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Functional mechanisms underlying pleiotropic risk alleles at the 19p13.1 breast-ovarian cancer susceptibility locus

Lawrenson K 1 , Kar S 2 , McCue K 3 , Kuchenbaeker K 4 , Michailidou K 4 , Tyrer J 2 Show all authors , Beesley J 3 , Ramus SJ 1 , Li Q 5 , Delgado MK 1 , Lee JM 1 , Aittomäki K 6 , Andrulis IL 7 , Anton-Culver H 8 , Arndt V 9 , Arun BK 10 , Arver B 11 , Bandera EV 12 , Barile M 13 , Barkardottir RB 14 , Barrowdale D 4 , Beckmann MW 15 , Benitez J 16 , Berchuck A 17 , Bisogna M 18 , Bjorge L 19 , Blomqvist C 20 , Blot W 21 , Bogdanova N 22 , Bojesen A 23 , Bojesen SE 24 , Bolla MK 4 , Bonanni B 13 , Børresen-Dale AL 25 , Brauch H 26 , Brennan P 27 , Brenner H 9 , Bruinsma F 28 , Brunet J 29 , Buhari SA 30 , Burwinkel B 31 , Butzow R 32 , Buys SS 33 , Cai Q 21 , Caldes T 34 , Campbell I 35 , Canniotto R 36 , Chang-Claude J 37 , Chiquette J 38 , Choi JY 39 , Claes KB 40 , GEMO Study Collaborators , Cook LS 41 , Cox A 42 , Cramer DW 43 , Cross SS 44 , Cybulski C 45 , Czene K 46 , Daly MB 47 , Damiola F 48 , Dansonka-Mieszkowska A 49 , Darabi H 46 , Dennis J 4 , Devilee P 50 , Diez O 51 , Doherty JA 52 , Domchek SM 53 , Dorfling CM 54 , Dörk T 22 , Dumont M 55 , Ehrencrona H 56 , Ejlertsen B 57 , Ellis S 4 , EMBRACE , Engel C 58 , Lee E 1 , Evans DG 59 , Fasching PA 15 , Feliubadalo L 60 , Figueroa J 61 , Flesch-Janys D 62 , Fletcher O 63 , Flyger H 64 , Foretova L 65 , Fostira F 66 , Foulkes WD 67 , Fridley BL 68 , Friedman E 69 , Frost D 4 , Gambino G 70 , Ganz PA 71 , Garber J 72 , García-Closas M 61 , Gentry-Maharaj A 73 , Ghoussaini M 2 , Giles GG 28 , Glasspool R 74 , Godwin AK 75 , Goldberg MS 76 , Goldgar DE 77 , González-Neira A 16 , Goode EL 78 , Goodman MT 79 , Greene MH 80 , Gronwald J 81 , Guénel P 82 , Haiman CA 1 , Hall P 46 , Hallberg E 78 , Hamann U 83 , Hansen TV 84 , Harrington PA 85 , Hartman M 30 , Hassan N 86 , Healey S 3 , Hereditary Breast and Ovarian Cancer Research Group Netherlands (HEBON) , Heitz F 87 , Herzog J 88 , Høgdall E 89 , Høgdall CK 90 , Hogervorst FB 91 , Hollestelle A 92 , Hopper JL 93 , Hulick PJ 94 , Huzarski T 45 , Imyanitov EN 95 , KConFab Investigators , Australian Ovarian Cancer Study Group , Isaacs C 96 , Ito H 97 , Jakubowska A 45 , Janavicius R 98 , Jensen A 90 , John EM 99 , Johnson N 63 , Kabisch M 83 , Kang D 39 , Kapuscinski M 100 , Karlan BY 101 , Khan S 32 , Kiemeney LA 102 , Kjaer SK 103 , Knight JA 104 , Konstantopoulou I 66 , Kosma VM 105 , Kristensen V 25 , Kupryjanczyk J 49 , Kwong A 106 , de la Hoya M 34 , Laitman Y 69 , Lambrechts D 107 , Le N 1 , De Leeneer K 40 , Lester J 101 , Levine DA 18 , Li J 46 , Lindblom A 108 , Long J 21 , Lophatananon A 109 , Loud JT 80 , Lu K 110 , Lubinski J 45 , Mannermaa A 105 , Manoukian S 111 , Le Marchand L 112 , Margolin S 113 , Marme F 114 , Massuger LF 115 , Matsuo K 116 , Mazoyer S 48 , McGuffog L 4 , McLean C 117 , McNeish I 118 , Meindl A 119 , Menon U 73 , Mensenkamp AR 120 , Milne RL 28 , Montagna M 121 , Moysich KB 122 , Muir K 109 , Mulligan AM 123 , Nathanson KL 53 , Ness RB 124 , Neuhausen SL 125 , Nevanlinna H 32 , Nord S 126 , Nussbaum RL 127 , Odunsi K 128 , Offit K 129 , Olah E 130 , Olopade OI 131 , Olson JE 78 , Olswold C 78 , O'Malley D 132 , Orlow I 133 , Orr N 63 , Osorio A 134 , Park SK 135 , Pearce CL 1 , Pejovic T 136 , Peterlongo P 137 , Pfeiler G 138 , Phelan CM 139 , Poole EM 140 , Pylkäs K 141 , Radice P 142 , Rantala J 143 , Rashid MU 83 , Rennert G 144 , Rhenius V 2 , Rhiem K 145 , Risch HA 146 , Rodriguez G 147 , Rossing MA 148 , Rudolph A 37 , Salvesen HB 19 , Sangrajrang S 149 , Sawyer EJ 150 , Schildkraut JM 151 , Schmidt MK 152 , Schmutzler RK 153 , Sellers TA 139 , Seynaeve C 92 , Shah M 2 , Shen CY 154 , Shu XO 21 , Sieh W 155 , Singer CF 138 , Sinilnikova OM 156 , Slager S 78 , Song H 2 , Soucy P 55 , Southey MC 157 , Stenmark-Askmalm M 158 , Stoppa-Lyonnet D 159 , Sutter C 160 , Swerdlow A 161 , Tchatchou S 7 , Teixeira MR 162 , Teo SH 86 , Terry KL 43 , Terry MB 163 , Thomassen M 164 , Tibiletti MG 165 , Tihomirova L 166 , Tognazzo S 167 , Toland AE 168 , Tomlinson I 169 , Torres D 83 , Truong T 82 , Tseng CC 1 , Tung N 170 , Tworoger SS 140 , Vachon C 78 , van den Ouweland AM 171 , van Doorn HC 172 , van Rensburg EJ 54 , Van't Veer LJ 152 , Vanderstichele A 173 , Vergote I 173 , Vijai J 129 , Wang Q 4 , Wang-Gohrke S , Weitzel JN 88 , Wentzensen N 174 , Whittemore AS 155 , Wildiers H 175 , Winqvist R 141 , Wu AH 1 , Yannoukakos D 176 , Yoon SY 177 , Yu JC 178 , Zheng W 21 , Zheng Y 179 , Khanna KK 3 , Simard J 55 , Monteiro AN 180 , French JD 3 , Couch FJ 78 , Freedman ML 181 , Easton DF 2 , Dunning AM 2 , Pharoah PD 2 , Edwards SL 3 , Chenevix-Trench G 3 , Antoniou AC 4 , Gayther SA 1

Affiliations 

  • 1 Department of Preventive Medicine, Keck School of Medicine, University of Southern California Norris Comprehensive Cancer Center, Los Angeles, California 90033, USA
  • 2 Department of Oncology, Centre for Cancer Genetic Epidemiology, University of Cambridge, Cambridge CB1 8RN, UK
  • 3 QIMR Berghofer Medical Research Institute, Brisbane, Queensland 4029, Australia
  • 4 Department of Public Health and Primary Care, Centre for Cancer Genetic Epidemiology, University of Cambridge, Cambridge CB1 8RN, UK
  • 5 Medical College, Xiamen University, Xiamen 361102, China
  • 6 Department of Clinical Genetics, Helsinki University Hospital, University of Helsinki, Helsinki 00029 HUS, Finland
  • 7 Lunenfeld-Tanenbaum Research Institute of Mount Sinai Hospital, Toronto, Ontario M5G 1X5, Canada
  • 8 Department of Epidemiology, Genetic Epidemiology Research Institute, School of Medicine, University of California Irvine, Irvine, California 92697, USA
  • 9 Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, 69120, Germany
  • 10 University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA
  • 11 Department of Oncology, Karolinska University Hospital, Stockholm 171 77, Sweden
  • 12 Cancer Prevention and Control, Rutgers Cancer Institute of New Jersey, New Brunswick, New Jersey 08903, USA
  • 13 Division of Cancer Prevention and Genetics, Istituto Europeo di Oncologia, Milan 20141, Italy
  • 14 Department of Pathology, Landspitali University Hospital and BMC (Biomedical Centre), Faculty of Medicine, University of Iceland, Reykjavik 600169-2039, Iceland
  • 15 University Hospital Erlangen, Department of Gynecology and Obstetrics, Friedrich-Alexander-University Erlangen-Nuremberg, Comprehensive Cancer Center Erlangen-EMN, Erlangen 91054, Germany
  • 16 Human Cancer Genetics Program, Spanish National Cancer Research Centre, Madrid E-28029, Spain
