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    Nature communications. 2016 Sep 7. pii: ncomms12675. doi: 10.1038/ncomms12675
    Functional mechanisms underlying pleiotropic risk alleles at the 19p13.1 breast-ovarian cancer susceptibility locus.
    Lawrenson K1,  Kar S2,  McCue K3,  Kuchenbaeker K4,  Michailidou K5,  Tyrer J6,  Beesley J7,  Ramus SJ8,  Li Q9,  Delgado MK10,  Lee JM11,  Aittomäki K12,  Andrulis IL13,  Anton-Culver H14,  Arndt V15,  Arun BK16,  Arver B17,  Bandera EV18,  Barile M19,  Barkardottir RB20,  Barrowdale D21,  Beckmann MW22,  Benitez J23,  Berchuck A24,  Bisogna M25,  Bjorge L26,  Blomqvist C27,  Blot W28,  Bogdanova N29,  Bojesen A30,  Bojesen SE31,  Bolla MK32,  Bonanni B33,  Børresen-Dale AL34,  Brauch H35,  Brennan P36,  Brenner H37,  Bruinsma F38,  Brunet J39,  Buhari SA40,  Burwinkel B41,  Butzow R42,  Buys SS43,  Cai Q44,  Caldes T45,  Campbell I46,  Canniotto R47,  Chang-Claude J48,  Chiquette J49,  Choi JY50,  Claes KB51,  Cook LS52,  Cox A53,  Cramer DW54,  Cross SS55,  Cybulski C56,  Czene K57,  Daly MB58,  Damiola F59,  Dansonka-Mieszkowska A60,  Darabi H61,  Dennis J62,  Devilee P63,  Diez O64,  Doherty JA65,  Domchek SM66,  Dorfling CM67,  Dörk T68,  Dumont M69,  Ehrencrona H70,  Ejlertsen B71,  Ellis S72,  Engel C73,  Lee E74,  Evans DG75,  Fasching PA76,  Feliubadalo L77,  Figueroa J78,  Flesch-Janys D79,  Fletcher O80,  Flyger H81,  Foretova L82,  Fostira F83,  Foulkes WD84,  Fridley BL85,  Friedman E86,  Frost D87,  Gambino G88,  Ganz PA89,  Garber J90,  García-Closas M91,  Gentry-Maharaj A92,  Ghoussaini M93,  Giles GG94,  Glasspool R95,  Godwin AK96,  Goldberg MS97,  Goldgar DE98,  González-Neira A99,  Goode EL100,  Goodman MT101,  Greene MH102,  Gronwald J103,  Guénel P104,  Haiman CA105,  Hall P106,  Hallberg E107,  Hamann U108,  Hansen TV109,  Harrington PA110,  Hartman M111,  Hassan N112,  Healey S113,  Heitz F114,  Herzog J115,  Høgdall E116,  Høgdall CK117,  Hogervorst FB118,  Hollestelle A119,  Hopper JL120,  Hulick PJ121,  Huzarski T122,  Imyanitov EN123,  Isaacs C124,  Ito H125,  Jakubowska A126,  Janavicius R127,  Jensen A128,  John EM129,  Johnson N130,  Kabisch M131,  Kang D132,  Kapuscinski M133,  Karlan BY134,  Khan S135,  Kiemeney LA136,  Kjaer SK137,  Knight JA138,  Konstantopoulou I139,  Kosma VM140,  Kristensen V141,  Kupryjanczyk J142,  Kwong A143,  de la Hoya M144,  Laitman Y145,  Lambrechts D146,  Le N147,  De Leeneer K148,  Lester J149,  Levine DA150,  Li J151,  Lindblom A152,  Long J153,  Lophatananon A154,  Loud JT155,  Lu K156,  Lubinski J157,  Mannermaa A158,  Manoukian S159,  Le Marchand L160,  Margolin S161,  Marme F162,  Massuger LF163,  Matsuo K164,  Mazoyer S165,  McGuffog L166,  McLean C167,  McNeish I168,  Meindl A169,  Menon U170,  Mensenkamp AR171,  Milne RL172,  Montagna M173,  Moysich KB174,  Muir K175,  Mulligan AM176,  Nathanson KL177,  Ness RB178,  Neuhausen SL179,  Nevanlinna H180,  Nord S181,  Nussbaum RL182,  Odunsi K183,  Offit K184,  Olah E185,  Olopade OI186,  Olson JE187,  Olswold C188,  O'Malley D189,  Orlow I190,  Orr N191,  Osorio A192,  Park SK193,  Pearce CL194,  Pejovic T195,  Peterlongo P196,  Pfeiler G197,  Phelan CM198,  Poole EM199,  Pylkäs K200,  Radice P201,  Rantala J202,  Rashid MU203,  Rennert G204,  Rhenius V205,  Rhiem K206,  Risch HA207,  Rodriguez G208,  Rossing MA209,  Rudolph A210,  Salvesen HB211,  Sangrajrang S212,  Sawyer EJ213,  Schildkraut JM214,  Schmidt MK215,  Schmutzler RK216,  Sellers TA217,  Seynaeve C218,  Shah M219,  Shen CY220,  Shu XO221,  Sieh W222,  Singer CF223,  Sinilnikova OM224,  Slager S225,  Song H226,  Soucy P227,  Southey MC228,  Stenmark-Askmalm M229,  Stoppa-Lyonnet D230,  Sutter C231,  Swerdlow A232,  Tchatchou S233,  Teixeira MR234,  Teo SH235,  Terry KL236,  