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    Breast cancer research and treatment. doi: 10.1007/s10549-016-4018-2. pii: 10.1007/s10549-016-4018-2
    Association of breast cancer risk in BRCA1 and BRCA2 mutation carriers with genetic variants showing differential allelic expression: identification of a modifier of breast cancer risk at locus 11q22.3.
    Hamdi Y1,  Soucy P2,  Kuchenbaeker KB3,  Pastinen T4,  Droit A5,  Lemaçon A6,  Adlard J7,  Aittomäki K8,  Andrulis IL9,  Arason A10,  Arnold N11,  Arun BK12,  Azzollini J13,  Bane A14,  Barjhoux L15,  Barrowdale D16,  Benitez J17,  Berthet P18,  Blok MJ19,  Bobolis K20,  Bonadona V21,  Bonanni B22,  Bradbury AR23,  Brewer C24,  Buecher B25,  Buys SS26,  Caligo MA27,  Chiquette J28,  Chung WK29,  Claes KB30,  Daly MB31,  Damiola F32,  Davidson R33,  De la Hoya M34,  De Leeneer K35,  Diez O36,  Ding YC37,  Dolcetti R38,  Domchek SM39,  Dorfling CM40,  Eccles D41,  Eeles R42,  Einbeigi Z43,  Ejlertsen B44,  Engel C45,  Gareth Evans D46,  Feliubadalo L47,  Foretova L48,  Fostira F49,  Foulkes WD50,  Fountzilas G51,  Friedman E52,  Frost D53,  Ganschow P54,  Ganz PA55,  Garber J56,  Gayther SA57,  Gerdes AM58,  Glendon G59,  Godwin AK60,  Goldgar DE61,  Greene MH62,  Gronwald J63,  Hahnen E64,  Hamann U65,  Hansen TV66,  Hart S67,  Hays JL68,  Hogervorst FB69,  Hulick PJ70,  Imyanitov EN71,  Isaacs C72,  Izatt L73,  Jakubowska A74,  James P75,  Janavicius R76,  Jensen UB77,  John EM78,  Joseph V79,  Just W80,  Kaczmarek K81,  Karlan BY82,  Kets CM83,  Kirk J84,  Kriege M85,  Laitman Y86,  Laurent M87,  Lazaro C88,  Leslie G89,  Lester J90,  Lesueur F91,  Liljegren A92,  Loman N93,  Loud JT94,  Manoukian S95,  Mariani M96,  Mazoyer S97,  McGuffog L98,  Meijers-Heijboer HE99,  Meindl A100,  Miller A101,  Montagna M102,  Mulligan AM103,  Nathanson KL104,  Neuhausen SL105,  Nevanlinna H106,  Nussbaum RL107,  Olah E108,  Olopade OI109,  Ong KR110,  Oosterwijk JC111,  Osorio A112,  Papi L113,  Park SK114,  Pedersen IS115,  Peissel B116,  Segura PP117,  Peterlongo P118,  Phelan CM119,  Radice P120,  Rantala J121,  Rappaport-Fuerhauser C122,  Rennert G123,  Richardson A124,  Robson M125,  Rodriguez GC126,  Rookus MA127,  Schmutzler RK128,  Sevenet N129,  Shah PD130,  Singer CF131,  Slavin TP132,  Snape K133,  Sokolowska J134,  Sønderstrup IM135,  Southey M136,  Spurdle AB137,  Stadler Z138,  Stoppa-Lyonnet D139,  Sukiennicki G140,  Sutter C141,  Tan Y142,  Tea MK143,  Teixeira MR144,  Teulé A145,  Teo SH146,  Terry MB147,  Thomassen M148,  Tihomirova L149,  Tischkowitz M150,  Tognazzo S151,  Toland AE152,  Tung N153,  van den Ouweland AM154,  van der Luijt RB155,  van Engelen K156,  van Rensburg EJ157,  Varon-Mateeva R158,  Wappenschmidt B159,  Wijnen JT160,  Rebbeck T161,  Chenevix-Trench G162,  Offit K163,  Couch FJ164,  Nord S165,  Easton DF166,  Antoniou AC167,  Simard J168
    Author information
    1Genomics Center, Centre Hospitalier Universitaire de Québec Research Center and Laval University, 2705 Laurier Boulevard, Quebec, QC, G1V 4G2, Canada.
