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Nat Commun. 2016 Sep 7;7:12675. 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 K4, Tyrer J2, Beesley J3, Ramus SJ1, Li Q5,6, Delgado MK1, Lee JM1, Aittomäki K7, Andrulis IL8,9, Anton-Culver H10, Arndt V11, Arun BK12, Arver B13, Bandera EV14, Barile M15, Barkardottir RB16, Barrowdale D4, Beckmann MW17, Benitez J18,19, Berchuck A20, Bisogna M21, Bjorge L22,23, Blomqvist C24, Blot W25,26, Bogdanova N27, Bojesen A28, Bojesen SE29,30,31, Bolla MK4, Bonanni B15, Børresen-Dale AL32,33, Brauch H34,35,36, Brennan P37, Brenner H11,36,38, Bruinsma F39, Brunet J40, Buhari SA41, Burwinkel B42,43, Butzow R44,45, Buys SS46, Cai Q25, Caldes T47, Campbell I48, Canniotto R49, Chang-Claude J50,51, Chiquette J52, Choi JY53,54, Claes KB55; GEMO Study Collaborators, Cook LS56, Cox A57, Cramer DW58,59, Cross SS60, Cybulski C61, Czene K62, Daly MB63, Damiola F64, Dansonka-Mieszkowska A65, Darabi H62, Dennis J4, Devilee P66,67, Diez O68, Doherty JA69, Domchek SM70, Dorfling CM71, Dörk T27, Dumont M72, Ehrencrona H73,74, Ejlertsen B75, Ellis S4; EMBRACE, Engel C76, Lee E1, Evans DG77, Fasching PA17,78, Feliubadalo L79, Figueroa J80, Flesch-Janys D81,82, Fletcher O83,84, Flyger H85, Foretova L86, Fostira F87, Foulkes WD88, Fridley BL89, Friedman E90, Frost D4, Gambino G91, Ganz PA92, Garber J93, García-Closas M80,94, Gentry-Maharaj A95, Ghoussaini M2, Giles GG39,96, Glasspool R97, Godwin AK98, Goldberg MS99,100, Goldgar DE101, González-Neira A18, Goode EL102, Goodman MT103,104, Greene MH105, Gronwald J106, Guénel P107,108, Haiman CA1, Hall P62, Hallberg E102, Hamann U109, Hansen TV110, Harrington PA111, Hartman M41,112, Hassan N113,114, Healey S3; Hereditary Breast and Ovarian Cancer Research Group Netherlands (HEBON), Heitz F115,116, Herzog J117, Høgdall E118,119, Høgdall CK120, Hogervorst FB121, Hollestelle A122, Hopper JL96, Hulick PJ123, Huzarski T61, Imyanitov EN124; KConFab Investigators; Australian Ovarian Cancer Study Group, Isaacs C125, Ito H126, Jakubowska A61, Janavicius R127, Jensen A120, John EM128, Johnson N83,84, Kabisch M109, Kang D53,54,129, Kapuscinski M130, Karlan BY131, Khan S44, Kiemeney LA132, Kjaer SK119,120, Knight JA133,134, Konstantopoulou I87, Kosma VM135,136,137, Kristensen V32,33,138, Kupryjanczyk J65, Kwong A139,140, de la Hoya M47, Laitman Y90, Lambrechts D141,142, Le N1, De Leeneer K55, Lester J131, Levine DA21, Li J62, Lindblom A143, Long J25, Lophatananon A144, Loud JT105, Lu K145, Lubinski J61, Mannermaa A135,136,137, Manoukian S146, Le Marchand L147, Margolin S148, Marme F43,149, Massuger LF150, Matsuo K151, Mazoyer S64, McGuffog L4, McLean C152, McNeish I153, Meindl A154, Menon U95, Mensenkamp AR155, Milne RL39,96, Montagna M156, Moysich KB157, Muir K144,158, Mulligan AM159,160, Nathanson KL70, Ness RB161, Neuhausen SL162, Nevanlinna H44, Nord S33, Nussbaum RL163, Odunsi K164, Offit K165, Olah E166, Olopade OI167, Olson JE102, Olswold C102, O'Malley D168, Orlow I169, Orr N83, Osorio A170,171, Park SK54,129,172, Pearce CL1, Pejovic T173,174, Peterlongo P175, Pfeiler G176, Phelan CM177, Poole EM178,179, Pylkäs K180,181, Radice P182, Rantala J183, Rashid MU109,184, Rennert G185, Rhenius V2, Rhiem K186, Risch HA187, Rodriguez G188, Rossing MA189,190, Rudolph A50, Salvesen HB22,23, Sangrajrang S191, Sawyer EJ192, Schildkraut JM193,194, Schmidt MK195, Schmutzler RK196,197,198,199, Sellers TA177, Seynaeve