Terry MB237,  Thomassen M238,  Tibiletti MG239,  Tihomirova L240,  Tognazzo S241,  Toland AE242,  Tomlinson I243,  Torres D244,  Truong T245,  Tseng CC246,  Tung N247,  Tworoger SS248,  Vachon C249,  van den Ouweland AM250,  van Doorn HC251,  van Rensburg EJ252,  Van't Veer LJ253,  Vanderstichele A254,  Vergote I255,  Vijai J256,  Wang Q257,  Wang-Gohrke S,  Weitzel JN258,  Wentzensen N259,  Whittemore AS260,  Wildiers H261,  Winqvist R262,  Wu AH263,  Yannoukakos D264,  Yoon SY265,  Yu JC266,  Zheng W267,  Zheng Y268,  Khanna KK269,  Simard J270,  Monteiro AN271,  French JD272,  Couch FJ273,  Freedman ML274,  Easton DF275,  Dunning AM276,  Pharoah PD277,  Edwards SL278,  Chenevix-Trench G279,  Antoniou AC280,  Gayther SA281
    Collaborators
    Collonge-Rame MA Damette A Barouk-Simonet E Bonnet F Bubien V Sevenet N Longy M Berthet P Vaur D Castera L Ferrer SF Bignon YJ Uhrhammer N Coron F Faivre L Baurand A Jacquot C Bertolone G Lizard S Leroux D Dreyfus H Rebischung C Peysselon M Peyrat JP Fournier J Révillion F Adenis C Vénat-Bouvet L Léone M Boutry-Kryza N Calender A Giraud S Verny-Pierre C Lasset C Bonadona V Barjhoux L Sobol H Bourdon V Noguchi T Remenieras A Coupier I Pujol P Sokolowska J Bronner M Delnatte C Bézieau S Mari V Gauthier-Villars M Buecher B Rouleau E Golmard L Moncoutier V Belotti M de Pauw A Elan C Fourme E Birot AM Saule C Laurent M Houdayer C Lesueur F Mebirouk N Coulet F Colas C Soubrier F Warcoin M Prieur F Lebrun M Kientz C Muller D Fricker JP Toulas C Guimbaud R Gladieff L Feillel V Mortemousque I Bressac-de-Paillerets B Caron O Guillaud-Bataille M Gregory H Miedzybrodzka Z Morrison PJ Donaldson A Rogers MT Kennedy MJ Porteous ME Brady A Barwell J Foo C Lalloo F Side LE Eason J Henderson A Walker L Cook J Snape K Murray A McCann E Rookus MA van Leeuwen FE van der Kolk LE Schmidt MK Russell NS de Lange JL Wijnands R Collée JM Hooning MJ Seynaeve C van Deurzen CH Obdeijn IM van Asperen CJ Tollenaar RA van Cronenburg TC Kets CM Ausems MG van der Pol CC van Os TA Waisfisz Q Meijers-Heijboer HE Gómez-Garcia EB Oosterwijk JC Mourits MJ de Bock GH Vasen HF Siesling S Verloop J Overbeek LI Fox S Kirk J Lindeman G Price M Bowtell D deFazio A Webb P
    Author information
    1Department of Preventive Medicine, Keck School of Medicine, University of Southern California Norris Comprehensive Cancer Center, Los Angeles, California 90033, USA.
    2Department of Oncology, Centre for Cancer Genetic Epidemiology, University of Cambridge, Cambridge CB1 8RN, UK.
    3QIMR Berghofer Medical Research Institute, Brisbane, Queensland 4029, Australia.
    4Department of Public Health and Primary Care, Centre for Cancer Genetic Epidemiology, University of Cambridge, Cambridge CB1 8RN, UK.
    5Department of Public Health and Primary Care, Centre for Cancer Genetic Epidemiology, University of Cambridge, Cambridge CB1 8RN, UK.
    6Department of Oncology, Centre for Cancer Genetic Epidemiology, University of Cambridge, Cambridge CB1 8RN, UK.
    7QIMR Berghofer Medical Research Institute, Brisbane, Queensland 4029, Australia.
    8Department of Preventive Medicine, Keck School of Medicine, University of Southern California Norris Comprehensive Cancer Center, Los Angeles, California 90033, USA.
    9Medical College, Xiamen University, Xiamen 361102, China.
    10Department of Preventive Medicine, Keck School of Medicine, University of Southern California Norris Comprehensive Cancer Center, Los Angeles, California 90033, USA.
    11Department of Preventive Medicine, Keck School of Medicine, University of Southern California Norris Comprehensive Cancer Center, Los Angeles, California 90033, USA.
    12Department of Clinical Genetics, Helsinki University Hospital, University of Helsinki, Helsinki 00029 HUS, Finland.
