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    Breast cancer research : BCR. 2016 Jun 21. doi: 10.1186/s13058-016-0718-0. pii: 10.1186/s13058-016-0718-0
    Identification of independent association signals and putative functional variants for breast cancer risk through fine-scale mapping of the 12p11 locus.
    Zeng C1,  Guo X2,  Long J3,  Kuchenbaecker KB4,  Droit A5,  Michailidou K6,  Ghoussaini M7,  Kar S8,  Freeman A9,  Hopper JL10,  Milne RL11,  Bolla MK12,  Wang Q13,  Dennis J14,  Agata S15,  Ahmed S16,  Aittomäki K17,  Andrulis IL18,  Anton-Culver H19,  Antonenkova NN20,  Arason A21,  Arndt V22,  Arun BK23,  Arver B24,  Bacot F25,  Barrowdale D26,  Baynes C27,  Beeghly-Fadiel A28,  Benitez J29,  Bermisheva M30,  Blomqvist C31,  Blot WJ32,  Bogdanova NV33,  Bojesen SE34,  Bonanni B35,  Borresen-Dale AL36,  Brand JS37,  Brauch H38,  Brennan P39,  Brenner H40,  Broeks A41,  Brüning T42,  Burwinkel B43,  Buys SS44,  Cai Q45,  Caldes T46,  Campbell I47,  Carpenter J48,  Chang-Claude J49,  Choi JY50,  Claes KB51,  Clarke C52,  Cox A53,  Cross SS54,  Czene K55,  Daly MB56,  de la Hoya M57,  De Leeneer K58,  Devilee P59,  Diez O60,  Domchek SM61,  Doody M62,  Dorfling CM63,  Dörk T64,  Dos-Santos-Silva I65,  Dumont M66,  Dwek M67,  Dworniczak B68,  Egan K69,  Eilber U70,  Einbeigi Z71,  Ejlertsen B72,  Ellis S73,  Frost D74,  Lalloo F75,  Fasching PA76,  Figueroa J77,  Flyger H78,  Friedlander M79,  Friedman E80,  Gambino G81,  Gao YT82,  Garber J83,  García-Closas M84,  Gehrig A85,  Damiola F86,  Lesueur F87,  Mazoyer S88,  Stoppa-Lyonnet D89,  Giles GG90,  Godwin AK91,  Goldgar DE92,  González-Neira A93,  Greene MH94,  Guénel P95,  Haeberle L96,  Haiman CA97,  Hallberg E98,  Hamann U99,  Hansen TV100,  Hart S101,  Hartikainen JM102,  Hartman M103,  Hassan N104,  Healey S105,  Hogervorst FB106,  Verhoef S107,  Hendricks CB108,  Hillemanns P109,  Hollestelle A110,  Hulick PJ111,  Hunter DJ112,  Imyanitov EN113,  Isaacs C114,  Ito H115,  Jakubowska A116,  Janavicius R117,  Jaworska-Bieniek K118,  Jensen UB119,  John EM120,  Joly Beauparlant C121,  Jones M122,  Kabisch M123,  Kang D124,  Karlan BY125,  Kauppila S126,  Kerin MJ127,  Khan S128,  Khusnutdinova E129,  Knight JA130,  Konstantopoulou I131,  Kraft P132,  Kwong A133,  Laitman Y134,  Lambrechts D135,  Lazaro C136,  Le Marchand L137,  Lee CN138,  Lee MH139,  Lester J140,  Li J141,  Liljegren A142,  Lindblom A143,  Lophatananon A144,  Lubinski J145,  Mai PL146,  Mannermaa A147,  Manoukian S148,  Margolin S149,  Marme F150,  Matsuo K151,  McGuffog L152,  Meindl A153,  Menegaux F154,  Montagna M155,  Muir K156,  Mulligan AM157,  Nathanson KL158,  Neuhausen SL159,  Nevanlinna H160,  Newcomb PA161,  Nord S162,  Nussbaum RL163,  Offit K164,  Olah E165,  Olopade OI166,  Olswold C167,  Osorio A168,  Papi L169,  Park-Simon TW170,  Paulsson-Karlsson Y171,  Peeters S172,  Peissel B173,  Peterlongo P174,  Peto J175,  Pfeiler G176,  Phelan CM177,  Presneau N178,  Radice P179,  Rahman N180,  Ramus SJ181,  Rashid MU182,  Rennert G183,  Rhiem K184,  Rudolph A185,  Salani R186,  Sangrajrang S187,  Sawyer EJ188,  Schmidt MK189,  Schmutzler RK190,  Schoemaker MJ191,  Schürmann P192,  Seynaeve C193,  Shen CY194,  Shrubsole MJ195,  Shu XO196,  Sigurdson A197,  Singer CF198,  Slager S199,  Soucy P200,  Southey M201,  Steinemann D202,  Swerdlow A203,  Szabo CI204,  Tchatchou S205,  Teixeira MR206,  Teo SH207,  Terry MB208,  Tessier DC209,  Teulé A210,  Thomassen M211,  Tihomirova L212,  Tischkowitz M213,  Toland AE214,  Tung N215,  Turnbull C216,  van den Ouweland AM217,  van Rensburg EJ218,  Ven den Berg D219,  Vijai J220,  Wang-Gohrke S221,  Weitzel JN222,  Whittemore AS223,  Winqvist R224,  Wong TY225,  Wu AH226,  Yannoukakos D227,  Yu JC228,  Pharoah PD229,  Hall P230,  Chenevix-Trench G231,  Dunning AM232,  Simard J233,  Couch FJ234,  Antoniou AC235,  Easton DF236,  Zheng W237