    2Genomics Center, Centre Hospitalier Universitaire de Québec Research Center and Laval University, 2705 Laurier Boulevard, Quebec, QC, G1V 4G2, Canada.
    3Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Strangeways Research Laboratory, Worts Causeway, Cambridge, UK.
    4Department of Human Genetics, McGill University, Montreal, QC, H3A 1B1, Canada.
    5Genomics Center, Centre Hospitalier Universitaire de Québec Research Center and Laval University, 2705 Laurier Boulevard, Quebec, QC, G1V 4G2, Canada.
    6Genomics Center, Centre Hospitalier Universitaire de Québec Research Center and Laval University, 2705 Laurier Boulevard, Quebec, QC, G1V 4G2, Canada.
    7Yorkshire Regional Genetics Service, Chapel Allerton Hospital, Leeds, LS7 4SA, UK.
    8Department of Clinical Genetics, Helsinki University Hospital, HUS, Meilahdentie 2, P.O. BOX 160, 00029, Helsinki, Finland.
    9Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, ON, M5G 1X5, Canada.
    10Department of Pathology hus 9, Landspitali-LSH v/Hringbraut, 101, Reykjavík, Iceland.
    11Department of Gynaecology and Obstetrics, University Hospital of Schleswig-Holstein, Christian-Albrechts University Kiel, Campus Kiel, 24105, Kiel, Germany.
    12Department of Breast Medical Oncology and Clinical Cancer Genetics Program, University of Texas MD Anderson Cancer Center, 1515 Pressler Street CBP 5, Houston, TX, 77030, USA.
    13Unit of Medical Genetics, Department of Preventive and Predictive Medicine, Fondazione IRCCS (Istituto Di Ricovero e Cura a Carattere Scientifico) Istituto Nazionale Tumori (INT), Via Giacomo Venezian 1, 20133, Milan, Italy.
    14Department of Pathology & Molecular Medicine, Juravinski Hospital and Cancer Centre, McMaster University, 711 Concession Street, Hamilton, ON, L8V 1C3, Canada.
    15Bâtiment Cheney D, Centre Léon Bérard, 28 rue Laënnec, 69373, Lyon, France.
    16Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Strangeways Research Laboratory, Worts Causeway, Cambridge, UK.
    17Human Genetics Group, Spanish National Cancer Centre (CNIO), Madrid, Spain.
    18Centre François Baclesse, 3 avenue Général Harris, 14076, Caen, France.
    19Department of Clinical Genetics, Maastricht University Medical Center, P.O. Box 5800, 6202 AZ, Maastricht, The Netherlands.
    20City of Hope Clinical Cancer Genomics Community Research Network, 1500 East Duarte Road, Duarte, CA, 91010, USA.
    21Unité de Prévention et d'Epidémiologie Génétique, Centre Léon Bérard, 28 rue Laënnec, 69373, Lyon, France.
    22Division of Cancer Prevention and Genetics, Istituto Europeo di Oncologia (IEO), Via Ripamonti 435, 20141, Milan, Italy.
    23Department of Medicine, Abramson Cancer Center, Perelman School of Medicine at the University of Pennsylvania, 3400 Civic Center Boulevard, Philadelphia, PA, 19104, USA.
    24Department of Clinical Genetics, Royal Devon & Exeter Hospital, Exeter, EX1 2ED, UK.
    25Service de Génétique Oncologique, Institut Curie, 26 rue d'Ulm, 75248, Paris Cedex 05, France.
    26Department of Medicine, Huntsman Cancer Institute, 2000 Circle of Hope, Salt Lake City, UT, 84112, USA.
    27Section of Genetic Oncology, Department of Laboratory Medicine, University and University Hospital of Pisa, Pisa, Italy.
    28Unité de recherche en santé des populations, Centre des maladies du sein Deschênes-Fabia, Hôpital du Saint-Sacrement, 1050 chemin Sainte-Foy, Quebec, QC, G1S 4L8, Canada.
    29Departments of Pediatrics and Medicine, Columbia University, 1150 St. Nicholas Avenue, New York, NY, 10032, USA.
    30Center for Medical Genetics, Ghent University, De Pintelaan 185, 9000, Ghent, Belgium.
    31Division of Population Science, Fox Chase Cancer Center, 333 Cottman Avenue, Philadelphia, PA, 19111, USA.