    13Lunenfeld-Tanenbaum Research Institute of Mount Sinai Hospital, Toronto, Ontario M5G 1X5, Canada.
    14Department of Epidemiology, Genetic Epidemiology Research Institute, School of Medicine, University of California Irvine, Irvine, California 92697, USA.
    15Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, 69120, Germany.
    16University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
    17Department of Oncology, Karolinska University Hospital, Stockholm 171 77, Sweden.
    18Cancer Prevention and Control, Rutgers Cancer Institute of New Jersey, New Brunswick, New Jersey 08903, USA.
    19Division of Cancer Prevention and Genetics, Istituto Europeo di Oncologia, Milan 20141, Italy.
    20Department of Pathology, Landspitali University Hospital and BMC (Biomedical Centre), Faculty of Medicine, University of Iceland, Reykjavik 600169-2039, Iceland.
    21Department of Public Health and Primary Care, Centre for Cancer Genetic Epidemiology, University of Cambridge, Cambridge CB1 8RN, UK.
    22University Hospital Erlangen, Department of Gynecology and Obstetrics, Friedrich-Alexander-University Erlangen-Nuremberg, Comprehensive Cancer Center Erlangen-EMN, Erlangen 91054, Germany.
    23Human Cancer Genetics Program, Spanish National Cancer Research Centre, Madrid E-28029, Spain.
    24Department of Obstetrics and Gynecology, Duke University Medical Center, Durham, North Carolina 27710, USA.
    25Gynecology Service, Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York 10065, USA.
    26Department of Gynecology and Obstetrics, Haukeland University Hospital, 5021 Bergen, Norway.
    27Department of Oncology, Helsinki University Hospital, University of Helsinki, Helsinki FIN-00029, Finland.
    28Division of Epidemiology, Department of Medicine, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, Tennessee 37203, USA.
    29Gynaecology Research Unit, Hannover Medical School, Hannover D-30625, Germany.
    30Department of Clinical Genetics, Vejle Hospital, Vejle 7100, Denmark.
    31Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen 2200, Denmark.
    32Department of Public Health and Primary Care, Centre for Cancer Genetic Epidemiology, University of Cambridge, Cambridge CB1 8RN, UK.
    33Division of Cancer Prevention and Genetics, Istituto Europeo di Oncologia, Milan 20141, Italy.
    34Department of Genetics, Institute for Cancer Research, Oslo University Hospital Radiumhospitalet, Oslo N-0310, Norway.
    35Dr Margarete Fischer-Bosch-Institute of Clinical Pharmacology, Stuttgart D-70376, Germany.
    36International Agency for Research on Cancer, Lyon 69008, France.
    37Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, 69120, Germany.
    38Cancer Epidemiology Centre, Cancer Council Victoria, Melbourne, Victoria 3004, Australia.
    39Genetic Counseling Unit, Hereditary Cancer Program, IDIBGI (Institut d'Investigació Biomèdica de Girona), Catalan Institute of Oncology, Girona 08908, Spain.
    40Department of Surgery, National University Health System, Singapore 119077, Singapore.
    41Molecular Epidemiology Group, German Cancer Research Center (DKFZ), Heidelberg 69120, Germany.
    42Department of Obstetrics and Gynecology, University of Helsinki and Helsinki University Central Hospital, Helsinki 00029 HUS, Finland.
    43Department of Medicine, Huntsman Cancer Institute, University of Utah School of Medicine, Salt Lake City, Utah 84112, USA.
    44Division of Epidemiology, Department of Medicine, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, Tennessee 37203, USA.
    45Molecular Oncology Laboratory, Hospital Clinico San Carlos, IdISSC (El Instituto de Investigación Sanitaria del Hospital Clínico San Carlos), Madrid 28040, Spain.
    46Cancer Genetics Laboratory, Peter MacCallum Cancer Centre, Melbourne, Victoria 3002, Australia.
    47Cancer Pathology &Prevention, Division of Cancer Prevention and Population Sciences, Roswell Park Cancer Institute, Elm and Carlton Streets, Buffalo 14263, New York, USA.
    48Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg 69121, Germany.
    49Unité 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.
    50Cancer Research Institute, Seoul National University, Seoul 08826, Korea.
    51Center for Medical Genetics, Ghent University, Ghent 9000, Belgium.
    52Division of Epidemiology and Biostatistics, Department of Internal Medicine, University of New Mexico, Albuquerque, New Mexico 87131, USA.
    53Sheffield Cancer Research, Department of Oncology, University of Sheffield, Sheffield S10 2TN, UK.
    54Harvard HT Chan School of Public Health, Boston, Massachusetts 02115, USA.
    55Academic Unit of Pathology, Department of Neuroscience, University of Sheffield, Sheffield S10 2TN, UK.
    56Department of Genetics and Pathology, Pomeranian Medical University, Szczecin 70-115, Poland.
    57Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm SE-171 77, Sweden.
    58Department of Clinical Genetics, Fox Chase Cancer Center, Philadelphia, Pennsylvania 19111, USA.
    59INSERM U1052, CNRS UMR5286, Université Lyon, Centre de Recherche en Cancérologie de Lyon, Lyon 69373, France.