  • 17 Department of Obstetrics and Gynecology, Duke University Medical Center, Durham, North Carolina 27710, USA
  • 18 Gynecology Service, Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York 10065, USA
  • 19 Department of Gynecology and Obstetrics, Haukeland University Hospital, 5021 Bergen, Norway
  • 20 Department of Oncology, Helsinki University Hospital, University of Helsinki, Helsinki FIN-00029, Finland
  • 21 Division of Epidemiology, Department of Medicine, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, Tennessee 37203, USA
  • 22 Gynaecology Research Unit, Hannover Medical School, Hannover D-30625, Germany
  • 23 Department of Clinical Genetics, Vejle Hospital, Vejle 7100, Denmark
  • 24 Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen 2200, Denmark
  • 25 Department of Genetics, Institute for Cancer Research, Oslo University Hospital Radiumhospitalet, Oslo N-0310, Norway
  • 26 Dr Margarete Fischer-Bosch-Institute of Clinical Pharmacology, Stuttgart D-70376, Germany
  • 27 International Agency for Research on Cancer, Lyon 69008, France
  • 28 Cancer Epidemiology Centre, Cancer Council Victoria, Melbourne, Victoria 3004, Australia
  • 29 Genetic Counseling Unit, Hereditary Cancer Program, IDIBGI (Institut d'Investigació Biomèdica de Girona), Catalan Institute of Oncology, Girona 08908, Spain
  • 30 Department of Surgery, National University Health System, Singapore 119077, Singapore
  • 31 Molecular Epidemiology Group, German Cancer Research Center (DKFZ), Heidelberg 69120, Germany
  • 32 Department of Obstetrics and Gynecology, University of Helsinki and Helsinki University Central Hospital, Helsinki 00029 HUS, Finland
  • 33 Department of Medicine, Huntsman Cancer Institute, University of Utah School of Medicine, Salt Lake City, Utah 84112, USA
  • 34 Molecular Oncology Laboratory, Hospital Clinico San Carlos, IdISSC (El Instituto de Investigación Sanitaria del Hospital Clínico San Carlos), Madrid 28040, Spain
  • 35 Cancer Genetics Laboratory, Peter MacCallum Cancer Centre, Melbourne, Victoria 3002, Australia
  • 36 Cancer Pathology &Prevention, Division of Cancer Prevention and Population Sciences, Roswell Park Cancer Institute, Elm and Carlton Streets, Buffalo 14263, New York, USA
  • 37 Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg 69121, Germany
  • 38 Unité de recherche en santé des populations, Centre des maladies du sein Deschênes-Fabia, Centre de recherche FRSQ du Centre hospitalier affilié universitaire de Québec, Québec City, Québec G1J 1Z4, Canada
  • 39 Cancer Research Institute, Seoul National University, Seoul 08826, Korea
  • 40 Center for Medical Genetics, Ghent University, Ghent 9000, Belgium
  • 41 Division of Epidemiology and Biostatistics, Department of Internal Medicine, University of New Mexico, Albuquerque, New Mexico 87131, USA
  • 42 Sheffield Cancer Research, Department of Oncology, University of Sheffield, Sheffield S10 2TN, UK
  • 43 Harvard HT Chan School of Public Health, Boston, Massachusetts 02115, USA
  • 44 Academic Unit of Pathology, Department of Neuroscience, University of Sheffield, Sheffield S10 2TN, UK
  • 45 Department of Genetics and Pathology, Pomeranian Medical University, Szczecin 70-115, Poland
  • 46 Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm SE-171 77, Sweden
  • 47 Department of Clinical Genetics, Fox Chase Cancer Center, Philadelphia, Pennsylvania 19111, USA