    Author information
    1Division of Epidemiology, Department of Medicine, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, 2525 West End Avenue, 8th Floor, Nashville, TN, 37203-1738, USA.
    2Division of Epidemiology, Department of Medicine, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, 2525 West End Avenue, 8th Floor, Nashville, TN, 37203-1738, USA.
    3Division of Epidemiology, Department of Medicine, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, 2525 West End Avenue, 8th Floor, Nashville, TN, 37203-1738, USA.
    4Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.
    5Proteomics Center, CHU de Québec Research Center and Department of Molecular Medicine, Laval University, Quebec, Canada.
    6Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.
    7Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Cambridge, CB1 8RN, UK.
    8Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Cambridge, CB1 8RN, UK.
    9Department of Surgery, St Vincent's Hospital, Melbourne, VIC, Australia.
    10Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global health, The University of Melbourne, Melbourne, Australia.
    11Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global health, The University of Melbourne, Melbourne, Australia.
    12Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.
    13Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.
    14Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.
    15Immunology and Molecular Oncology Unit, Istituto Oncologico Veneto IOV - IRCCS (Istituto Di Ricovero e Cura a Carattere Scientifico), Padua, Italy.
    16Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Cambridge, UK.
    17Department of Clinical Genetics, Helsinki University Hospital, University of Helsinki, Helsinki, Finland.
    18Lunenfeld-Tanenbaum Research Institute of Mount Sinai Hospital, Toronto, Canada.
    19Department of Epidemiology, University of California Irvine, Irvine, CA, USA.
    20N.N. Alexandrov Research Institute of Oncology and Medical Radiology, Minsk, Belarus.
    21Department of Pathology, Landspitali University Hospital and BMC (Biomedical Centre), Faculty of Medicine, University of Iceland, Reykjavik, Iceland.
    22Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany.
    23University of Texas MD Anderson Cancer Center, Houston, TX, USA.
    24Department of Oncology, Karolinska University Hospital, Stockholm, Sweden.
    25McGill University and Génome Québec Innovation Centre, Montréal, Canada.
    26Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.
    27Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Cambridge, UK.
    28Division of Epidemiology, Department of Medicine, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, 2525 West End Avenue, 8th Floor, Nashville, TN, 37203-1738, USA.
    29Human Cancer Genetics Program, Spanish National Cancer Research Centre, Madrid, Spain.
    30Institute of Biochemistry and Genetics, Ufa Scientific Center of Russian Academy of Sciences, Ufa, Russia.
    31Department of Oncology, Helsinki University Hospital, University of Helsinki, Helsinki, Finland.
    32Division of Epidemiology, Department of Medicine, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, 2525 West End Avenue, 8th Floor, Nashville, TN, 37203-1738, USA.
    33Department of Radiation Oncology, Hannover Medical School, Hannover, Germany.
    34Copenhagen General Population Study, Herlev Hospital, Copenhagen University Hospital, Herlev, Denmark.
