes, Sorbonne Paris Cité, Paris, France.

    • Dominique Stoppa-Lyonnet
  138. Unité Mixte de Génétique Constitutionnelle des Cancers Fréquents, Hospices Civils de Lyon–Centre Léon Bérard, Lyon, France.

    • Olga M Sinilnikova
  139. Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC, USA.

    • Claudine Isaacs
  140. Center for Medical Genetics, Ghent University, Ghent, Belgium.

    • Kathleen B M Claes
    •  & Kim De Leeneer
  141. Molecular Oncology Laboratory, Hospital Clinico San Carlos, IdISSC (El Instituto de Investigación Sanitaria del Hospital Clínico San Carlos), Madrid, Spain.

    • Miguel de la Hoya
    •  & Trinidad Caldes
  142. Department of Obstetrics and Gynecology, University of Helsinki and Helsinki University Central Hospital, Helsinki, Finland.

    • Heli Nevanlinna
    •  & Sofia Khan
  143. Department of Human Genetics, Radboud University Nijmegen Medical Centre, Nijmegen, the Netherlands.

    • Arjen R Mensenkamp
  144. Department of Medical Oncology, Family Cancer Clinic, Erasmus University Medical Center, Rotterdam, the Netherlands.

    • Maartje J Hooning
  145. Department of Epidemiology, Netherlands Cancer Institute, Amsterdam, the Netherlands.

    • Matti A Rookus
  146. Hong Kong Hereditary Breast Cancer Family Registry, Cancer Genetics Center, Hong Kong Sanatorium and Hospital, Hong Kong.

    • Ava Kwong
  147. Department of Surgery, University of Hong Kong, Hong Kong.

    • Ava Kwong
  148. Department of Molecular Genetics, National Institute of Oncology, Budapest, Hungary.

    • Edith Olah
  149. Oncogenetics Laboratory, Vall d'Hebron Institute of Oncology (VHIO), Vall d'Hebron University Hospital, Barcelona, Spain.

    • Orland Diez
  150. Genetic Counseling Unit, Hereditary Cancer Program, IDIBGI (Institut d'Investigació Biomèdica de Girona), Catalan Institute of Oncology, Girona, Spain.

    • Joan Brunet
  151. Breast Cancer and Systems Biology Unit, IDIBELL (Bellvitge Biomedical Research Institute), Catalan Institute of Oncology, Barcelona, Spain.

    • Miquel Angel Pujana
  152. Department of Pathology, Landspitali University Hospital and Biomedical Centre (BMC), Faculty of Medicine, University of Iceland, Reykjavik, Iceland.

    • Rosa B Barkardottir
  153. Medical Genetic Division, Centre Hospitalier Universitaire de Québec and Laval University, Quebec City, Quebec, Canada.

    • Rachel Laframboise
  154. Centre Hospitalier Universitaire de Québec and Laval University, Quebec City, Quebec, Canada.

    • Penny Soucy
    •  & Jacques Simard
  155. Immunology and Molecular Oncology Unit, Istituto Oncologico Veneto (IOV), IRCCS (Istituto di Ricovero e Cura a Carattere Scientifico), Padua, Italy.

    • Marco Montagna
    •  & Simona Agata
  156. Department of Genetics, Portuguese Oncology Institute, Porto, Portugal.

    • Manuel R Teixeira
  157. Biomedical Sciences Institute (ICBAS), Porto University, Porto, Portugal.

    • Manuel R Teixeira
  158. Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota, USA.

    • Fergus J Couch
  159. Program in Cancer Genetics, McGill University, Montreal, Quebec, Canada.

    • Marc Tischkowitz
  160. Masaryk Memorial Cancer Institute and Medical Faculty, Masaryk University, Brno, Czech Republic.

    • Lenka Foretova
  161. Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York, USA.

    • Joseph Vijai
    •  & Kenneth Offit
  162. Department of Obstetrics and Gynecology, Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria.

    • Christian F Singer
    •  & Christine Rappaport
  163. Department of Cancer Epidemiology, Moffitt Cancer Center, Tampa, Florida, USA.

    • Catherine M Phelan
  164. Clinical Genetics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, US National Institutes of Health, Rockville, Maryland, USA.

    • Mark H Greene
    •  & Phuong L Mai
  165. Department of Community Medicine and Epidemiology, Carmel Medical Center and B. Rappaport Faculty of Medicine, Haifa, Israel.

    • Gad Rennert
  166. Clalit National Israeli Cancer Control Center, Haifa, Israel.

    • Gad Rennert
  167. N.N. Petrov Institute of Oncology, St. Petersburg, Russia.

