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

Dunning AM 1 , Michailidou K 2 , Kuchenbaecker KB 2 , Thompson D 2 , French JD 3 , Beesley J 3 Show all authors , Healey CS 1 , Kar S 1 , Pooley KA 2 , Lopez-Knowles E 4 , Dicks E 1 , Barrowdale D 2 , Sinnott-Armstrong NA 5 , Sallari RC 6 , Hillman KM 3 , Kaufmann S 3 , Sivakumaran H 3 , Moradi Marjaneh M 3 , Lee JS 3 , Hills M 7 , Jarosz M 4 , Drury S 4 , Canisius S 8 , Bolla MK 2 , Dennis J 2 , Wang Q 2 , Hopper JL 9 , Southey MC 10 , Broeks A 8 , Schmidt MK 8 , Lophatananon A 11 , Muir K 11 , Beckmann MW 12 , Fasching PA 12 , Dos-Santos-Silva I 13 , Peto J 13 , Sawyer EJ 14 , Tomlinson I 15 , Burwinkel B 16 , Marme F 17 , Guénel P 18 , Truong T 18 , Bojesen SE 19 , Flyger H 20 , González-Neira A 21 , Perez JI 22 , Anton-Culver H 23 , Eunjung L 24 , Arndt V 25 , Brenner H 25 , Meindl A 26 , Schmutzler RK 27 , Brauch H 28 , Hamann U 29 , Aittomäki K 30 , Blomqvist C 31 , Ito H 32 , Matsuo K 33 , Bogdanova N 34 , Dörk T 35 , Lindblom A 36 , Margolin S 37 , Kosma VM 38 , Mannermaa A 38 , Tseng CC 24 , Wu AH 24 , Lambrechts D 39 , Wildiers H 40 , Chang-Claude J 41 , Rudolph A 41 , Peterlongo P 42 , Radice P 43 , Olson JE 44 , Giles GG 9 , Milne RL 9 , Haiman CA 24 , Henderson BE 24 , Goldberg MS 45 , Teo SH 46 , Yip CH 47 , Nord S 48 , Borresen-Dale AL 48 , Kristensen V 48 , Long J 49 , Zheng W 49 , Pylkäs K 50 , Winqvist R 50 , Andrulis IL 51 , Knight JA 52 , Devilee P 53 , Seynaeve C 54 , Figueroa J 55 , Sherman ME 55 , Czene K 56 , Darabi H 56 , Hollestelle A 54 , van den Ouweland AM 57 , Humphreys K 56 , Gao YT 58 , Shu XO 49 , Cox A 59 , Cross SS 60 , Blot W 49 , Cai Q 49 , Ghoussaini M 1 , Perkins BJ 1 , Shah M 1 , Choi JY 61 , Kang D 61 , Lee SC 62 , Hartman M 63 , Kabisch M 29 , Torres D 29 , Jakubowska A 64 , Lubinski J 64 , Brennan P 65 , Sangrajrang S 66 , Ambrosone CB 67 , Toland AE 68 , Shen CY 69 , Wu PE 70 , Orr N 71 , Swerdlow A 72 , McGuffog L 2 , Healey S 3 , Lee A 2 , Kapuscinski M 73 , John EM 74 , Terry MB 75 , Daly MB 76 , Goldgar DE 77 , Buys SS 78 , Janavicius R 79 , Tihomirova L 80 , Tung N 81 , Dorfling CM 82 , van Rensburg EJ 82 , Neuhausen SL 83 , Ejlertsen B 84 , Hansen TV 85 , Osorio A 86 , Benitez J 86 , Rando R 87 , Weitzel JN 88 , Bonanni B 89 , Peissel B 90 , Manoukian S 90 , Papi L 91 , Ottini L 92 , Konstantopoulou I 93 , Apostolou P 93 , Garber J 94 , Rashid MU 29 , Frost D 2 , EMBRACE , Izatt L 95 , Ellis S 2 , Godwin AK 96 , Arnold N 97 , Niederacher D 98 , Rhiem K 99 , Bogdanova-Markov N 100 , Sagne C 101 , Stoppa-Lyonnet D 102 , Damiola F 101 , GEMO Study Collaborators , Sinilnikova OM 101 , Mazoyer S 101 , Isaacs C 103 , Claes KB 104 , De Leeneer K 104 , de la Hoya M 105 , Caldes T 105 , Nevanlinna H 106 , Khan S 106 , Mensenkamp AR 107 , HEBON , Hooning MJ 108 , Rookus MA 109 , Kwong A 110 , Olah E 111 , Diez O 112 , Brunet J 113 , Pujana MA 114 , Gronwald J 64 , Huzarski T 64 , Barkardottir RB 115 , Laframboise R 116 , Soucy P 117 , Montagna M 118 , Agata S 118 , Teixeira MR 119 , kConFab Investigators , Park SK 61 , Lindor N 44 , Couch FJ 44 , Tischkowitz M 120 , Foretova L 121 , Vijai J 122 , Offit K 122 , Singer CF 123 , Rappaport C 123 , Phelan CM 124 , Greene MH 125 , Mai PL 125 , Rennert G 126 , Imyanitov EN 127 , Hulick PJ 128 , Phillips KA 129 , Piedmonte M 130 , Mulligan AM 131 , Glendon G 51 , Bojesen A 132 , Thomassen M 133 , Caligo MA 134 , Yoon SY 46 , Friedman E 135 , Laitman Y 135 , Borg A 136 , von Wachenfeldt A 37 , Ehrencrona H 137 , Rantala J 138 , Olopade OI 139 , Ganz PA 140 , Nussbaum RL 141 , Gayther SA 24 , Nathanson KL 142 , Domchek SM 142 , Arun BK 143 , Mitchell G 144 , Karlan BY 145 , Lester J 145 , Maskarinec G 146 , Woolcott C 147 , Scott C 44 , Stone J 148 , Apicella C 9 , Tamimi R 149 , Luben R 150 , Khaw KT 150 , Helland Å 48 , Haakensen V 48 , Dowsett M 4 , Pharoah PD 1 , Simard J 117 , Hall P 56 , García-Closas M 71 , Vachon C 44 , Chenevix-Trench G 3 , Antoniou AC 2 , Easton DF 1 , Edwards SL 3