    35Division of Cancer Prevention and Genetics, Istituto Europeo di Oncologia, Milan, Italy.
    36Department of Genetics, Institute for Cancer Research, Oslo University Hospital Radiumhospitalet, Oslo, Norway.
    37Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    38Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology, Stuttgart, Germany.
    39International Agency for Research on Cancer, Lyon, France.
    40Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany.
    41Netherlands Cancer Institute, Antoni van Leeuwenhoek Hospital, Amsterdam, The Netherlands.
    42Institute for Prevention and Occupational Medicine of the German Social Accident Insurance, Institute of the Ruhr University Bochum, Bochum, Germany.
    43Department of Obstetrics and Gynecology, University of Heidelberg, Heidelberg, Germany.
    44Department of Medicine, Huntsman Cancer Institute, University of Utah School of Medicine, Salt Lake City, UT, USA.
    45Division of Epidemiology, Department of Medicine, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, 2525 West End Avenue, 8th Floor, Nashville, TN, 37203-1738, USA.
    46Molecular Oncology Laboratory, Hospital Clinico San Carlos, IdISSC (El Instituto de Investigación Sanitaria del Hospital Clínico San Carlos), Madrid, Spain.
    47Cancer Genetics Laboratory, Peter MacCallum Cancer Centre, Melbourne, Australia.
    48Australian Breast Cancer Tissue Bank, Westmead Millennium Institute, University of Sydney, Sydney, Australia.
    49Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
    50Department of Preventive Medicine, Seoul National University College of Medicine, Seoul, South Korea.
    51Center for Medical Genetics, Ghent University, Ghent, Belgium.
    52Westmead Millenium Institute for Medical Research, University of Sydney, Sydney, Australia.
    53Sheffield Cancer Research, Department of Oncology, University of Sheffield, Sheffield, UK.
    54Academic Unit of Pathology, Department of Neuroscience, University of Sheffield, Sheffield, UK.
    55Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    56Department of Clinical Genetics, Fox Chase Cancer Center, Philadelphia, PA, USA.
    57Molecular Oncology Laboratory, Hospital Clinico San Carlos, IdISSC (El Instituto de Investigación Sanitaria del Hospital Clínico San Carlos), Madrid, Spain.
    58Center for Medical Genetics, Ghent University, Ghent, Belgium.
    59Department of Pathology, Leiden University Medical Center, Leiden, The Netherlands.
    60Oncogenetics Group, University Hospital Vall d'Hebron, Vall d'Hebron Institute of Oncology (VHIO) and Universitat Autònoma de Barcelona, Barcelona, Spain.
    61Department of Medicine, Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
    62Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD, USA.
    63Department of Genetics, University of Pretoria, Pretoria, South Africa.
    64Clinics of Obstetrics and Gynaecology, Hannover Medical School, Hannover, Germany.
    65Department of Non-Communicable Disease Epidemiology, London School of Hygiene and Tropical Medicine, London, UK.
    66Genomics Center, Centre Hospitalier Universitaire de Québec Research Center, Laval University, Québec City, Canada.
    67Department of Biomedical Sciences, Faculty of Science and Technology, University of Westminster, London, UK.
    68Institute of Human Genetics, Muenster, Germany.
    69Division of Population Sciences, Moffitt Cancer Center & Research Institute, Tampa, FL, USA.
    70Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
    71Department of Oncology, Sahlgrenska University Hospital, Gothenburg, Sweden.
    72Department of Oncology, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark.
    73Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.
    74Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.
    75Genetic Medicine, Manchester Academic Health Sciences Centre, Central Manchester University Hospitals NHS Foundation Trust, Manchester, UK.
    76Department of Gynaecology and Obstetrics, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nuremberg, Comprehensive Cancer Center Erlangen-EMN, Erlangen, Germany.
    77Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD, USA.
    78Department of Breast Surgery, Herlev Hospital, Copenhagen University Hospital, Herlev, Denmark.
    79ANZ GOTG Coordinating Centre, Australia New Zealand GOG, Camperdown, NSW, Australia.
    80Susanne Levy Gertner Oncogenetics Unit, Sheba Medical Center, Tel-Hashomer, Israel.