    60Department of Pathology and Laboratory Diagnostics the Maria Sklodowska Curie Memorial Cancer Center and Institute of Oncology, Warsaw 44-101, Poland.
    61Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm SE-171 77, Sweden.
    62Department of Public Health and Primary Care, Centre for Cancer Genetic Epidemiology, University of Cambridge, Cambridge CB1 8RN, UK.
    63Department of Pathology, Leiden University Medical Center, Leiden 2333, The Netherlands.
    64Oncogenetics Group, University Hospital Vall d'Hebron, Vall d'Hebron Institute of Oncology (VHIO) and Universitat Autònoma de Barcelona, Barcelona 08035, Spain.
    65Department of Community and Family Medicine, Section of Biostatistics &Epidemiology, The Geisel School of Medicine at Dartmouth, Lebanon, New Hampshire 03755, USA.
    66Department of Medicine, Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
    67Department of Genetics, University of Pretoria, Pretoria 0083, South Africa.
    68Gynaecology Research Unit, Hannover Medical School, Hannover D-30625, Germany.
    69Genomics Center, Centre Hospitalier Universitaire de Québec Research Center, Laval University, Québec City, Québec G1V 4G2, Canada.
    70Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala 751 05, Sweden.
    71Department of Oncology, Rigshospitalet, Copenhagen University Hospital, 2100 Copenhagen, Denmark.
    72Department of Public Health and Primary Care, Centre for Cancer Genetic Epidemiology, University of Cambridge, Cambridge CB1 8RN, UK.
    73Institute for Medical Informatics, Statistics and Epidemiology, University of Leipzig, 04107 Leipzig, Germany.
    74Department of Preventive Medicine, Keck School of Medicine, University of Southern California Norris Comprehensive Cancer Center, Los Angeles, California 90033, USA.
    75Genomic Medicine, Manchester Academic Health Sciences Centre, Institute of Human Development, Manchester University, Central Manchester University Hospitals NHS Foundation Trust, Manchester M13 9PL, UK.
    76University Hospital Erlangen, Department of Gynecology and Obstetrics, Friedrich-Alexander-University Erlangen-Nuremberg, Comprehensive Cancer Center Erlangen-EMN, Erlangen 91054, Germany.
    77Molecular Diagnostic Unit, Hereditary Cancer Program, IDIBELL (Bellvitge Biomedical Research Institute),Catalan Institute of Oncology, Barcelona 08908, Spain.
    78Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, Maryland 20892, USA.
    79Institute for Medical Biometrics and Epidemiology, University Medical Center Hamburg-Eppendorf, Hamburg 20246, Germany.
    80Breakthrough Breast Cancer Research Centre, The Institute of Cancer Research, London SW3 6JB, UK.
    81Department of Breast Surgery, Herlev Hospital, Copenhagen University Hospital, 2730 Herlev, Denmark.
    82Masaryk Memorial Cancer Institute and Medical Faculty MU, 625 00 Brno, Czech Republic.
    83Molecular Diagnostics Laboratory, (INRASTES) Institute of Nuclear and Radiological Sciences and Technology, National Centre for Scientific Research 'Demokritos', Aghia Paraskevi Attikis, Athens 153 10, Greece.
    84Program in Cancer Genetics, Departments of Human Genetics and Oncology, McGill University, Montreal, Montreal, Quebec H2W 1S6, Canada.
    85Biostatistics and Informatics Shared Resource, University of Kansas Medical Center, Kansas City, Kansas 66160, USA.
    86Susanne Levy Gertner Oncogenetics Unit, Sheba Medical Center, Tel-Hashomer 52621, Israel.
    87Department of Public Health and Primary Care, Centre for Cancer Genetic Epidemiology, University of Cambridge, Cambridge CB1 8RN, UK.
    88Section of Genetic Oncology, Department of Laboratory Medicine, University and University Hospital of Pisa, Pisa 56126, Italy.
    89UCLA Schools of Medicine and Public Health, Division of Cancer Prevention &Control Research, Jonsson Comprehensive Cancer Center, Los Angeles, California 90024, USA.
    90Cancer Risk and Prevention Clinic, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA.
    91Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, Maryland 20892, USA.
    92Women's Cancer, UCL EGA Institute for Women's Health, London WC1E 6AU, UK.
    93Department of Oncology, Centre for Cancer Genetic Epidemiology, University of Cambridge, Cambridge CB1 8RN, UK.
    94Cancer Epidemiology Centre, Cancer Council Victoria, Melbourne, Victoria 3004, Australia.
    95Cancer Research UK Clinical Trials Unit, The Beatson West of Scotland Cancer Centre, Glasgow G12 0YN, UK.
    96Department of Pathology and Laboratory Medicine, University of Kansas Medical Center, Kansas City, Kansas 66160, USA.
    97Division of Clinical Epidemiology, Royal Victoria Hospital, McGill University, Montreal, Québec H3A 1A1, Canada.
    98Department of Dermatology, Huntsman Cancer Institute, University of Utah School of Medicine, Salt Lake City, Utah 84132, USA.