Affiliations 

  • 1 Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Cambridge, UK
  • 2 Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK
  • 3 Cancer Division, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia
  • 4 Breast Cancer Research, Breakthrough Breast Cancer Research Centre, London, UK
  • 5 Department of Genetics, Stanford University School of Medicine, Stanford, California, USA
  • 6 Computer Science and Artificial Intelligence Laboratory, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA
  • 7 Academic Biochemistry, Royal Marsden Hospital, London, UK
  • 8 Netherlands Cancer Institute, Antoni van Leeuwenhoek Hospital, Amsterdam, the Netherlands
  • 9 Centre for Epidemiology and Biostatistics, School of Population and Global Health, University of Melbourne, Melbourne, Victoria, Australia
  • 10 Department of Pathology, University of Melbourne, Melbourne, Victoria, Australia
  • 11 Division of Health Sciences, Warwick Medical School, Warwick University, Coventry, UK
  • 12 Department of Gynecology and Obstetrics, University Hospital Erlangen, Friedrich Alexander University Erlangen-Nuremberg, Comprehensive Cancer Center Erlangen-Nuremberg Metropolitan Region, Erlangen, Germany
  • 13 Department of Non-Communicable Disease Epidemiology, London School of Hygiene and Tropical Medicine, London, UK
  • 14 Research Oncology, Division of Cancer Studies, King's College London, Guy's Hospital, London, UK
  • 15 Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK
  • 16 Division of Molecular Genetic Epidemiology, German Cancer Research Center, Heidelberg, Germany
  • 17 National Center for Tumor Diseases, University of Heidelberg, Heidelberg, Germany
  • 18 Environmental Epidemiology of Cancer, Center for Research in Epidemiology and Population Health, INSERM, Villejuif, France
  • 19 Copenhagen General Population Study, Herlev Hospital, Copenhagen University Hospital, Herlev, Denmark
  • 20 Department of Breast Surgery, Herlev Hospital, Copenhagen University Hospital, Herlev, Denmark
  • 21 Human Cancer Genetics Program, Spanish National Cancer Centre (CNIO), Madrid, Spain
  • 22 Servicio de Cirugía General y Especialidades, Hospital Monte Naranco, Oviedo, Spain
  • 23 Department of Epidemiology, University of California-Irvine, Irvine, California, USA
  • 24 Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California, USA
  • 25 Division of Clinical Epidemiology and Aging Research, German Cancer Research Center, Heidelberg, Germany
  • 26 Department of Gynaecology and Obstetrics, Technical University of Munich, Munich, Germany
  • 27 Division of Molecular Gyneco-Oncology, Department of Gynaecology and Obstetrics, University Hospital of Cologne, Cologne, Germany
  • 28 German Cancer Consortium, German Cancer Research Center, Heidelberg, Germany
  • 29 Molecular Genetics of Breast Cancer, German Cancer Research Center, Heidelberg, Germany
  • 30 Department of Clinical Genetics, Helsinki University Central Hospital, Helsinki, Finland
  • 31 Department of Oncology, Helsinki University Central Hospital, University of Helsinki, Helsinki, Finland
  • 32 Division of Epidemiology and Prevention, Aichi Cancer Center Research Institute, Aichi, Japan
  • 33 Division of Molecular Medicine, Aichi Cancer Center Research Institute, Nagoya, Japan
  • 34 Radiation Oncology Research Unit, Hannover Medical School, Hannover, Germany
  • 35 Gynaecology Research Unit, Hannover Medical School, Hannover, Germany
  • 36 Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden
  • 37 Department of Oncology-Pathology, Karolinska University Hospital, Stockholm, Sweden
  • 38 Cancer Center, Kuopio University Hospital, Kuopio, Finland