    • Evgeny N Imyanitov
  168. Center for Medical Genetics, NorthShore University Health System, Evanston, Illinois, USA.

    • Peter J Hulick
  169. Division of Cancer Medicine, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia.

    • Kelly-Anne Phillips
  170. NRG Oncology, Statistics and Data Management Center, Roswell Park Cancer Institute, Buffalo, New York, USA.

    • Marion Piedmonte
  171. Laboratory Medicine Program, University Health Network, Toronto, Ontario, Canada.

    • Anna Marie Mulligan
  172. Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada.

    • Anna Marie Mulligan
  173. Department of Clinical Genetics, Vejle Hospital, Vejle, Denmark.

    • Anders Bojesen
  174. Department of Clinical Genetics, Odense University Hospital, Odense, Denmark.

    • Mads Thomassen
  175. Section of Genetic Oncology, Department of Laboratory Medicine, University of Pisa and University Hospital of Pisa, Pisa, Italy.

    • Maria A Caligo
  176. University Malaya Cancer Research Institute, Faculty of Medicine, University Malaya Medical Centre, University Malaya, Kuala Lumpur, Malaysia.

    • Sook-Yee Yoon
  177. Susanne Levy Gertner Oncogenetics Unit, Sheba Medical Center, Tel-Hashomer, Israel.

    • Eitan Friedman
    •  & Yael Laitman
  178. Department of Oncology, Lund University, Lund, Sweden.

    • Ake Borg
  179. Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden.

    • Hans Ehrencrona
  180. Department of Clinical Genetics, Lund University Hospital, Lund, Sweden.

    • Hans Ehrencrona
  181. Department of Clinical Genetics, Karolinska University Hospital, Stockholm, Sweden.

    • Johanna Rantala
  182. Center for Clinical Cancer Genetics and Global Health, University of Chicago Medical Center, Chicago, Illinois, USA.

    • Olufunmilayo I Olopade
  183. Division of Cancer Prevention and Control Research, Jonsson Comprehensive Cancer Center, University of California Los Angeles School of Medicine and School of Public Health, Los Angeles, California, USA.

    • Patricia A Ganz
  184. Department of Medicine and Genetics, University of California, San Francisco, San Francisco, California, USA.

    • Robert L Nussbaum
  185. Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.

    • Katherine L Nathanson
    •  & Susan M Domchek
  186. University of Texas MD Anderson Cancer Center, Houston, Texas, USA.

    • Banu K Arun
  187. Familial Cancer Centre, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia.

    • Gillian Mitchell
  188. Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, Victoria, Australia.

    • Gillian Mitchell
  189. Women's Cancer Program at the Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA.

    • Beth Y Karlan
    •  & Jenny Lester
  190. University of Hawaii Cancer Center, Honolulu, Hawaii, USA.

    • Gertraud Maskarinec
  191. Department of Obstetrics, Gynaecology and Pediatrics, Dalhousie University, Halifax, Nova Scotia, Canada.

    • Christy Woolcott
  192. Centre for Genetic Origins of Health and Disease, University of Western Australia, Perth, Western Australia, Australia.

    • Jennifer Stone
  193. Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA.

    • Rulla Tamimi
  194. Department of Epidemiology, Harvard School of Public Health, Boston, Massachusetts, USA.

    • Rulla Tamimi
  195. Program in Genetic Epidemiology and Statistical Genetics, Harvard School of Public Health, Boston, Massachusetts, USA.

    • Rulla Tamimi
  196. Clinical Gerontology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.

    • Robert Luben
    •  & Kay-Tee Khaw

Consortia

  1. EMBRACE

    A full list of members appears in the Supplementary Note.

  2. GEMO Study Collaborators

    A full list of members appears in the Supplementary Note.

  3. HEBON

    A full list of members appears in the Supplementary Note.

  4. kConFab Investigators

    A full list of members appears in the Supplementary Note.