    99Human Cancer Genetics Program, Spanish National Cancer Research Centre, Madrid E-28029, Spain.
    100Department of Health Sciences Research, Mayo Clinic, Rochester, Minnesota 55902, USA.
    101Cancer Prevention and Control, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, California 90048, USA.
    102Clinical Genetics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Rockville, Maryland 20892, USA.
    103Department of Genetics and Pathology, Pomeranian Medical University, 70-204 Szczecin, Poland.
    104Environmental Epidemiology of Cancer, Center for Research in Epidemiology and Population Health, INSERM, 94805 Villejuif, France.
    105Department of Preventive Medicine, Keck School of Medicine, University of Southern California Norris Comprehensive Cancer Center, Los Angeles, California 90033, USA.
    106Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm SE-171 77, Sweden.
    107Department of Health Sciences Research, Mayo Clinic, Rochester, Minnesota 55902, USA.
    108Molecular Genetics of Breast Cancer, German Cancer Research Center (DKFZ), Heidelberg 69120, Germany.
    109Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital, 2100 Copenhagen, Denmark.
    110Department of Oncology, Department of Public Health and Primary Care, University of Cambridge, Strangeways Research Laboratory, Cambridge CB1 8RN, UK.
    111Department of Surgery, National University Health System, Singapore 119077, Singapore.
    112Breast Cancer Research Unit, Cancer Research Institute, University Malaya Medical Centre, 50603 Kuala Lumpur, Malaysia.
    113QIMR Berghofer Medical Research Institute, Brisbane, Queensland 4029, Australia.
    114Department of Gynecology and Gynecologic Oncology, Kliniken Essen-Mitte, 45136 Essen, Germany.
    115Clinical Cancer Genetics, for the City of Hope Clinical Cancer Genetics Community Research Network, Duarte California 91010, USA.
    116Molecular Unit, Department of Pathology, Herlev Hospital, University of Copenhagen, 2730 Copenhagen, Denmark.
    117Department of Gynecology, Rigshospitalet, University of Copenhagen, 2100 Copenhagen, Denmark.
    118Family Cancer Clinic, Netherlands Cancer Institute, 1006 Amsterdam, The Netherlands.
    119Department of Medical Oncology, Family Cancer Clinic, Erasmus MC Cancer Institute, 3015 Rotterdam, The Netherlands.
    120Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, Victoria 3010, Australia.
    121Center for Medical Genetics, NorthShore University Health System, Evanston, Illinois, 60201, USA.
    122Department of Genetics and Pathology, Pomeranian Medical University, Szczecin 70-115, Poland.
    123N.N. Petrov Institute of Oncology, St Petersburg 197758, Russia.
    124Lombardi Comprehensive Cancer Center, Georgetown University, Washington District of Columbia 20057, USA.
    125Division of Epidemiology and Prevention, Aichi Cancer Center Research Institute, Aichi 464-8681, Japan.
    126Department of Genetics and Pathology, Pomeranian Medical University, Szczecin 70-115, Poland.
    127State Research Institute Centre for Innovative Medicine, LT-01102 Vilnius, Lithuania.
    128Department of Gynecology, Rigshospitalet, University of Copenhagen, 2100 Copenhagen, Denmark.
    129Department of Epidemiology, Cancer Prevention Institute of California, Fremont, California 94538, USA.
    130Breakthrough Breast Cancer Research Centre, The Institute of Cancer Research, London SW3 6JB, UK.
    131Molecular Genetics of Breast Cancer, German Cancer Research Center (DKFZ), Heidelberg 69120, Germany.
    132Cancer Research Institute, Seoul National University, Seoul 08826, Korea.
    133Centre for Epidemiology and Biostatistics, University of Melbourne, Melbourne, Victoria 3010, Australia.
    134Women's Cancer Program at the Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, California 90048, USA.
    135Department of Obstetrics and Gynecology, University of Helsinki and Helsinki University Central Hospital, Helsinki 00029 HUS, Finland.
    136Radboud University Medical Centre, Radboud Institute for Health Sciences, 6500 Nijmegen, The Netherlands.
    137Department of Virus, Lifestyle and Genes, Danish Cancer Society Research Center, DK-2100 Copenhagen, Denmark.
    138Prosserman Centre for Health Research, Lunenfeld-Tanenbaum Research Institute of Mount Sinai Hospital, Toronto, Ontario M5G 1X5, Canada.
    139Molecular Diagnostics Laboratory, (INRASTES) Institute of Nuclear and Radiological Sciences and Technology, National Centre for Scientific Research 'Demokritos', Aghia Paraskevi Attikis, Athens 153 10, Greece.
    140Imaging Center, Department of Clinical Pathology, Kuopio University Hospital, 70210 Kuopio, Finland.
    141Department of Genetics, Institute for Cancer Research, Oslo University Hospital Radiumhospitalet, Oslo N-0310, Norway.
    142Department of Pathology and Laboratory Diagnostics the Maria Sklodowska Curie Memorial Cancer Center and Institute of Oncology, Warsaw 44-101, Poland.