    32Bâtiment Cheney D, Centre Léon Bérard, 28 rue Laënnec, 69373, Lyon, France.
    33Department of Clinical Genetics, South Glasgow University Hospitals, Glasgow, G51 4TF, UK.
    34Molecular Oncology Laboratory, Hospital Clinico San Carlos, IdISSC (El Instituto de Investigación Sanitaria del Hospital Clínico San Carlos), Martin Lagos s/n, Madrid, Spain.
    35Center for Medical Genetics, Ghent University, De Pintelaan 185, 9000, Ghent, Belgium.
    36Oncogenetics Group, Vall d'Hebron Institute of Oncology (VHIO), Vall d'Hebron University Hospital, Clinical and Molecular Genetics Area, Passeig Vall d'Hebron 119-129, 08035, Barcelona, Spain.
    37Department of Population Sciences, Beckman Research Institute of City of Hope, Duarte, CA, USA.
    38Cancer Bioimmunotherapy Unit, Department of Medical Oncology, Centro di Riferimento Oncologico, IRCCS (Istituto Di Ricovero e Cura a Carattere Scientifico) National Cancer Institute, Via Franco Gallini 2, 33081, Aviano, PN, Italy.
    39Department of Medicine, Abramson Cancer Center, Perelman School of Medicine at the University of Pennsylvania, 3400 Civic Center Boulevard, Philadelphia, PA, 19104, USA.
    40Cancer Genetics Laboratory, Department of Genetics, University of Pretoria, Private Bag X323, Arcadia, 0007, South Africa.
    41Faculty of Medicine, University of Southampton, Southampton University Hospitals NHS Trust, Southampton, UK.
    42Oncogenetics Team, The Institute of Cancer Research and Royal Marsden NHS Foundation Trust, Sutton, SM2 5NG, UK.
    43Department of Oncology, Sahlgrenska University Hospital, 41345, Göteborg, Sweden.
    44Department of Oncology, Rigshospitalet, Copenhagen University Hospital, Blegdamsvej 9, 2100, Copenhagen, Denmark.
    45Institute for Medical Informatics, Statistics and Epidemiology, University of Leipzig, 04107, Leipzig, Germany.
    46Genomic Medicine, Manchester Academic Health Sciences Centre, Institute of Human Development, Manchester University, Central Manchester University Hospitals, NHS Foundation Trust, Manchester, M13 9WL, UK.
    47Molecular Diagnostic Unit, Hereditary Cancer Program, IDIBELL (Bellvitge Biomedical Research Institute), Catalan Institute of Oncology, Gran Via de l'Hospitalet, 199-203, L'Hospitalet, 08908, Barcelona, Spain.
    48Department of Cancer Epidemiology and Genetics, Masaryk Memorial Cancer Institute, Zluty kopec 7, 65653, Brno, Czech Republic.
    49Molecular Diagnostics Laboratory, (INRASTES) Institute of Nuclear and Radiological Sciences and Technology, National Centre for Scientific Research "Demokritos", Patriarchou Gregoriou & Neapoleos str., Aghia Paraskevi Attikis, Athens, Greece.
    50Program in Cancer Genetics, Departments of Human Genetics and Oncology, McGill University, Montreal, QC, Canada.
    51Department of Medical Oncology, Papageorgiou Hospital, Aristotle University of Thessaloniki School of Medicine, Thessaloníki, Greece.
    52The Susanne Levy Gertner Oncogenetics Unit, Institute of Human Genetics, Chaim Sheba Medical Center, 52621, Ramat Gan, Israel.
    53Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Strangeways Research Laboratory, Worts Causeway, Cambridge, UK.
    54Clinical Cancer Genetics, City of Hope, 1500 East Duarte Road, Duarte, CA, 91010, USA.
    55UCLA Schools of Medicine and Public Health, Division of Cancer Prevention & Control Research, Jonsson Comprehensive Cancer Center, 650 Charles Young Drive South, Room A2-125 HS, Los Angeles, CA, 90095-6900, USA.
    56Cancer Risk and Prevention Clinic, Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston, MA, USA.
    57Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, 90033, USA.
    58Department of Clincial Genetics, Rigshospitalet, Blegdamsvej 9, 4062, Copenhagen, Denmark.
    59Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, ON, M5G 1X5, Canada.