  • 39 Vesalius Research Center, Leuven, Belgium
  • 40 Multidisciplinary Breast Center, Department of General Medical Oncology, University Hospitals Leuven, Leuven, Belgium
  • 41 Division of Cancer Epidemiology, German Cancer Research Center, Heidelberg, Germany
  • 42 IFOM, Fondazione Istituto FIRC di Oncologia Molecolare, Milan, Italy
  • 43 Unit of Molecular Basis of Genetic Risk and Genetic Testing, Department of Preventive and Predictive Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
  • 44 Department of Health Sciences Research, Mayo Clinic, Rochester, Minnesota, USA
  • 45 Department of Medicine, McGill University, Montreal, Quebec, Canada
  • 46 Cancer Research Initiatives Foundation, Sime Darby Medical Centre, Subang Jaya, Malaysia
  • 47 Breast Cancer Research Unit, University Malaya Cancer Research Institute, University Malaya Medical Centre, Kuala Lumpur, Malaysia
  • 48 Department of Genetics, Institute for Cancer Research, Oslo University Hospital, Radiumhospitalet, Oslo, Norway
  • 49 Division of Epidemiology, Department of Medicine, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, Tennessee, USA
  • 50 Laboratory of Cancer Genetics and Tumor Biology, Department of Clinical Chemistry and Biocenter Oulu, University of Oulu, NordLab Oulu University Hospital, Oulu, Finland
  • 51 Lunenfeld-Tanenbaum Research Institute of Mount Sinai Hospital, Toronto, Ontario, Canada
  • 52 Prosserman Centre for Health Research, Lunenfeld-Tanenbaum Research Institute of Mount Sinai Hospital, Toronto, Ontario, Canada
  • 53 Department of Pathology, Leiden University Medical Center, Leiden, the Netherlands
  • 54 Department of Medical Oncology, Erasmus University Medical Center, Rotterdam, the Netherlands
  • 55 Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, Maryland, USA
  • 56 Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden
  • 57 Department of Clinical Genetics, Erasmus University Medical Center, Rotterdam, the Netherlands
  • 58 Department of Epidemiology, Shanghai Cancer Institute, Shanghai, China
  • 59 Sheffield Cancer Research, Department of Oncology, University of Sheffield, Sheffield, UK
  • 60 Academic Unit of Pathology, Department of Neuroscience, University of Sheffield, Sheffield, UK
  • 61 Department of Preventive Medicine, Seoul National University College of Medicine, Seoul, Korea
  • 62 Department of Haematology-Oncology, National University Health System, Singapore
  • 63 Saw Swee Hock School of Public Health, National University of Singapore, Singapore
  • 64 Department of Genetics and Pathology, Pomeranian Medical University, Szczecin, Poland
  • 65 International Agency for Research on Cancer, Lyon, France
  • 66 National Cancer Institute, Bangkok, Thailand
  • 67 Roswell Park Cancer Institute, Buffalo, New York, USA
  • 68 Department of Molecular Virology, Immunology and Medical Genetics, Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio, USA
  • 69 School of Public Health, China Medical University, Taichung, Taiwan
  • 70 Taiwan Biobank, Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan
  • 71 Division of Cancer Studies, Breakthrough Breast Cancer Research Centre, Institute of Cancer Research, London, UK
  • 72 Division of Genetics and Epidemiology, Institute of Cancer Research, London, UK
  • 73 Centre for Epidemiology and Biostatistics, University of Melbourne, Melbourne, Victoria, Australia
  • 74 Department of Epidemiology, Cancer Prevention Institute of California, Fremont, California, USA
  • 75 Department of Epidemiology, Mailman School of Public Health, Columbia University, New York, New York, USA
  • 76 Department of Clinical Genetics, Fox Chase Cancer Center, Philadelphia, Pennsylvania, USA
  • 77 Department of Dermatology, Huntsman Cancer Institute, University of Utah School of Medicine, Salt Lake City, Utah, USA