    143The Hong Kong Hereditary Breast Cancer Family Registry, Cancer Genetics Center, Hong Kong Sanatorium and Hospital, Hong Kong, China.
    144Molecular Oncology Laboratory, Hospital Clinico San Carlos, IdISSC (El Instituto de Investigación Sanitaria del Hospital Clínico San Carlos), Madrid 28040, Spain.
    145Susanne Levy Gertner Oncogenetics Unit, Sheba Medical Center, Tel-Hashomer 52621, Israel.
    146Vesalius Research Center, VIB, 3000 Leuven, Belgium.
    147Department of Preventive Medicine, Keck School of Medicine, University of Southern California Norris Comprehensive Cancer Center, Los Angeles, California 90033, USA.
    148Center for Medical Genetics, Ghent University, Ghent 9000, Belgium.
    149Women's Cancer Program at the Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, California 90048, USA.
    150Gynecology Service, Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York 10065, USA.
    151Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm SE-171 77, Sweden.
    152Department of Molecular Medicine and Surgery, Karolinska Institutet, SE-171 77 Stockholm, Sweden.
    153Division of Epidemiology, Department of Medicine, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, Tennessee 37203, USA.
    154Division of Health Sciences, Warwick Medical School, Warwick University, Coventry CV4 7AL, UK.
    155Clinical Genetics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Rockville, Maryland 20892, USA.
    156Department of Gynecologic Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
    157Department of Genetics and Pathology, Pomeranian Medical University, Szczecin 70-115, Poland.
    158Imaging Center, Department of Clinical Pathology, Kuopio University Hospital, 70210 Kuopio, Finland.
    159Unit 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.
    160University of Hawaii Cancer Center, Honolulu, Hawaii 96813, USA.
    161Department of Oncology - Pathology, Karolinska Institutet, SE-171 77 Stockholm, Sweden.
    162Department of Obstetrics and Gynecology, University of Heidelberg, Heidelberg 69120, Germany.
    163Department of Gynaecology, Radboud University Medical Centre, 6500 Nijmegen, The Netherlands.
    164Department of Preventive Medicine, Kyushu University Faculty of Medical Sciences, Fukuoka 812-8582, Japan.
    165INSERM U1052, CNRS UMR5286, Université Lyon, Centre de Recherche en Cancérologie de Lyon, Lyon 69373, France.
    166Department of Public Health and Primary Care, Centre for Cancer Genetic Epidemiology, University of Cambridge, Cambridge CB1 8RN, UK.
    167Anatomical Pathology, The Alfred Hospital, Melbourne, Victoria 3004, Australia.
    168Institute of Cancer Sciences, University of Glasgow, Wolfson Wohl Cancer Research Centre, Beatson Institute for Cancer Research, Glasgow G61 1BD, UK.
    169Division of Gynaecology and Obstetrics, Technische Universität München, 81675 Munich, Germany.
    170Women's Cancer, UCL EGA Institute for Women's Health, London WC1E 6AU, UK.
    171Department of Human Genetics, Radboud University Medical Centre, 6500 Nijmegen, The Netherlands.
    172Cancer Epidemiology Centre, Cancer Council Victoria, Melbourne, Victoria 3004, Australia.
    173Immunology and Molecular Oncology Unit, Instituto Oncologico Veneto IOV, IRCCS, 35128 Padua, Italy.
    174Department of Cancer Prevention and Control, Roswell Park Cancer Institute, Buffalo, New York 14263, USA.
    175Division of Health Sciences, Warwick Medical School, Warwick University, Coventry CV4 7AL, UK.
    176Laboratory Medicine Program, University Health Network, Toronto, Ontario M5G 1L7, Canada.
    177Department of Medicine, Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
    178The University of Texas School of Public Health, Houston, Texas 77030, USA.
    179Department of Population Sciences, Beckman Research Institute of City of Hope, Duarte, California 91010, USA.
    180Department of Obstetrics and Gynecology, University of Helsinki and Helsinki University Central Hospital, Helsinki 00029 HUS, Finland.
    181K.G. Jebsen Center for Breast Cancer Research, Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo N-0310, Norway.
    182Department of Medicine and Genetics, University of California, San Francisco, California 94143, USA.
    183Department of Gynecological Oncology, Roswell Park Cancer Institute, Buffalo, New York 14263, USA.
    184Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York 10065, USA.
    185Department of Molecular Genetics, National Institute of Oncology, 1122 Budapest, Hungary.
    186Center for Clinical Cancer Genetics and Global Health, University of Chicago Medical Center, Chicago, Illinois 60637, USA.
    187Department of Health Sciences Research, Mayo Clinic, Rochester, Minnesota 55902, USA.
    188Department of Health Sciences Research, Mayo Clinic, Rochester, Minnesota 55902, USA.
    189The Ohio State University and the James Cancer Center, Columbus, Ohio 43210, USA.
    190Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York 10017, USA.
    191Breakthrough Breast Cancer Research Centre, The Institute of Cancer Research, London SW3 6JB, UK.
    192Human Genetics Group, Human Cancer Genetics Program, Spanish National Cancer Centre (CNIO), 28019 Madrid, Spain.
    193Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul 03080, Korea.