    60Department of Pathology and Laboratory Medicine, University of Kansas Medical Center, 3901 Rainbow Boulevard, 4019 Wahl Hall East, MS 3040, Kansas City, Kansas, USA.
    61Department of Dermatology, University of Utah School of Medicine, 30 North 1900 East, SOM 4B454, Salt Lake City, UT, 84132, USA.
    62Clinical Genetics Branch, DCEG, NCI NIH, 9609 Medical Center Drive, Room 6E-454, Bethesda, MD, USA.
    63Department of Genetics and Pathology, Pomeranian Medical University, Polabska 4, 70-115, Szczecin, Poland.
    64Centre 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.
    65Molecular Genetics of Breast Cancer, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 580, 69120, Heidelberg, Germany.
    66Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital, Blegdamsvej 9, 2100, Copenhagen, Denmark.
    67Department of Health Sciences Research, Mayo Clinic, 200 First Street SW, Rochester, MN, 55905, USA.
    68Division of Medical Oncology, Department of Internal Medicine, The Ohio State University, Columbus, OH, 43210, USA.
    69Family Cancer Clinic, Netherlands Cancer Institute, P.O. Box 90203, 1006 BE, Amsterdam, The Netherlands.
    70Center for Medical Genetics, NorthShore University HealthSystem, University of Chicago Pritzker School of Medicine, 1000 Central Street, Suite 620, Evanston, IL, 60201, USA.
    71N.N. Petrov Institute of Oncology, St. Petersburg, Russia, 197758.
    72Lombardi Comprehensive Cancer Center, Georgetown University, 3800 Reservoir Road NW, Washington, DC, 20007, USA.
    73Clinical Genetics, Guy's and St. Thomas' NHS Foundation Trust, London, SE1 9RT, UK.
    74Department of Genetics and Pathology, Pomeranian Medical University, Polabska 4, 70-115, Szczecin, Poland.
    75Familial Cancer Centre, Peter MacCallum Cancer Centre, Melbourne, VIC, 3000, Australia.
    76Hematology, Oncology and Transfusion Medicine Center, Department of Molecular and Regenerative Medicine, Vilnius University Hospital Santariskiu Clinics, Santariskiu st. 2, 08661, Vilnius, Lithuania.
    77Department of Clinical Genetics, Aarhus University Hospital, Brendstrupgaardsvej 21C, Århus N, Denmark.
    78Department of Epidemiology, Cancer Prevention Institute of California, 2201 Walnut Avenue Suite 300, Fremont, CA, 94538, USA.
    79Clinical Genetics Research Laboratory, Department of Medicine, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY, 10044, USA.
    80Institute of Human Genetics, University of Ulm, 89091, Ulm, Germany.
    81Department of Genetics and Pathology, Pomeranian Medical University, Polabska 4, 70-115, Szczecin, Poland.
    82Women's Cancer Program at the Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, 8700 Beverly Boulevard, Suite 290W, Los Angeles, CA, 90048, USA.
    83Department of Human Genetics, Radboud University Medical Center, P.O. Box 9101, 6500 HB, Nijmegen, The Netherlands.
    84Westmead Hospital, Familial Cancer Service, Hawkebury Road, P.O. Box 533, Wentworthville, NSW, 2145, Australia.
    85Department of Medical Oncology, Family Cancer Clinic, Erasmus University Medical Center, P.O. Box 5201, 3008 AE, Rotterdam, The Netherlands.
    86The Susanne Levy Gertner Oncogenetics Unit, Institute of Human Genetics, Chaim Sheba Medical Center, 52621, Ramat Gan, Israel.
    87Service de Génétique Oncologique, Institut Curie, 26 rue d'Ulm, 75248, Paris Cedex 05, France.
    88Molecular Diagnostic Unit, Hereditary Cancer Program, IDIBELL (Bellvitge Biomedical Research Institute), Catalan Institute of Oncology, Gran Via de l'Hospitalet, 199-203, L'Hospitalet, 08908, Barcelona, Spain.
    89Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Strangeways Research Laboratory, Worts Causeway, Cambridge, UK.
    90Women's Cancer Program at the Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, 8700 Beverly Boulevard, Suite 290W, Los Angeles, CA, 90048, USA.
    91Genetic Epidemiology of Cancer Team, INSERM U900, Institut Curie Mines ParisTech, PSL University, 26 rue d'Ulm, 75248, Paris Cedex 05, France.