    81Section of Genetic Oncology, Deparment of Laboratory Medicine, University and University Hospital of Pisa, Pisa, Italy.
    82Department of Epidemiology, Shanghai Cancer Institute, Shanghai, China.
    83Cancer Risk and Prevention Clinic, Dana-Farber Cancer Institute, Boston, MA, USA.
    84Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD, USA.
    85Institute of Human Genetics, University Würzburg, Wurzburg, Germany.
    86INSERM U1052, CNRS UMR5286, Université Lyon, Centre de Recherche en Cancérologie de Lyon, Lyon, France.
    87Genetic Epidemiology of Cancer team, Inserm, U900, Institut Curie, Mines ParisTech, 75248, Paris, France.
    88INSERM U1052, CNRS UMR5286, Université Lyon, Centre de Recherche en Cancérologie de Lyon, Lyon, France.
    89Department of Tumour Biology, Institut Curie, Paris, France.
    90Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global health, The University of Melbourne, Melbourne, Australia.
    91Department of Pathology and Laboratory Medicine, University of Kansas Medical Center, Kansas City, KS, USA.
    92Department of Dermatology, Huntsman Cancer Institute, University of Utah School of Medicine, Salt Lake City, UT, USA.
    93Human Cancer Genetics Program, Spanish National Cancer Research Centre, Madrid, Spain.
    94Clinical Genetics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Rockville, MD, USA.
    95Environmental Epidemiology of Cancer, Center for Research in Epidemiology and Population Health, INSERM, Villejuif, France.
    96Department of Gynaecology and Obstetrics, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nuremberg, Comprehensive Cancer Center Erlangen-EMN, Erlangen, Germany.
    97Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
    98Department of Health Sciences Research, Mayo Clinic, Rochester, MN, USA.
    99Molecular Genetics of Breast Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany.
    100Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark.
    101Department of Health Sciences Research, Mayo Clinic, Rochester, MN, USA.
    102Cancer Center, Kuopio University Hospital, Kuopio, Finland.
    103Saw Swee Hock School of Public Health, National University of Singapore, Singapore, Singapore.
    104Cancer Research Initiatives Foundation, Subang Jaya, Selangor, Malaysia.
    105Cancer Division, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia.
    106Family Cancer Clinic, Netherlands Cancer Institute, Amsterdam, The Netherlands.
    107Family Cancer Clinic, Netherlands Cancer Institute, Amsterdam, The Netherlands.
    108Suburban Hospital, Bethesda, MD, USA.
    109Clinics of Obstetrics and Gynaecology, Hannover Medical School, Hannover, Germany.
    110Department of Medical Oncology, Family Cancer Clinic, Erasmus MC Cancer Institute, Rotterdam, The Netherlands.
    111Center for Medical Genetics, NorthShore University HealthSystem, Evanston, IL, USA.
    112Program in Genetic Epidemiology and Statistical Genetics, Harvard School of Public Health, Boston, MA, USA.
    113N.N. Petrov Institute of Oncology, St. Petersburg, Russia.
    114Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC, USA.
    115Division of Epidemiology and Prevention, Aichi Cancer Center Research Institute, Aichi, Japan.
    116Department of Genetics and Pathology, Pomeranian Medical University, Szczecin, Poland.
    117State Research Institute Centre for Innovative Medicine, Vilnius, Lithuania.
    118Department of Genetics and Pathology, Pomeranian Medical University, Szczecin, Poland.
    119Department of Clinical Genetics, Aarhus University Hospital, Aarhus, N, Denmark.
    120Department of Epidemiology, Cancer Prevention Institute of California, Fremont, CA, USA.
    121Genomics Center, Centre Hospitalier Universitaire de Québec Research Center and Laval University, Quebec City, QC, Canada.
    122Division of Genetics and Epidemiology, The Institute of Cancer Research, London, UK.
    123Molecular Genetics of Breast Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany.
    124Department of Preventive Medicine, Seoul National University College of Medicine, Seoul, South Korea.
    125Women's Cancer Program at the Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
    126Department of Pathology, Oulu University Hospital, University of Oulu, Oulu, Finland.
    127School of Medicine, National University of Ireland, Galway, Ireland.
    128Department of Obstetrics and Gynecology, Helsinki University Hospital, University of Helsinki, Helsinki, Finland.