  • 48 INSERM U1052, CNRS UMR5286, Université Lyon, Centre de Recherche en Cancérologie de Lyon, Lyon 69373, France
  • 49 Department of Pathology and Laboratory Diagnostics the Maria Sklodowska Curie Memorial Cancer Center and Institute of Oncology, Warsaw 44-101, Poland
  • 50 Department of Pathology, Leiden University Medical Center, Leiden 2333, The Netherlands
  • 51 Oncogenetics Group, University Hospital Vall d'Hebron, Vall d'Hebron Institute of Oncology (VHIO) and Universitat Autònoma de Barcelona, Barcelona 08035, Spain
  • 52 Department of Community and Family Medicine, Section of Biostatistics &Epidemiology, The Geisel School of Medicine at Dartmouth, Lebanon, New Hampshire 03755, USA
  • 53 Department of Medicine, Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA
  • 54 Department of Genetics, University of Pretoria, Pretoria 0083, South Africa
  • 55 Genomics Center, Centre Hospitalier Universitaire de Québec Research Center, Laval University, Québec City, Québec G1V 4G2, Canada
  • 56 Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala 751 05, Sweden
  • 57 Department of Oncology, Rigshospitalet, Copenhagen University Hospital, 2100 Copenhagen, Denmark
  • 58 Institute for Medical Informatics, Statistics and Epidemiology, University of Leipzig, 04107 Leipzig, Germany
  • 59 Genomic Medicine, Manchester Academic Health Sciences Centre, Institute of Human Development, Manchester University, Central Manchester University Hospitals NHS Foundation Trust, Manchester M13 9PL, UK
  • 60 Molecular Diagnostic Unit, Hereditary Cancer Program, IDIBELL (Bellvitge Biomedical Research Institute),Catalan Institute of Oncology, Barcelona 08908, Spain
  • 61 Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, Maryland 20892, USA
  • 62 Institute for Medical Biometrics and Epidemiology, University Medical Center Hamburg-Eppendorf, Hamburg 20246, Germany
  • 63 Breakthrough Breast Cancer Research Centre, The Institute of Cancer Research, London SW3 6JB, UK
  • 64 Department of Breast Surgery, Herlev Hospital, Copenhagen University Hospital, 2730 Herlev, Denmark
  • 65 Masaryk Memorial Cancer Institute and Medical Faculty MU, 625 00 Brno, Czech Republic
  • 66 Molecular Diagnostics Laboratory, (INRASTES) Institute of Nuclear and Radiological Sciences and Technology, National Centre for Scientific Research 'Demokritos', Aghia Paraskevi Attikis, Athens 153 10, Greece
  • 67 Program in Cancer Genetics, Departments of Human Genetics and Oncology, McGill University, Montreal, Montreal, Quebec H2W 1S6, Canada
  • 68 Biostatistics and Informatics Shared Resource, University of Kansas Medical Center, Kansas City, Kansas 66160, USA
  • 69 Susanne Levy Gertner Oncogenetics Unit, Sheba Medical Center, Tel-Hashomer 52621, Israel
  • 70 Section of Genetic Oncology, Department of Laboratory Medicine, University and University Hospital of Pisa, Pisa 56126, Italy
  • 71 UCLA Schools of Medicine and Public Health, Division of Cancer Prevention &Control Research, Jonsson Comprehensive Cancer Center, Los Angeles, California 90024, USA
  • 72 Cancer Risk and Prevention Clinic, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA
  • 73 Women's Cancer, UCL EGA Institute for Women's Health, London WC1E 6AU, UK