    92Department of Oncology, Karolinska University Hospital, 17176, Stockholm, Sweden.
    93Department of Oncology, Lund University Hospital, 22185, Lund, Sweden.
    94Clinical Genetics Branch, DCEG, NCI NIH, 9609 Medical Center Drive, Room 6E-454, Bethesda, MD, USA.
    95Unit of Medical Genetics, Department of Preventive and Predictive Medicine, Fondazione IRCCS (Istituto Di Ricovero e Cura a Carattere Scientifico) Istituto Nazionale Tumori (INT), Via Giacomo Venezian 1, 20133, Milan, Italy.
    96Unit of Medical Genetics, Department of Preventive and Predictive Medicine, Fondazione IRCCS (Istituto Di Ricovero e Cura a Carattere Scientifico) Istituto Nazionale Tumori (INT), Via Giacomo Venezian 1, 20133, Milan, Italy.
    97Lyon Neuroscience Research Center-CRNL, INSERM U1028, CNRS UMR5292, University of Lyon, Lyon, France.
    98Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Strangeways Research Laboratory, Worts Causeway, Cambridge, UK.
    99Department of Clinical Genetics, VU University Medical Center, P.O. Box 7057, 1007 MB, Amsterdam, The Netherlands.
    100Department of Gynaecology and Obstetrics, University Hospital of Schleswig-Holstein, Christian-Albrechts University Kiel, Campus Kiel, 24105, Kiel, Germany.
    101NRG Oncology Statistics and Data Management Center, Roswell Park Cancer Institute, Elm St & Carlton St, Buffalo, NY, 14263, USA.
    102Immunology and Molecular Oncology Unit, Veneto Institute of Oncology IOV-IRCCS, Via Gattamelata 64, 35128, Padua, Italy.
    103Departments of Molecular Genetics and Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada.
    104Department of Medicine, Abramson Cancer Center, Perelman School of Medicine at the University of Pennsylvania, 3400 Civic Center Boulevard, Philadelphia, PA, 19104, USA.
    105Department of Population Sciences, Beckman Research Institute of City of Hope, Duarte, CA, USA.
    106Department of Obstetrics and Gynecology, University of Helsinki and Helsinki University Hospital, Biomedicum Helsinki, Haartmaninkatu 8, HUS, P.O. BOX 700, 00029, Helsinki, Finland.
    107Department of Medicine and Genetics, University of California, 513 Parnassus Ave., HSE 901E, San Francisco, CA, 94143-0794, USA.
    108Department of Molecular Genetics, National Institute of Oncology, Budapest, Hungary.
    109Department of Medicine, University of Chicago, 5841 South Maryland Avenue, MC 2115, Chicago, IL, USA.
    110West Midlands Regional Genetics Service, Birmingham Women's Hospital Healthcare NHS Trust, Edgbaston, Birmingham, UK.
    111Department of Genetics, University Medical Center Groningen, University of Groningen, 9700 RB, Groningen, The Netherlands.
    112Human Genetics Group, Spanish National Cancer Centre (CNIO), Madrid, Spain.
    113Unit of Medical Genetics, Department of Biomedical Experimental and Clinical Sciences, University of Florence, Viale Morgagni 50, 50134, Florence, Italy.
    114Department of Preventive Medicine, Seoul National University College of Medicine, 103 Daehak-ro, Jongno-gu, Seoul, 110-799, Korea.
    115Section of Molecular Diagnostics, Department of Biochemistry, Aalborg University Hospital, Reberbansgade 15, Ålborg, Denmark.
    116Unit of Medical Genetics, Department of Preventive and Predictive Medicine, Fondazione IRCCS (Istituto Di Ricovero e Cura a Carattere Scientifico) Istituto Nazionale Tumori (INT), Via Giacomo Venezian 1, 20133, Milan, Italy.
    117Department of Oncology, Hospital Clinico San Carlos, IdISSC (El Instituto de Investigación Sanitaria del Hospital Clínico San Carlos), Martin Lagos s/n, Madrid, Spain.
    118IFOM, The FIRC (Italian Foundation for Cancer Research) Institute of Molecular Oncology, c/o IFOM-IEO Campus, Via Adamello 16, 20139, Milan, Italy.
    119Department of Cancer Epidemiology, Moffitt Cancer Center, Tampa, FL, 33612, USA.