C122, Shah M2, Shen CY200,201, Shu XO25, Sieh W202, Singer CF176, Sinilnikova OM203,204, Slager S102, Song H2, Soucy P72, Southey MC205, Stenmark-Askmalm M74,206, Stoppa-Lyonnet D207,208, Sutter C209, Swerdlow A84,94, Tchatchou S8, Teixeira MR210,211, Teo SH113,114, Terry KL58,59, Terry MB212, Thomassen M213, Tibiletti MG214, Tihomirova L215, Tognazzo S216, Toland AE217, Tomlinson I218, Torres D109,219, Truong T107,108, Tseng CC1, Tung N220, Tworoger SS178,179, Vachon C102, van den Ouweland AM221, van Doorn HC222, van Rensburg EJ71, Van't Veer LJ195, Vanderstichele A223, Vergote I223, Vijai J165, Wang Q4, Wang-Gohrke S, Weitzel JN117, Wentzensen N224, Whittemore AS202, Wildiers H225, Winqvist R180,181, Wu AH1, Yannoukakos D226, Yoon SY227,228, Yu JC229, Zheng W25, Zheng Y230, Khanna KK3, Simard J72, Monteiro AN231, French JD3, Couch FJ102,232, Freedman ML6, Easton DF2,4, Dunning AM2, Pharoah PD2, Edwards SL3, Chenevix-Trench G3, Antoniou AC4, Gayther SA1.

Collaborators (134)

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

1
Department of Preventive Medicine, Keck School of Medicine, University of Southern California Norris Comprehensive Cancer Center, Los Angeles, California 90033, USA.
2
Department of Oncology, Centre for Cancer Genetic Epidemiology, University of Cambridge, Cambridge CB1 8RN, UK.
3
QIMR Berghofer Medical Research Institute, Brisbane, Queensland 4029, Australia.
4
Department of Public Health and Primary Care, Centre for Cancer Genetic Epidemiology, University of Cambridge, Cambridge CB1 8RN, UK.
5
Medical College, Xiamen University, Xiamen 361102, China.
6
Department of Medical Oncology, The Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA.
7
Department of Clinical Genetics, Helsinki University Hospital, University of Helsinki, Helsinki 00029 HUS, Finland.
8
Lunenfeld-Tanenbaum Research Institute of Mount Sinai Hospital, Toronto, Ontario M5G 1X5, Canada.
9
Department of Molecular Genetics, University of Toronto, Toronto, Ontario M5S 1A8, Canada.
10
Department of Epidemiology, Genetic Epidemiology Research Institute, School of Medicine, University of California Irvine, Irvine, California 92697, USA.
11
Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, 69120, Germany.
12
University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
13
Department of Oncology, Karolinska University Hospital, Stockholm 171 77, Sweden.
14
Cancer Prevention and Control, Rutgers Cancer Institute of New Jersey, New Brunswick, New Jersey 08903, USA.
15
Division of Cancer Prevention and Genetics, Istituto Europeo di Oncologia, Milan 20141, Italy.
16
Department of Pathology, Landspitali University Hospital and BMC (Biomedical Centre), Faculty of Medicine, University of Iceland, Reykjavik 600169-2039, Iceland.
17
University Hospital Erlangen, Department of Gynecology and Obstetrics, Friedrich-Alexander-University Erlangen-Nuremberg, Comprehensive Cancer Center Erlangen-EMN, Erlangen 91054, Germany.
18
Human Cancer Genetics Program, Spanish National Cancer Research Centre, Madrid E-28029, Spain.
19
Centro de Investigación en Red de Enfermedades Raras, Valencia 28029, Spain.
20
Department of Obstetrics and Gynecology, Duke University Medical Center, Durham, North Carolina 27710, USA.
21
Gynecology Service, Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York 10065, USA.
22
Department of Gynecology and Obstetrics, Haukeland University Hospital, 5021 Bergen, Norway.