  • 78 Department of Medicine, Huntsman Cancer Institute, University of Utah School of Medicine, Salt Lake City, Utah, USA
  • 79 State Research Institute Centre for Innovative Medicine, Vilnius, Lithuania
  • 80 Latvian Biomedical Research and Study Centre, Riga, Latvia
  • 81 Department of Medical Oncology, Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA
  • 82 Department of Genetics, University of Pretoria, Pretoria, South Africa
  • 83 Department of Population Sciences, Beckman Research Institute of City of Hope, Duarte, California, USA
  • 84 Department of Oncology, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark
  • 85 Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark
  • 86 Human Genetics Group, Spanish National Cancer Centre (CNIO), Madrid, Spain
  • 87 City of Hope Clinical Cancer Genomics Community Research Network, Duarte, California, USA
  • 88 Clinical Cancer Genetics, City of Hope, Duarte, California, USA
  • 89 Division of Cancer Prevention and Genetics, Istituto Europeo di Oncologia, Milan, Italy
  • 90 Unit of Medical Genetics, Department of Preventive and Predictive Medicine, Fondazione Istituto di Ricovero e Cura a Carattere Scientifico, Istituto Nazionale Tumori, Milan, Italy
  • 91 Unit of Medical Genetics, Department of Biomedical, Experimental and Clinical Sciences, University of Florence, Florence, Italy
  • 92 Department of Molecular Medicine, University La Sapienza, Rome, Italy
  • 93 Molecular Diagnostics Laboratory, INRASTES (Institute of Nuclear and Radiological Sciences and Technology), National Centre for Scientific Research 'Demokritos', Aghia Paraskevi Attikis, Athens, Greece
  • 94 Cancer Risk and Prevention Clinic, Dana-Farber Cancer Institute, Boston, Massachusetts, USA
  • 95 Clinical Genetics, Guy's and St. Thomas' National Health Service (NHS) Foundation Trust, London, UK
  • 96 Department of Pathology and Laboratory Medicine, University of Kansas Medical Center, Kansas City, Kansas, USA
  • 97 Department of Gynaecology and Obstetrics, University Hospital of Schleswig-Holstein, Campus Kiel, Christian Albrechts University Kiel, Kiel, Germany
  • 98 University Düsseldorf, Dusseldorf, Germany
  • 99 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
  • 100 Institute of Human Genetics, Münster, Germany
  • 101 INSERM U1052, CNRS UMR 5286, Université Lyon, Centre de Recherche en Cancérologie de Lyon, Lyon, France
  • 102 Institut Curie, Department of Tumour Biology, Paris, France
  • 103 Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC, USA
  • 104 Center for Medical Genetics, Ghent University, Ghent, Belgium
  • 105 Molecular Oncology Laboratory, Hospital Clinico San Carlos, IdISSC (El Instituto de Investigación Sanitaria del Hospital Clínico San Carlos), Madrid, Spain
  • 106 Department of Obstetrics and Gynecology, University of Helsinki and Helsinki University Central Hospital, Helsinki, Finland
  • 107 Department of Human Genetics, Radboud University Nijmegen Medical Centre, Nijmegen, the Netherlands
  • 108 Department of Medical Oncology, Family Cancer Clinic, Erasmus University Medical Center, Rotterdam, the Netherlands
  • 109 Department of Epidemiology, Netherlands Cancer Institute, Amsterdam, the Netherlands
  • 110 Hong Kong Hereditary Breast Cancer Family Registry, Cancer Genetics Center, Hong Kong Sanatorium and Hospital, Hong Kong
  • 111 Department of Molecular Genetics, National Institute of Oncology, Budapest, Hungary
  • 112 Oncogenetics Laboratory, Vall d'Hebron Institute of Oncology (VHIO), Vall d'Hebron University Hospital, Barcelona, Spain
  • 113 Genetic Counseling Unit, Hereditary Cancer Program, IDIBGI (Institut d'Investigació Biomèdica de Girona), Catalan Institute of Oncology, Girona, Spain