    120Unit of Molecular Bases of Genetic Risk and Genetic Testing, Department of Preventive and Predicted Medicine, Fondazione IRCCS (Istituto Di Ricovero e Cura a Carattere Scientifico) Istituto Nazionale Tumori (INT), c/o Amaedeolab via GA Amadeo 42, 20133, Milan, Italy.
    121Department of Clinical Genetics, Karolinska University Hospital, L5:03, 171 76, Stockholm, Sweden.
    122Department of OB/GYN, Medical University of Vienna, Waehringer Guertel 18-20, A, 1090, Vienna, Austria.
    123Clalit National Israeli Cancer Control Center and Department of Community Medicine and Epidemiology, Carmel Medical Center and B. Rappaport Faculty of Medicine, 7 Michal St., 34362, Haifa, Israel.
    124Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA.
    125Clinical Genetics, Services Department of Medicine, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY, 10065, USA.
    126Division of Gynecologic Oncology, NorthShore University HealthSystem, University of Chicago, 2650 Ridge Avenue, Suite 1507, Walgreens, Evanston, IL, 60201, USA.
    127Department of Epidemiology, Netherlands Cancer Institute, P.O. Box 90203, 1006 BE, Amsterdam, The Netherlands.
    128Centre 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.
    129Oncogénétique, Institut Bergonié, 229 cours de l'Argonne, 33076, Bordeaux, France.
    130Department of Medicine, Abramson Cancer Center, Perelman School of Medicine at the University of Pennsylvania, 3400 Civic Center Boulevard, Philadelphia, PA, 19104, USA.
    131Department of OB/GYN, Medical University of Vienna, Waehringer Guertel 18-20, A, 1090, Vienna, Austria.
    132Clinical Cancer Genetics, City of Hope, 1500 East Duarte Road, Duarte, CA, 91010, USA.
    133Medical Genetics Unit, St George's, University of London, London, SW17 0RE, UK.
    134Laboratoire de génétique médicale Nancy Université, Centre Hospitalier Régional et Universitaire, Rue du Morvan cedex 1, 54511, Vandoeuvre-les-Nancy, France.
    135Department of Pathology Region Zealand Section Slagelse, Slagelse Hospital, Ingemannsvej 18 Slagelse, Cpoenhagen, Denmark.
    136Genetic Epidemiology Laboratory, Department of Pathology, University of Melbourne, Parkville, VIC, 3010, Australia.
    137Genetics and Computational Biology Department, QIMR Berghofer Medical Research Institute, Herston Road, Brisbane, QLD, 4006, Australia.
    138Clinical Genetics Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY, USA.
    139Service de Génétique Oncologique, Institut Curie, 26 rue d'Ulm, 75248, Paris Cedex 05, France.
    140Department of Genetics and Pathology, Pomeranian Medical University, Polabska 4, 70-115, Szczecin, Poland.
    141Institute of Human Genetics, Department of Human Genetics, University Hospital Heidelberg, Heidelberg, Germany.
    142Department of OB/GYN, Medical University of Vienna, Waehringer Guertel 18-20, A, 1090, Vienna, Austria.
    143Department of OB/GYN, Medical University of Vienna, Waehringer Guertel 18-20, A, 1090, Vienna, Austria.
    144Department of Genetics, Portuguese Oncology Institute, Rua Dr. António Bernardino de Almeida, 4200-072, Porto, Portugal.
    145Genetic Counseling Unit, Hereditary Cancer Program, IDIBELL (Bellvitge Biomedical Research Institute), Catalan Institute of Oncology, Gran Via de l'Hospitalet, 199-203, L'Hospitalet, 08908, Barcelona, Spain.
    146Cancer Research Initiatives Foundation, Sime Darby Medical Centre, 1 Jalan SS12/1A, 47500, Subang Jaya, Malaysia.
    147Department of Epidemiology, Columbia University, New York, NY, USA.
    148Department of Clinical Genetics, Odense University Hospital, Sonder Boulevard 29, Odense C, Denmark.
    149Latvian Biomedical Research and Study Centre, Ratsupites str 1, Riga, Latvia.
    150Program in Cancer Genetics, Departments of Human Genetics and Oncology, McGill University, Montreal, QC, Canada.
    151Immunology and Molecular Oncology Unit, Veneto Institute of Oncology IOV-IRCCS, Via Gattamelata 64, 35128, Padua, Italy.