  • 74 Cancer Research UK Clinical Trials Unit, The Beatson West of Scotland Cancer Centre, Glasgow G12 0YN, UK
  • 75 Department of Pathology and Laboratory Medicine, University of Kansas Medical Center, Kansas City, Kansas 66160, USA
  • 76 Division of Clinical Epidemiology, Royal Victoria Hospital, McGill University, Montreal, Québec H3A 1A1, Canada
  • 77 Department of Dermatology, Huntsman Cancer Institute, University of Utah School of Medicine, Salt Lake City, Utah 84132, USA
  • 78 Department of Health Sciences Research, Mayo Clinic, Rochester, Minnesota 55902, USA
  • 79 Cancer Prevention and Control, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, California 90048, USA
  • 80 Clinical Genetics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Rockville, Maryland 20892, USA
  • 81 Department of Genetics and Pathology, Pomeranian Medical University, 70-204 Szczecin, Poland
  • 82 Environmental Epidemiology of Cancer, Center for Research in Epidemiology and Population Health, INSERM, 94805 Villejuif, France
  • 83 Molecular Genetics of Breast Cancer, German Cancer Research Center (DKFZ), Heidelberg 69120, Germany
  • 84 Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital, 2100 Copenhagen, Denmark
  • 85 Department of Oncology, Department of Public Health and Primary Care, University of Cambridge, Strangeways Research Laboratory, Cambridge CB1 8RN, UK
  • 86 Breast Cancer Research Unit, Cancer Research Institute, University Malaya Medical Centre, 50603 Kuala Lumpur, Malaysia
  • 87 Department of Gynecology and Gynecologic Oncology, Kliniken Essen-Mitte, 45136 Essen, Germany
  • 88 Clinical Cancer Genetics, for the City of Hope Clinical Cancer Genetics Community Research Network, Duarte California 91010, USA
  • 89 Molecular Unit, Department of Pathology, Herlev Hospital, University of Copenhagen, 2730 Copenhagen, Denmark
  • 90 Department of Gynecology, Rigshospitalet, University of Copenhagen, 2100 Copenhagen, Denmark
  • 91 Family Cancer Clinic, Netherlands Cancer Institute, 1006 Amsterdam, The Netherlands
  • 92 Department of Medical Oncology, Family Cancer Clinic, Erasmus MC Cancer Institute, 3015 Rotterdam, The Netherlands
  • 93 Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, Victoria 3010, Australia
  • 94 Center for Medical Genetics, NorthShore University Health System, Evanston, Illinois, 60201, USA
  • 95 N.N. Petrov Institute of Oncology, St Petersburg 197758, Russia
  • 96 Lombardi Comprehensive Cancer Center, Georgetown University, Washington District of Columbia 20057, USA
  • 97 Division of Epidemiology and Prevention, Aichi Cancer Center Research Institute, Aichi 464-8681, Japan
  • 98 State Research Institute Centre for Innovative Medicine, LT-01102 Vilnius, Lithuania
  • 99 Department of Epidemiology, Cancer Prevention Institute of California, Fremont, California 94538, USA
  • 100 Centre for Epidemiology and Biostatistics, University of Melbourne, Melbourne, Victoria 3010, Australia
  • 101 Women's Cancer Program at the Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, California 90048, USA
  • 102 Radboud University Medical Centre, Radboud Institute for Health Sciences, 6500 Nijmegen, The Netherlands
  • 103 Department of Virus, Lifestyle and Genes, Danish Cancer Society Research Center, DK-2100 Copenhagen, Denmark