    129Institute of Biochemistry and Genetics, Ufa Scientific Center of Russian Academy of Sciences, Ufa, Russia.
    130Prosserman Centre for Health Research, Lunenfeld-Tanenbaum Research Institute of Mount Sinai Hospital, Toronto, Canada.
    131Molecular Diagnostics Laboratory, IRRP, National Centre for Scientific Research "Demokritos", Athens, Greece.
    132Program in Genetic Epidemiology and Statistical Genetics, Harvard School of Public Health, Boston, MA, USA.
    133The Hong Kong Hereditary Breast Cancer Family Registry, Cancer Genetics Center, Hong Kong Sanatorium and Hospital, Hong Kong, China.
    134Susanne Levy Gertner Oncogenetics Unit, Sheba Medical Center, Tel-Hashomer, Israel.
    135Vesalius Research Center, Leuven, Belgium.
    136Molecular Diagnostic Unit, Hereditary Cancer Program, IDIBELL (Bellvitge Biomedical Research Institute), Catalan Institute of Oncology, Barcelona, Spain.
    137University of Hawaii Cancer Center, Honolulu, HI, USA.
    138Saw Swee Hock School of Public Health, National University of Singapore, Singapore, Singapore.
    139Department of Surgery, Soonchunhyang University and Hospital, Seoul, South Korea.
    140Women's Cancer Program at the Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
    141Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    142Department of Oncology, Karolinska University Hospital, Stockholm, Sweden.
    143Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.
    144Division of Health Sciences, Warwick Medical School, Warwick University, Coventry, UK.
    145Department of Genetics and Pathology, Pomeranian Medical University, Szczecin, Poland.
    146Clinical Genetics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Rockville, MD, USA.
    147Cancer Center, Kuopio University Hospital, Kuopio, Finland.
    148Unit of Medical Genetics, Department of Preventive and Predictive Medicine, Fondazione IRCCS (Istituto di Ricovero e Cura a Carattere Scientifico) Istituto Nazionale Tumori (INT), Milan, Italy.
    149Department of Oncology - Pathology, Karolinska Institutet, Stockholm, Sweden.
    150Department of Obstetrics and Gynecology, University of Heidelberg, Heidelberg, Germany.
    151Department of Preventive Medicine, Kyushu University Faculty of Medical Sciences, Fukuoka, Japan.
    152Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.
    153Division of Gynaecology and Obstetrics, Technische Universität München, Munich, Germany.
    154Environmental Epidemiology of Cancer, Center for Research in Epidemiology and Population Health, INSERM, Villejuif, France.
    155Immunology and Molecular Oncology Unit, Istituto Oncologico Veneto IOV - IRCCS (Istituto Di Ricovero e Cura a Carattere Scientifico), Padua, Italy.
    156Division of Health Sciences, Warwick Medical School, Warwick University, Coventry, UK.
    157Laboratory Medicine Program, University Health Network, Toronto, ON, Canada.
    158Department of Medicine, Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
    159Beckman Research Institute of City of Hope, Duarte, CA, USA.
    160Department of Obstetrics and Gynecology, Helsinki University Hospital, University of Helsinki, Helsinki, Finland.
    161Carbone Cancer Center, University of Wisconsin, Madison, WI, USA.
    162Department of Genetics, Institute for Cancer Research, Oslo University Hospital Radiumhospitalet, Oslo, Norway.
    163Department of Medicine and Genetics, University of California, San Francisco, San Francisco, CA, USA.
    164Clinical Genetics Research Lab, Department of Cancer Biology and Genetics, Memorial Sloan-Kettering Cancer Center, New York, NY, USA.
    165Department of Molecular Genetics, National Institute of Oncology, Budapest, Hungary.
    166Center for Clinical Cancer Genetics and Global Health, University of Chicago Medical Center, Chicago, IL, USA.
    167Department of Health Sciences Research, Mayo Clinic, Rochester, MN, USA.
    168Human Genetics Group, Human Cancer Genetics Program, Spanish National Cancer Centre (CNIO), Madrid, Spain.
    169Unit of Medical Genetics, Department of Biomedical, Experimental and Clinical Sciences, University of Florence, Florence, Italy.
    170Clinics of Obstetrics and Gynaecology, Hannover Medical School, Hannover, Germany.
    171Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden.