    194Department of Preventive Medicine, Keck School of Medicine, University of Southern California Norris Comprehensive Cancer Center, Los Angeles, California 90033, USA.
    195Department of Obstetrics and Gynecology, Oregon Health and Science University, Portland, Oregon 97239, USA.
    196IFOM, The FIRC (Italian Foundation for Cancer Research) Institute of Molecular Oncology, 16 20139 Milan, Italy.
    197Department of Obstetrics and Gynecology, Comprehensive Cancer Center, Medical University of Vienna, 1090 Vienna, Austria.
    198Department of Cancer Epidemiology, Moffitt Cancer Center, Tampa, Florida 33606, USA.
    199Channing Division of Network Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA.
    200Laboratory of Cancer Genetics and Tumour Biology, Northern Finland Laboratory Centre NordLab, FI-90014 Oulu, Finland.
    201Unit 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.
    202Department of Clinical Genetics, Karolinska University Hospital, 171 76 Stockholm, Sweden.
    203Molecular Genetics of Breast Cancer, German Cancer Research Center (DKFZ), Heidelberg 69120, Germany.
    204Clalit National Israeli Cancer Control Center and Department of Community Medicine and Epidemiology, Carmel Medical Center and B. Rappaport Faculty of Medicine, Haifa 34362, Israel.
    205Department of Oncology, Centre for Cancer Genetic Epidemiology, University of Cambridge, Cambridge CB1 8RN, UK.
    206Centre 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.
    207Department of Chronic Disease Epidemiology, Yale School of Public Health, New Haven, Connecticut 06510, USA.
    208Division of Gynecologic Oncology, NorthShore University HealthSystem, Evanston, Illinois 60201, USA.
    209Program in Epidemiology, Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington 98109, USA.
    210Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg 69121, Germany.
    211Department of Gynecology and Obstetrics, Haukeland University Hospital, 5021 Bergen, Norway.
    212National Cancer Institute, Bangkok 10400, Thailand.
    213Research Oncology, Guy's Hospital, King's College London, London SE1 9RT, UK.
    214Department of Community and Family Medicine, Duke University Medical Center, Durham, North Carolina 27710, USA.
    215Netherlands Cancer Institute, Antoni van Leeuwenhoek Hospital, 1066 CX Amsterdam, The Netherlands.
    216Division of Molecular Gyneco-Oncology, Department of Gynaecology and Obstetrics, University Hospital of Cologne, 50676 Cologne, Germany.
    217Department of Cancer Epidemiology, Moffitt Cancer Center, Tampa, Florida 33606, USA.
    218Department of Medical Oncology, Family Cancer Clinic, Erasmus MC Cancer Institute, 3015 Rotterdam, The Netherlands.
    219Department of Oncology, Centre for Cancer Genetic Epidemiology, University of Cambridge, Cambridge CB1 8RN, UK.
    220Taiwan Biobank, Institute of Biomedical Sciences, Academia Sinica, Taipei 115, Taiwan.
    221Division of Epidemiology, Department of Medicine, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, Tennessee 37203, USA.
    222Department of Health Research and Policy - Epidemiology, Stanford University School of Medicine, Stanford California 94305, USA.
    223Department of Obstetrics and Gynecology, Comprehensive Cancer Center, Medical University of Vienna, 1090 Vienna, Austria.
    224Unité Mixte de Génétique Constitutionnelle des Cancers Fréquents, Hospices Civils de Lyon - Centre Léon Bérard, Lyon 69008, France.
    225Department of Health Sciences Research, Mayo Clinic, Rochester, Minnesota 55902, USA.
    226Department of Oncology, Centre for Cancer Genetic Epidemiology, University of Cambridge, Cambridge CB1 8RN, UK.
    227Genomics Center, Centre Hospitalier Universitaire de Québec Research Center, Laval University, Québec City, Québec G1V 4G2, Canada.
    228Department of Pathology, University of Melbourne, Parkville, Victoria 3010, Australia.
    229Department of Clinical Genetics, Lund University Hospital, Lund 221 00, Sweden.
    230Institut Curie, Department of Tumour Biology, Paris, France; Institut Curie, INSERM U830, 75248 Paris, France.
    231Institute of Human Genetics, Department of Human Genetics, University Hospital Heidelberg, 69120 Heidelberg, Germany.
    232Division of Breast Cancer Research, The Institute of Cancer Research, London SW7 3RP, UK.
    233Lunenfeld-Tanenbaum Research Institute of Mount Sinai Hospital, Toronto, Ontario M5G 1X5, Canada.
    234Department of Genetics, Portuguese Oncology Institute, Porto 4200-072, Portugal.
    235Breast Cancer Research Unit, Cancer Research Institute, University Malaya Medical Centre, 50603 Kuala Lumpur, Malaysia.
    236Harvard HT Chan School of Public Health, Boston, Massachusetts 02115, USA.
    237Department of Epidemiology, Mailman School of Public Health, Columbia University, New York 10027, USA.
    238Department of Clinical Genetics, Odense University Hospital, 5000 Odense C, Denmark.
    239UO Anatomia Patologica, Ospedale di Circolo-Università dell'Insubria, 21100 Varese, Italy.