  • 104 Prosserman Centre for Health Research, Lunenfeld-Tanenbaum Research Institute of Mount Sinai Hospital, Toronto, Ontario M5G 1X5, Canada
  • 105 Imaging Center, Department of Clinical Pathology, Kuopio University Hospital, 70210 Kuopio, Finland
  • 106 The Hong Kong Hereditary Breast Cancer Family Registry, Cancer Genetics Center, Hong Kong Sanatorium and Hospital, Hong Kong, China
  • 107 Vesalius Research Center, VIB, 3000 Leuven, Belgium
  • 108 Department of Molecular Medicine and Surgery, Karolinska Institutet, SE-171 77 Stockholm, Sweden
  • 109 Division of Health Sciences, Warwick Medical School, Warwick University, Coventry CV4 7AL, UK
  • 110 Department of Gynecologic Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA
  • 111 Unit of Medical Genetics, Department of Preventive and Predictive Medicine, Fondazione IRCCS (Istituto Di Ricovero e Cura a Carattere Scientifico) Istituto Nazionale Tumori (INT), 20133 Milan, Italy
  • 112 University of Hawaii Cancer Center, Honolulu, Hawaii 96813, USA
  • 113 Department of Oncology - Pathology, Karolinska Institutet, SE-171 77 Stockholm, Sweden
  • 114 Department of Obstetrics and Gynecology, University of Heidelberg, Heidelberg 69120, Germany
  • 115 Department of Gynaecology, Radboud University Medical Centre, 6500 Nijmegen, The Netherlands
  • 116 Department of Preventive Medicine, Kyushu University Faculty of Medical Sciences, Fukuoka 812-8582, Japan
  • 117 Anatomical Pathology, The Alfred Hospital, Melbourne, Victoria 3004, Australia
  • 118 Institute of Cancer Sciences, University of Glasgow, Wolfson Wohl Cancer Research Centre, Beatson Institute for Cancer Research, Glasgow G61 1BD, UK
  • 119 Division of Gynaecology and Obstetrics, Technische Universität München, 81675 Munich, Germany
  • 120 Department of Human Genetics, Radboud University Medical Centre, 6500 Nijmegen, The Netherlands
  • 121 Immunology and Molecular Oncology Unit, Instituto Oncologico Veneto IOV, IRCCS, 35128 Padua, Italy
  • 122 Department of Cancer Prevention and Control, Roswell Park Cancer Institute, Buffalo, New York 14263, USA
  • 123 Laboratory Medicine Program, University Health Network, Toronto, Ontario M5G 1L7, Canada
  • 124 The University of Texas School of Public Health, Houston, Texas 77030, USA
  • 125 Department of Population Sciences, Beckman Research Institute of City of Hope, Duarte, California 91010, USA
  • 126 K.G. Jebsen Center for Breast Cancer Research, Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo N-0310, Norway
  • 127 Department of Medicine and Genetics, University of California, San Francisco, California 94143, USA
  • 128 Department of Gynecological Oncology, Roswell Park Cancer Institute, Buffalo, New York 14263, USA
  • 129 Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York 10065, USA
  • 130 Department of Molecular Genetics, National Institute of Oncology, 1122 Budapest, Hungary
  • 131 Center for Clinical Cancer Genetics and Global Health, University of Chicago Medical Center, Chicago, Illinois 60637, USA
  • 132 The Ohio State University and the James Cancer Center, Columbus, Ohio 43210, USA
  • 133 Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York 10017, USA
  • 134 Human Genetics Group, Human Cancer Genetics Program, Spanish National Cancer Centre (CNIO), 28019 Madrid, Spain
  • 135 Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul 03080, Korea