    172University Hospital Gashuisberg, Leuven, Belgium.
    173Unit of Medical Genetics, Department of Preventive and Predictive Medicine, Fondazione IRCCS (Istituto Di Ricovero e Cura a Carattere Scientifico) Istituto Nazionale Tumori (INT), Milan, Italy.
    174IFOM, Fondazione Istituto FIRC (Italian Foundation of Cancer Research) di Oncologia Molecolare, Milan, Italy.
    175Department of Non-Communicable Disease Epidemiology, London School of Hygiene and Tropical Medicine, London, UK.
    176Department of Obstetrics and Gynecology, and Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria.
    177Department of Cancer Epidemiology, Moffitt Cancer Center, Tampa, FL, USA.
    178Department of Biomedical Sciences, Faculty of Science and Technology, University of Westminster, London, UK.
    179Unit 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 Tumori (INT), Milan, Italy.
    180Section of Cancer Genetics, The Institute of Cancer Research, London, UK.
    181Department of Preventive Medicine, Keck School of Medicine, University of Southern California Norris Comprehensive Cancer Center, Los Angeles, CA, USA.
    182Molecular Genetics of Breast Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany.
    183Clalit National Israeli Cancer Control Center and Department of Community Medicine and Epidemiology, Carmel Medical Center and B. Rappaport Faculty of Medicine, Haifa, Israel.
    184Centre 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, Cologne, Germany.
    185Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
    186Obstetrics and Gynecology, Ohio State University College of Medicine, Columbus, OH, USA.
    187National Cancer Institute, Bangkok, Thailand.
    188Research Oncology, Guy's Hospital, King's College London, London, UK.
    189Netherlands Cancer Institute, Antoni van Leeuwenhoek Hospital, Amsterdam, The Netherlands.
    190Division of Molecular Gyneco-Oncology, Department of Gynaecology and Obstetrics, University Hospital of Cologne, Cologne, Germany.
    191Division of Genetics and Epidemiology, The Institute of Cancer Research, London, UK.
    192Clinics of Obstetrics and Gynaecology, Hannover Medical School, Hannover, Germany.
    193Department of Medical Oncology, Family Cancer Clinic, Erasmus MC Cancer Institute, Rotterdam, The Netherlands.
    194School of Public Health, China Medical University, Taichung, Taiwan.
    195Division of Epidemiology, Department of Medicine, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, 2525 West End Avenue, 8th Floor, Nashville, TN, 37203-1738, USA.
    196Division of Epidemiology, Department of Medicine, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, 2525 West End Avenue, 8th Floor, Nashville, TN, 37203-1738, USA.
    197Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD, USA.
    198Department of Obstetrics and Gynecology, Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria.
    199Department of Health Sciences Research, Mayo Clinic, Rochester, MN, USA.
    200Centre Hospitalier Universitaire de Québec Research Center and Laval University, Quebec City, QC, Canada.
    201Genetic Epidemiology Laboratory, Department of Pathology, University of Melbourne, Parkville, VIC, Australia.
    202Hannover Medical School, Hannover, Germany.
    203Division of Genetics and Epidemiology, The Institute of Cancer Research, London, UK.
    204National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA.
    205Lunenfeld-Tanenbaum Research Institute of Mount Sinai Hospital, Toronto, ON, Canada.
    206Department of Genetics, Portuguese Oncology Institute, Porto, Portugal.
    207Cancer Research Initiatives Foundation, Subang Jaya, Selangor, Malaysia.
    208Department of Epidemiology, Mailman School of Public Health, Columbia University, New York, NY, USA.
    209McGill University and Génome Québec Innovation Centre, Montréal, Canada.
    210Genetic Counseling Unit, Hereditary Cancer Program, IDIBELL (Bellvitge Biomedical Research Institute), Catalan Institute of Oncology, Barcelona, Spain.
    211Department of Clinical Genetics, Odense University Hospital, Odense, C, Denmark.
    212Latvian Biomedical Research and Study Centre, Riga, Latvia.
    213Program in Cancer Genetics, Departments of Human Genetics and Oncology, McGill University, Montreal, QC, Canada.
    214Department of Molecular Virology, Immunology and Medical Genetics, Comprehensive Cancer Center, The Ohio State University, Columbus, OH, USA.