23
Centre for Cancer Biomarkers, Department of Clinical Science, University of Bergen, N-5020 Bergen, Norway.
24
Department of Oncology, Helsinki University Hospital, University of Helsinki, Helsinki FIN-00029, Finland.
25
Division of Epidemiology, Department of Medicine, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, Tennessee 37203, USA.
26
International Epidemiology Institute, Rockville, Maryland 20850, USA.
27
Gynaecology Research Unit, Hannover Medical School, Hannover D-30625, Germany.
28
Department of Clinical Genetics, Vejle Hospital, Vejle 7100, Denmark.
29
Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen 2200, Denmark.
30
Department of Clinical Biochemistry, Herlev Hospital, Copenhagen University Hospital, Herlev 2730, Denmark.
31
Copenhagen General Population Study, Herlev Hospital, Copenhagen University Hospital, Herlev 2730, Denmark.
32
Department of Genetics, Institute for Cancer Research, Oslo University Hospital Radiumhospitalet, Oslo N-0310, Norway.
33
K.G. Jebsen Center for Breast Cancer Research, Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo N-0310, Norway.
34
Dr Margarete Fischer-Bosch-Institute of Clinical Pharmacology, Stuttgart D-70376, Germany.
35
University of Tübingen, Tübingen 72074, Germany.
36
German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg 69120, Germany.
37
International Agency for Research on Cancer, Lyon 69008, France.
38
Division of Preventive Oncology, German Cancer Research Center (DKFZ), Heidelberg 69121, Germany.
39
Cancer Epidemiology Centre, Cancer Council Victoria, Melbourne, Victoria 3004, Australia.
40
Genetic Counseling Unit, Hereditary Cancer Program, IDIBGI (Institut d'Investigació Biomèdica de Girona), Catalan Institute of Oncology, Girona 08908, Spain.
41
Department of Surgery, National University Health System, Singapore 119077, Singapore.
42
Molecular Epidemiology Group, German Cancer Research Center (DKFZ), Heidelberg 69120, Germany.
43
Department of Obstetrics and Gynecology, University of Heidelberg, Heidelberg 69120, Germany.
44
Department of Obstetrics and Gynecology, University of Helsinki and Helsinki University Central Hospital, Helsinki 00029 HUS, Finland.
45
Department of Pathology, Helsinki University Central Hospital, Helsinki 00029, Finland.
46
Department of Medicine, Huntsman Cancer Institute, University of Utah School of Medicine, Salt Lake City, Utah 84112, USA.
47
Molecular Oncology Laboratory, Hospital Clinico San Carlos, IdISSC (El Instituto de Investigación Sanitaria del Hospital Clínico San Carlos), Madrid 28040, Spain.
48
Cancer Genetics Laboratory, Peter MacCallum Cancer Centre, Melbourne, Victoria 3002, Australia.
49
Cancer Pathology &Prevention, Division of Cancer Prevention and Population Sciences, Roswell Park Cancer Institute, Elm and Carlton Streets, Buffalo 14263, New York, USA.
50
Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg 69121, Germany.
51
University Cancer Center Hamburg (UCCH), University Medical Center Hamburg-Eppendorf, Hamburg 20246, Germany.
52
Unité de recherche en santé des populations, Centre des maladies du sein Deschênes-Fabia, Centre de recherche FRSQ du Centre hospitalier affilié universitaire de Québec, Québec City, Québec G1J 1Z4, Canada.
53
Cancer Research Institute, Seoul National University, Seoul 08826, Korea.
54
Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul 03080, Korea.
55
Center for Medical Genetics, Ghent University, Ghent 9000, Belgium.
56
Division of Epidemiology and Biostatistics, Department of Internal Medicine, University of New Mexico, Albuquerque, New Mexico 87131, USA.
57
Sheffield Cancer Research, Department of Oncology, University of Sheffield, Sheffield S10 2TN, UK.
58
Harvard HT Chan School of Public Health, Boston, Massachusetts 02115, USA.
59
Obstetrics and Gynecology Epidemiology Center, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA.
60
Academic Unit of Pathology, Department of Neuroscience, University of Sheffield, Sheffield S10 2TN, UK.
61
Department of Genetics and Pathology, Pomeranian Medical University, Szczecin 70-115, Poland.
62
Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm SE-171 77, Sweden.
63
Department of Clinical Genetics, Fox Chase Cancer Center, Philadelphia, Pennsylvania 19111, USA.