  • 136 Department of Obstetrics and Gynecology, Oregon Health and Science University, Portland, Oregon 97239, USA
  • 137 IFOM, The FIRC (Italian Foundation for Cancer Research) Institute of Molecular Oncology, 16 20139 Milan, Italy
  • 138 Department of Obstetrics and Gynecology, Comprehensive Cancer Center, Medical University of Vienna, 1090 Vienna, Austria
  • 139 Department of Cancer Epidemiology, Moffitt Cancer Center, Tampa, Florida 33606, USA
  • 140 Channing Division of Network Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA
  • 141 Laboratory of Cancer Genetics and Tumour Biology, Northern Finland Laboratory Centre NordLab, FI-90014 Oulu, Finland
  • 142 Unit of Molecular Bases of Genetic Risk and Genetic Testing, Department of Preventive and Predictive Medicine, Fondazione IRCCS (Istituto Di Ricovero e Cura a Carattere Scientifico) Istituto Nazionale dei Tumori (INT), 20133 Milan, Italy
  • 143 Department of Clinical Genetics, Karolinska University Hospital, 171 76 Stockholm, Sweden
  • 144 Clalit National Israeli Cancer Control Center and Department of Community Medicine and Epidemiology, Carmel Medical Center and B. Rappaport Faculty of Medicine, Haifa 34362, Israel
  • 145 Centre of Familial Breast and Ovarian Cancer, Department of Gynaecology and Obstetrics and Centre for Integrated Oncology (CIO), Center for Molecular Medicine Cologne (CMMC), University Hospital of Cologne, 50931 Cologne, Germany
  • 146 Department of Chronic Disease Epidemiology, Yale School of Public Health, New Haven, Connecticut 06510, USA
  • 147 Division of Gynecologic Oncology, NorthShore University HealthSystem, Evanston, Illinois 60201, USA
  • 148 Program in Epidemiology, Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington 98109, USA
  • 149 National Cancer Institute, Bangkok 10400, Thailand
  • 150 Research Oncology, Guy's Hospital, King's College London, London SE1 9RT, UK
  • 151 Department of Community and Family Medicine, Duke University Medical Center, Durham, North Carolina 27710, USA
  • 152 Netherlands Cancer Institute, Antoni van Leeuwenhoek Hospital, 1066 CX Amsterdam, The Netherlands
  • 153 Division of Molecular Gyneco-Oncology, Department of Gynaecology and Obstetrics, University Hospital of Cologne, 50676 Cologne, Germany
  • 154 Taiwan Biobank, Institute of Biomedical Sciences, Academia Sinica, Taipei 115, Taiwan
  • 155 Department of Health Research and Policy - Epidemiology, Stanford University School of Medicine, Stanford California 94305, USA
  • 156 Unité Mixte de Génétique Constitutionnelle des Cancers Fréquents, Hospices Civils de Lyon - Centre Léon Bérard, Lyon 69008, France
  • 157 Department of Pathology, University of Melbourne, Parkville, Victoria 3010, Australia
  • 158 Department of Clinical Genetics, Lund University Hospital, Lund 221 00, Sweden
  • 159 Institut Curie, Department of Tumour Biology, Paris, France; Institut Curie, INSERM U830, 75248 Paris, France
  • 160 Institute of Human Genetics, Department of Human Genetics, University Hospital Heidelberg, 69120 Heidelberg, Germany
  • 161 Division of Breast Cancer Research, The Institute of Cancer Research, London SW7 3RP, UK
  • 162 Department of Genetics, Portuguese Oncology Institute, Porto 4200-072, Portugal
  • 163 Department of Epidemiology, Mailman School of Public Health, Columbia University, New York 10027, USA