  • 114 Breast Cancer and Systems Biology Unit, IDIBELL (Bellvitge Biomedical Research Institute), Catalan Institute of Oncology, Barcelona, Spain
  • 115 Department of Pathology, Landspitali University Hospital and Biomedical Centre (BMC), Faculty of Medicine, University of Iceland, Reykjavik, Iceland
  • 116 Medical Genetic Division, Centre Hospitalier Universitaire de Québec and Laval University, Quebec City, Quebec, Canada
  • 117 Centre Hospitalier Universitaire de Québec and Laval University, Quebec City, Quebec, Canada
  • 118 Immunology and Molecular Oncology Unit, Istituto Oncologico Veneto (IOV), IRCCS (Istituto di Ricovero e Cura a Carattere Scientifico), Padua, Italy
  • 119 Department of Genetics, Portuguese Oncology Institute, Porto, Portugal
  • 120 Program in Cancer Genetics, McGill University, Montreal, Quebec, Canada
  • 121 Masaryk Memorial Cancer Institute and Medical Faculty, Masaryk University, Brno, Czech Republic
  • 122 Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York, USA
  • 123 Department of Obstetrics and Gynecology, Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria
  • 124 Department of Cancer Epidemiology, Moffitt Cancer Center, Tampa, Florida, USA
  • 125 Clinical Genetics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, US National Institutes of Health, Rockville, Maryland, USA
  • 126 Department of Community Medicine and Epidemiology, Carmel Medical Center and B. Rappaport Faculty of Medicine, Haifa, Israel
  • 127 N.N. Petrov Institute of Oncology, St. Petersburg, Russia
  • 128 Center for Medical Genetics, NorthShore University Health System, Evanston, Illinois, USA
  • 129 Division of Cancer Medicine, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia
  • 130 NRG Oncology, Statistics and Data Management Center, Roswell Park Cancer Institute, Buffalo, New York, USA
  • 131 Laboratory Medicine Program, University Health Network, Toronto, Ontario, Canada
  • 132 Department of Clinical Genetics, Vejle Hospital, Vejle, Denmark
  • 133 Department of Clinical Genetics, Odense University Hospital, Odense, Denmark
  • 134 Section of Genetic Oncology, Department of Laboratory Medicine, University of Pisa and University Hospital of Pisa, Pisa, Italy
  • 135 Susanne Levy Gertner Oncogenetics Unit, Sheba Medical Center, Tel-Hashomer, Israel
  • 136 Department of Oncology, Lund University, Lund, Sweden
  • 137 Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden
  • 138 Department of Clinical Genetics, Karolinska University Hospital, Stockholm, Sweden
  • 139 Center for Clinical Cancer Genetics and Global Health, University of Chicago Medical Center, Chicago, Illinois, USA
  • 140 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
  • 141 Department of Medicine and Genetics, University of California, San Francisco, San Francisco, California, USA
  • 142 Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
  • 143 University of Texas MD Anderson Cancer Center, Houston, Texas, USA
  • 144 Familial Cancer Centre, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia
  • 145 Women's Cancer Program at the Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA
  • 146 University of Hawaii Cancer Center, Honolulu, Hawaii, USA
  • 147 Department of Obstetrics, Gynaecology and Pediatrics, Dalhousie University, Halifax, Nova Scotia, Canada
  • 148 Centre for Genetic Origins of Health and Disease, University of Western Australia, Perth, Western Australia, Australia
  • 149 Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA
  • 150 Clinical Gerontology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK
Nat Genet, 2016 Apr;48(4):374-86.
PMID: 26928228 DOI: 10.1038/ng.3521

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.

* Title and MeSH Headings from MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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