64
INSERM U1052, CNRS UMR5286, Université Lyon, Centre de Recherche en Cancérologie de Lyon, Lyon 69373, France.
65
Department of Pathology and Laboratory Diagnostics the Maria Sklodowska Curie Memorial Cancer Center and Institute of Oncology, Warsaw 44-101, Poland.
66
Department of Pathology, Leiden University Medical Center, Leiden 2333, The Netherlands.
67
Department of Human Genetics, Leiden University Medical Center, Leiden 2333, The Netherlands.
68
Oncogenetics Group, University Hospital Vall d'Hebron, Vall d'Hebron Institute of Oncology (VHIO) and Universitat Autònoma de Barcelona, Barcelona 08035, Spain.
69
Department of Community and Family Medicine, Section of Biostatistics &Epidemiology, The Geisel School of Medicine at Dartmouth, Lebanon, New Hampshire 03755, USA.
70
Department of Medicine, Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
71
Department of Genetics, University of Pretoria, Pretoria 0083, South Africa.
72
Genomics Center, Centre Hospitalier Universitaire de Québec Research Center, Laval University, Québec City, Québec G1V 4G2, Canada.
73
Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala 751 05, Sweden.
74
Department of Clinical Genetics, Lund University Hospital, Lund 221 00, Sweden.
75
Department of Oncology, Rigshospitalet, Copenhagen University Hospital, 2100 Copenhagen, Denmark.
76
Institute for Medical Informatics, Statistics and Epidemiology, University of Leipzig, 04107 Leipzig, Germany.
77
Genomic Medicine, Manchester Academic Health Sciences Centre, Institute of Human Development, Manchester University, Central Manchester University Hospitals NHS Foundation Trust, Manchester M13 9PL, UK.
78
University of California at Los Angeles, David Geffen School of Medicine, Department of Medicine, Division of Hematology and Oncology, Los Angeles California 90095, USA.
79
Molecular Diagnostic Unit, Hereditary Cancer Program, IDIBELL (Bellvitge Biomedical Research Institute),Catalan Institute of Oncology, Barcelona 08908, Spain.
80
Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, Maryland 20892, USA.
81
Institute for Medical Biometrics and Epidemiology, University Medical Center Hamburg-Eppendorf, Hamburg 20246, Germany.
82
Department of Cancer Epidemiology, Clinical Cancer Registry, University Medical Center Hamburg-Eppendorf, Hamburg 20246, Germany.
83
Breakthrough Breast Cancer Research Centre, The Institute of Cancer Research, London SW3 6JB, UK.
84
Division of Breast Cancer Research, The Institute of Cancer Research, London SW7 3RP, UK.
85
Department of Breast Surgery, Herlev Hospital, Copenhagen University Hospital, 2730 Herlev, Denmark.
86
Masaryk Memorial Cancer Institute and Medical Faculty MU, 625 00 Brno, Czech Republic.
87
Molecular Diagnostics Laboratory, (INRASTES) Institute of Nuclear and Radiological Sciences and Technology, National Centre for Scientific Research 'Demokritos', Aghia Paraskevi Attikis, Athens 153 10, Greece.
88
Program in Cancer Genetics, Departments of Human Genetics and Oncology, McGill University, Montreal, Montreal, Quebec H2W 1S6, Canada.
89
Biostatistics and Informatics Shared Resource, University of Kansas Medical Center, Kansas City, Kansas 66160, USA.
90
Susanne Levy Gertner Oncogenetics Unit, Sheba Medical Center, Tel-Hashomer 52621, Israel.
91
Section of Genetic Oncology, Department of Laboratory Medicine, University and University Hospital of Pisa, Pisa 56126, Italy.
92
UCLA Schools of Medicine and Public Health, Division of Cancer Prevention &Control Research, Jonsson Comprehensive Cancer Center, Los Angeles, California 90024, USA.
93
Cancer Risk and Prevention Clinic, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA.
94
Division of Genetics and Epidemiology, The Institute of Cancer Research, London SW7 3RP, UK.
95
Women's Cancer, UCL EGA Institute for Women's Health, London WC1E 6AU, UK.
96
Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, Victoria 3010, Australia.
97
Cancer Research UK Clinical Trials Unit, The Beatson West of Scotland Cancer Centre, Glasgow G12 0YN, UK.