    152Division of Human Genetics, Departments of Internal Medicine and Cancer Biology and Genetics Comprehensive Cancer Center, The Ohio State University, 998 Biomedical Research Tower, Columbus, OH, 43210, USA.
    153Department of Medical Oncology, Beth Israel Deaconess Medical Center, 330 Brookline Avenue, Boston, MA, 02215, USA.
    154Department of Clinical Genetics, Family Cancer Clinic, Erasmus University Medical Center, 330 Brookline Avenue, P.O. Box 2040, 3000 CA, Rotterdam, The Netherlands.
    155Department of Medical Genetics, University Medical Center Utrecht, 3584 EA, Utrecht, The Netherlands.
    156Department of Clinical Genetics, Academic Medical Center, P.O. Box 22700, 1100 DE, Amsterdam, The Netherlands.
    157Cancer Genetics Laboratory, Department of Genetics, University of Pretoria, Private Bag X323, Arcadia, 0007, South Africa.
    158Institute of Human Genetics, Charite Berlin, Campus Virchov Klinikum, 13353, Berlin, Germany.
    159Centre 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.
    160Department of Human Genetics & Department of Clinical Genetics, Leiden University Medical Center, 2300 RC, Leiden, The Netherlands.
    161Department of Medicine, Abramson Cancer Center, Perelman School of Medicine at the University of Pennsylvania, 3400 Civic Center Boulevard, Philadelphia, PA, 19104, USA.
    162Genetics and Computational Biology Department, QIMR Berghofer Medical Research Institute, Herston Road, Brisbane, QLD, 4006, Australia.
    163Clinical Genetics Research Laboratory, Department of Medicine, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY, 10044, USA.
    164Department of Health Sciences Research, Mayo Clinic, 200 First Street SW, Rochester, MN, 55905, USA.
    165Department of Cancer Genetics, Institute for Cancer Research, Oslo University Hospital, Radiumhospitalet, 0372, Oslo, Norway.
    166Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Strangeways Research Laboratory, Worts Causeway, Cambridge, UK.
    167Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Strangeways Research Laboratory, Worts Causeway, Cambridge, UK.
    168Genomics Center, Centre Hospitalier Universitaire de Québec Research Center and Laval University, 2705 Laurier Boulevard, Quebec, QC, G1V 4G2, Canada. Jacques.Simard@crchudequebec.ulaval.ca.
    Abstract

    PURPOSE: Cis-acting regulatory SNPs resulting in differential allelic expression (DAE) may, in part, explain the underlying phenotypic variation associated with many complex diseases. To investigate whether common variants associated with DAE were involved in breast cancer susceptibility among BRCA1 and BRCA2 mutation carriers, a list of 175 genes was developed based of their involvement in cancer-related pathways.

    METHODS: Using data from a genome-wide map of SNPs associated with allelic expression, we assessed the association of ~320 SNPs located in the vicinity of these genes with breast and ovarian cancer risks in 15,252 BRCA1 and 8211 BRCA2 mutation carriers ascertained from 54 studies participating in the Consortium of Investigators of Modifiers of BRCA1/2.

    RESULTS: We identified a region on 11q22.3 that is significantly associated with breast cancer risk in BRCA1 mutation carriers (most significant SNP rs228595 p = 7 × 10(-6)). This association was absent in BRCA2 carriers (p = 0.57). The 11q22.3 region notably encompasses genes such as ACAT1, NPAT, and ATM. Expression quantitative trait loci associations were observed in both normal breast and tumors across this region, namely for ACAT1, ATM, and other genes. In silico analysis revealed some overlap between top risk-associated SNPs and relevant biological features in mammary cell data, which suggests potential functional significance.

    CONCLUSION: We identified 11q22.3 as a new modifier locus in BRCA1 carriers. Replication in larger studies using estrogen receptor (ER)-negative or triple-negative (i.e., ER-, progesterone receptor-, and HER2-negative) cases could therefore be helpful to confirm the association of this locus with breast cancer risk.


    KEYWORDS: BRCA1 and BRCA2 mutation carriers, Breast cancer, Cis-regulatory variants, Differential allelic expression, Genetic modifiers, Genetic susceptibility

    Publikations ID: 27796716
    Quelle: öffnen
     
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