    240Latvian Biomedical Research and Study Centre, Riga LV-1067, Latvia.
    241Immunology and Molecular Oncology Unit, Istituto Oncologico Veneto IOV - IRCCS (Istituto Di Ricovero e Cura a Carattere Scientifico), 64 - 35128 Padua, Italy.
    242Department of Molecular Virology, Immunology and Medical Genetics, The Ohio State University, Columbus, Ohio 43210, USA.
    243Wellcome Trust Centre for Human Genetics and Oxford Biomedical Research Centre, University of Oxford, Oxford OX3 7BN, UK.
    244Molecular Genetics of Breast Cancer, German Cancer Research Center (DKFZ), Heidelberg 69120, Germany.
    245Environmental Epidemiology of Cancer, Center for Research in Epidemiology and Population Health, INSERM, 94805 Villejuif, France.
    246Department of Preventive Medicine, Keck School of Medicine, University of Southern California Norris Comprehensive Cancer Center, Los Angeles, California 90033, USA.
    247Department of Medical Oncology, Beth Israel Deaconess Medical Center, Boston, Massachusetts 02215, USA.
    248Channing Division of Network Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA.
    249Department of Health Sciences Research, Mayo Clinic, Rochester, Minnesota 55902, USA.
    250Department of Clinical Genetics, Erasmus University Medical Center, 3015 CE Rotterdam, The Netherlands.
    251Department of Gynecology, Family Cancer Clinic, Erasmus MC Cancer Institute, 3015 CE Rotterdam, The Netherlands.
    252Department of Genetics, University of Pretoria, Pretoria 0083, South Africa.
    253Netherlands Cancer Institute, Antoni van Leeuwenhoek Hospital, 1066 CX Amsterdam, The Netherlands.
    254Division of Gynecological Oncology, Department of Oncology, University Hospitals Leuven, B-3000 Leuven, Belgium.
    255Division of Gynecological Oncology, Department of Oncology, University Hospitals Leuven, B-3000 Leuven, Belgium.
    256Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York 10065, USA.
    257Department of Public Health and Primary Care, Centre for Cancer Genetic Epidemiology, University of Cambridge, Cambridge CB1 8RN, UK.
    258Clinical Cancer Genetics, for the City of Hope Clinical Cancer Genetics Community Research Network, Duarte California 91010, USA.
    259Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda Maryland 20892, USA.
    260Department of Health Research and Policy - Epidemiology, Stanford University School of Medicine, Stanford California 94305, USA.
    261Multidisciplinary Breast Center, Department of General Medical Oncology, University Hospitals Leuven, B-3000 Leuven, Belgium.
    262Laboratory of Cancer Genetics and Tumour Biology, Northern Finland Laboratory Centre NordLab, FI-90014 Oulu, Finland.
    263Department of Preventive Medicine, Keck School of Medicine, University of Southern California Norris Comprehensive Cancer Center, Los Angeles, California 90033, USA.
    264Molecular Diagnostics Laboratory, IRRP, National Centre for Scientific Research 'Demokritos', Athens 153 10, Greece.
    265Cancer Research Initiatives Foundation, Sime Darby Medical Centre, 47500 Subang Jaya, Malaysia.
    266Department of Surgery, Tri-Service General Hospital, National Defense Medical Center, Taipei, 114 Taiwan.
    267Division of Epidemiology, Department of Medicine, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, Tennessee 37203, USA.
    268Shanghai Center for Disease Control and Prevention, Shanghai, China.
    269QIMR Berghofer Medical Research Institute, Brisbane, Queensland 4029, Australia.
    270Genomics Center, Centre Hospitalier Universitaire de Québec Research Center, Laval University, Québec City, Québec G1V 4G2, Canada.
    271Cancer Epidemiology Program, Division of Population Sciences, H. Lee Moffitt Cancer Center &Research Institute, Tampa, Florida 33612, USA.
    272QIMR Berghofer Medical Research Institute, Brisbane, Queensland 4029, Australia.
    273Department of Health Sciences Research, Mayo Clinic, Rochester, Minnesota 55902, USA.
    274Department of Medical Oncology, The Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA.
    275Department of Oncology, Centre for Cancer Genetic Epidemiology, University of Cambridge, Cambridge CB1 8RN, UK.
    276Department of Oncology, Centre for Cancer Genetic Epidemiology, University of Cambridge, Cambridge CB1 8RN, UK.
    277Department of Oncology, Centre for Cancer Genetic Epidemiology, University of Cambridge, Cambridge CB1 8RN, UK.
    278QIMR Berghofer Medical Research Institute, Brisbane, Queensland 4029, Australia.
    279QIMR Berghofer Medical Research Institute, Brisbane, Queensland 4029, Australia.
    280Department of Public Health and Primary Care, Centre for Cancer Genetic Epidemiology, University of Cambridge, Cambridge CB1 8RN, UK.
    281Department of Preventive Medicine, Keck School of Medicine, University of Southern California Norris Comprehensive Cancer Center, Los Angeles, California 90033, USA.
    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.


    Publikations ID: 27601076
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