  • 164 Department of Clinical Genetics, Odense University Hospital, 5000 Odense C, Denmark
  • 165 UO Anatomia Patologica, Ospedale di Circolo-Università dell'Insubria, 21100 Varese, Italy
  • 166 Latvian Biomedical Research and Study Centre, Riga LV-1067, Latvia
  • 167 Immunology and Molecular Oncology Unit, Istituto Oncologico Veneto IOV - IRCCS (Istituto Di Ricovero e Cura a Carattere Scientifico), 64 - 35128 Padua, Italy
  • 168 Department of Molecular Virology, Immunology and Medical Genetics, The Ohio State University, Columbus, Ohio 43210, USA
  • 169 Wellcome Trust Centre for Human Genetics and Oxford Biomedical Research Centre, University of Oxford, Oxford OX3 7BN, UK
  • 170 Department of Medical Oncology, Beth Israel Deaconess Medical Center, Boston, Massachusetts 02215, USA
  • 171 Department of Clinical Genetics, Erasmus University Medical Center, 3015 CE Rotterdam, The Netherlands
  • 172 Department of Gynecology, Family Cancer Clinic, Erasmus MC Cancer Institute, 3015 CE Rotterdam, The Netherlands
  • 173 Division of Gynecological Oncology, Department of Oncology, University Hospitals Leuven, B-3000 Leuven, Belgium
  • 174 Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda Maryland 20892, USA
  • 175 Multidisciplinary Breast Center, Department of General Medical Oncology, University Hospitals Leuven, B-3000 Leuven, Belgium
  • 176 Molecular Diagnostics Laboratory, IRRP, National Centre for Scientific Research 'Demokritos', Athens 153 10, Greece
  • 177 Cancer Research Initiatives Foundation, Sime Darby Medical Centre, 47500 Subang Jaya, Malaysia
  • 178 Department of Surgery, Tri-Service General Hospital, National Defense Medical Center, Taipei, 114 Taiwan
  • 179 Shanghai Center for Disease Control and Prevention, Shanghai, China
  • 180 Cancer Epidemiology Program, Division of Population Sciences, H. Lee Moffitt Cancer Center &Research Institute, Tampa, Florida 33612, USA
  • 181 Department of Medical Oncology, The Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA
Nat Commun, 2016 Sep 07;7:12675.
PMID: 27601076 DOI: 10.1038/ncomms12675

Abstract

A locus at 19p13 is associated with breast cancer (BC) and ovarian cancer (OC) risk. Here we analyse 438 SNPs in this region in 46,451 BC and 15,438 OC cases, 15,252 BRCA1 mutation carriers and 73,444 controls and identify 13 candidate causal SNPs associated with serous OC (P=9.2 × 10(-20)), ER-negative BC (P=1.1 × 10(-13)), BRCA1-associated BC (P=7.7 × 10(-16)) and triple negative BC (P-diff=2 × 10(-5)). Genotype-gene expression associations are identified for candidate target genes ANKLE1 (P=2 × 10(-3)) and ABHD8 (P<2 × 10(-3)). Chromosome conformation capture identifies interactions between four candidate SNPs and ABHD8, and luciferase assays indicate six risk alleles increased transactivation of the ADHD8 promoter. Targeted deletion of a region containing risk SNP rs56069439 in a putative enhancer induces ANKLE1 downregulation; and mRNA stability assays indicate functional effects for an ANKLE1 3'-UTR SNP. Altogether, these data suggest that multiple SNPs at 19p13 regulate ABHD8 and perhaps ANKLE1 expression, and indicate common mechanisms underlying breast and ovarian cancer risk.

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

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