Authors

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Contributions

Manuscript writing group: A.M.D., K. Michailidou, K.B.K., D. Thompson, J.D.F., K.A.P., J. Beesley, C.S.H., G.C.-T., A.C.A., D.F.E. and S.L.E. Locus SNP selection: A.M.D., C.S.H. and E.D. iCOGS genotyping, genotype calling and quality control: A.M.D., J. Beesley, C.S.H., M.G., G.C.-T., K.A.P. and D.F.E. Imputation: K. Michailidou, K.B.K., A.C.A. and D.F.E. Statistical analyses and programming: K. Michailidou, K.B.K., A.C.A. and D.F.E. Functional analysis and bioinformatics: S.L.E., J.D.F., K.M.H., S. Kaufmann, H.S., M.M.M., J.S.L., E.L.-K., M. Hills, M.J., S.D., J. Beesley, S. Kar, N.A.S.-A., R.C.S., S.C. and S.N. COGS coordination: P.H., D.F.E., J. Beesley and A.M.D. BCAC coordination: D.F.E., G.C.-T., P.D.P.P. and J. Stone. BCAC data management: M.K.B. and Q.W. CIMBA coordination: A.C.A., G.C.-T., J. Stone and F.J.C. CIMBA data management: L.M. and D.B. MODE coordination: D. Thompson, C.V. and F.J.C. Provided participant samples and phenotype information and read and approved the manuscript: A.M.D., K. Michailidou, K.B.K., D. Thompson, J.D.F., J. Beesley, C.S.H., S. Kar, K.A.P., E.L.-K., E.D., D.B., N.A.S.-A., R.C.S., K.M.H., S. Kaufmann, H.S., M.M.M., J.S.L., M. Hills, M.J., S.D., S.C., M.K.B., J.D., Q.W., J.L.H., M.C.S., A. Broeks, M.K.S., A. Lophatananon, K. Muir, M.W.B., P.A.F., I.d.-S.-S., J.P., E.J.S., I.T., B. Burwinkel, F.M., P.G., T.T., S.E.B., H.F., A.G.-N., J.I.A.P., H.A.-C., L.E., V.A., H. Brenner, A. Meindl, R.K.S., H. Brauch, U.H., K.A., C.B., H.I., K. Matsuo, N.B., T.D., A. Lindblom, S. Margolin, V.-M.K., A. Mannermaa, C.T., A.H.W., D.L., H.W., J.C.-C., A.R., P.P., P.R., J.E.O., G.G.G., R.L.M., C.A.H., B.E.H., M.S.G., S.H.T., C.H.Y., S.N., A.-L.B.-D., V.K., J. Long, W.Z., K.P., R.W., I.L.A., J.A.K., P.D., C. Seynaeve, J.F., M.E.S., K.C., H.D., A.Hollestelle, A.M.W.v.d.O., K.H., Y.-T.G., X.-O.S., A.C., S.S.C., W.B., Q.C., B.J.P., M.S., J.-Y.C., D.K., S.C.L., M. Hartman, M. Kabisch, D. Torres, A.J., J. Lubinski, P.B., S.S., C.B.A., A.E.T., C.-Y.S., P.-E.W., N.O., A.S., L.M., S.H., A. Lee, M. Kapuscinski, E.M.J., M.B.T., M.B.D., D.E.G., S.S.B., R.J., L.T., N.T., C.M.D., E.J.v.R., S.L.N., B.E., T.V.O.H., A.O., J. Benitez, R.R., J.N.W., B. Bonanni, B.P., S. Manoukian, L.P., L.O., I.K., P.A., J. Garber, M.U.R., D.F., L.I., S.E., A.K.G., N.A., D.N., K.R., N.B.-M., C. Sagne, D.S.-L., F.D., O.M.S., S. Mazoyer, C.I., K.B.M.C., K.D.L., M.d.l.H., T.C., H.N., S. Khan, A.R.M., M.J.H., M.A.R., A.K., E.O., O.D., J. Brunet, M.A.P., J. Gronwald, T.H., R.B.B., R. Laframboise, P.S., M.M., S.A., M.R.T., S.K.P., N.L., F.J.C., M. Tischkowitz, L.F., J.V., K.O., C.F.S., C.R., C.M.P., M.H.G., P.L.M., G.R., E.N.I., P.J.H., K.-A.P., M.P., A.M.M., G.G., A. Bojesen, M. Thomassen, M.A.C., S.-Y.Y., E.F., Y.L., A. Borg, A.v.W., H.E., J.R., O.I.O., P.A.G., R.L.N., S.A.G., K.L.N., S.M.D., B.K.A., G. Mitchell, B.Y.K., J. Lester, G. Maskarinec, C.W., C. Scott, J. Stone, C.A., R.T., R. Luben, K.-T.K., Å.Helland, V.H., M.D., P.D.P.P., J. Simard, P.H., M.G.-C., C.V., G.C.-T., A.C.A., D.F.E. and, S.L.E.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to Alison M Dunning or Douglas F Easton or Stacey L Edwards.

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    Supplementary Text and Figures

    Supplementary Figures 1–15, Supplementary Tables 1–18 and Supplementary Note.

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https://doi.org/10.1038/ng.3521

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