    215Department of Medical Oncology, Beth Israel Deaconess Medical Center, Boston, MA, USA.
    216Section of Cancer Genetics, The Institute of Cancer Research, London, UK.
    217Department of Clinical Genetics, Erasmus University Medical Center, Rotterdam, The Netherlands.
    218Department of Genetics, University of Pretoria, Pretoria, South Africa.
    219Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
    220Clinical Genetics Research Lab, Department of Cancer Biology and Genetics, Memorial Sloan-Kettering Cancer Center, New York, NY, USA.
    221Department of Obstetrics and Gynecology, University of Ulm, Ulm, Germany.
    222Clinical Cancer Genetics, for the City of Hope Clinical Cancer Genetics Community Research Network, Duarte, CA, USA.
    223Department of Health Research and Policy - Epidemiology, Stanford University School of Medicine, Stanford, CA, USA.
    224Laboratory of Cancer Genetics and Tumor Biology, Department of Clinical Chemistry and Biocenter Oulu, University of Oulu, Oulu, Finland.
    225Singapore Eye Research Institute, National University of Singapore, Singapore, Singapore.
    226Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
    227Department of Medical Oncology, Papageorgiou Hospital, Aristotle University of Thessaloniki School of Medicine, Thessaloniki, Greece.
    228Department of Surgery, National Taiwan University Hospital, Taipei, Taiwan.
    229Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.
    230Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    231Department of Genetics, QIMR Berghofer Medical Research Institute, Brisbane, Australia.
    232Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Cambridge, UK.
    233Genomics Center, Centre Hospitalier Universitaire de Québec Research Center, Laval University, Québec City, Canada.
    234Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA.
    235Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.
    236Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.
    237Division of Epidemiology, Department of Medicine, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, 2525 West End Avenue, 8th Floor, Nashville, TN, 37203-1738, USA. wei.zheng@vanderbilt.edu.
    Abstract

    BACKGROUND: Multiple recent genome-wide association studies (GWAS) have identified a single nucleotide polymorphism (SNP), rs10771399, at 12p11 that is associated with breast cancer risk.

    METHOD: We performed a fine-scale mapping study of a 700 kb region including 441 genotyped and more than 1300 imputed genetic variants in 48,155 cases and 43,612 controls of European descent, 6269 cases and 6624 controls of East Asian descent and 1116 cases and 932 controls of African descent in the Breast Cancer Association Consortium (BCAC; http://bcac.ccge.medschl.cam.ac.uk/ ), and in 15,252 BRCA1 mutation carriers in the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA). Stepwise regression analyses were performed to identify independent association signals. Data from the Encyclopedia of DNA Elements project (ENCODE) and the Cancer Genome Atlas (TCGA) were used for functional annotation.

    RESULTS: Analysis of data from European descendants found evidence for four independent association signals at 12p11, represented by rs7297051 (odds ratio (OR) = 1.09, 95 % confidence interval (CI) = 1.06-1.12; P = 3 × 10(-9)), rs805510 (OR = 1.08, 95 % CI = 1.04-1.12, P = 2 × 10(-5)), and rs1871152 (OR = 1.04, 95 % CI = 1.02-1.06; P = 2 × 10(-4)) identified in the general populations, and rs113824616 (P = 7 × 10(-5)) identified in the meta-analysis of BCAC ER-negative cases and BRCA1 mutation carriers. SNPs rs7297051, rs805510 and rs113824616 were also associated with breast cancer risk at P < 0.05 in East Asians, but none of the associations were statistically significant in African descendants. Multiple candidate functional variants are located in putative enhancer sequences. Chromatin interaction data suggested that PTHLH was the likely target gene of these enhancers. Of the six variants with the strongest evidence of potential functionality, rs11049453 was statistically significantly associated with the expression of PTHLH and its nearby gene CCDC91 at P < 0.05.

    CONCLUSION: This study identified four independent association signals at 12p11 and revealed potentially functional variants, providing additional insights into the underlying biological mechanism(s) for the association observed between variants at 12p11 and breast cancer risk.


    KEYWORDS: BRAC1 mutation carriers, Breast cancer, CCDC91, Fine-scale mapping, Genetic risk factor, PTHLH

    Publikations ID: 27459855
    Quelle: öffnen
     
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