98
Department of Pathology and Laboratory Medicine, University of Kansas Medical Center, Kansas City, Kansas 66160, USA.
99
Division of Clinical Epidemiology, Royal Victoria Hospital, McGill University, Montreal, Québec H3A 1A1, Canada.
100
Department of Medicine, McGill University, Montreal, Québec H3A 1A1, Canada.
101
Department of Dermatology, Huntsman Cancer Institute, University of Utah School of Medicine, Salt Lake City, Utah 84132, USA.
102
Department of Health Sciences Research, Mayo Clinic, Rochester, Minnesota 55902, USA.
103
Cancer Prevention and Control, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, California 90048, USA.
104
Community and Population Health Research Institute, Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, California 90048, USA.
105
Clinical Genetics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Rockville, Maryland 20892, USA.
106
Department of Genetics and Pathology, Pomeranian Medical University, 70-204 Szczecin, Poland.
107
Environmental Epidemiology of Cancer, Center for Research in Epidemiology and Population Health, INSERM, 94805 Villejuif, France.
108
University Paris-Sud, 91405 Villejuif, France.
109
Molecular Genetics of Breast Cancer, German Cancer Research Center (DKFZ), Heidelberg 69120, Germany.
110
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital, 2100 Copenhagen, Denmark.
111
Department of Oncology, Department of Public Health and Primary Care, University of Cambridge, Strangeways Research Laboratory, Cambridge CB1 8RN, UK.
112
Saw Swee Hock School of Public Health, National University of Singapore Singapore 119077, Singapore.
113
Breast Cancer Research Unit, Cancer Research Institute, University Malaya Medical Centre, 50603 Kuala Lumpur, Malaysia.
114
Cancer Research Initiatives Foundation, Subang Jaya, 47500 Selangor, Malaysia.
115
Department of Gynecology and Gynecologic Oncology, Kliniken Essen-Mitte, 45136 Essen, Germany.
116
Department of Gynecology and Gynecologic Oncology, Dr Horst Schmidt Kliniken Wiesbaden, 65199 Wiesbaden, Germany.
117
Clinical Cancer Genetics, for the City of Hope Clinical Cancer Genetics Community Research Network, Duarte California 91010, USA.
118
Molecular Unit, Department of Pathology, Herlev Hospital, University of Copenhagen, 2730 Copenhagen, Denmark.
119
Department of Virus, Lifestyle and Genes, Danish Cancer Society Research Center, DK-2100 Copenhagen, Denmark.
120
Department of Gynecology, Rigshospitalet, University of Copenhagen, 2100 Copenhagen, Denmark.
121
Family Cancer Clinic, Netherlands Cancer Institute, 1006 Amsterdam, The Netherlands.
122
Department of Medical Oncology, Family Cancer Clinic, Erasmus MC Cancer Institute, 3015 Rotterdam, The Netherlands.
123
Center for Medical Genetics, NorthShore University Health System, Evanston, Illinois, 60201, USA.
124
N.N. Petrov Institute of Oncology, St Petersburg 197758, Russia.
125
Lombardi Comprehensive Cancer Center, Georgetown University, Washington District of Columbia 20057, USA.
126
Division of Epidemiology and Prevention, Aichi Cancer Center Research Institute, Aichi 464-8681, Japan.
127
State Research Institute Centre for Innovative Medicine, LT-01102 Vilnius, Lithuania.
128
Department of Epidemiology, Cancer Prevention Institute of California, Fremont, California 94538, USA.
129
Department of Preventive Medicine, Seoul National University College of Medicine, Seoul 08826, Korea.
130
Centre for Epidemiology and Biostatistics, University of Melbourne, Melbourne, Victoria 3010, Australia.
131
Women's Cancer Program at the Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, California 90048, USA.
132
Radboud University Medical Centre, Radboud Institute for Health Sciences, 6500 Nijmegen, The Netherlands.
133
Prosserman Centre for Health Research, Lunenfeld-Tanenbaum Research Institute of Mount Sinai Hospital, Toronto, Ontario M5G 1X5, Canada.
134
Division of Epidemiology, Dalla Lana School of Public Health, University of Toronto, Toronto, Ontario M5T 3M7, Canada.
135
Imaging Center, Department of Clinical Pathology, Kuopio University Hospital, 70210 Kuopio, Finland.
136
Cancer Center, Kuopio University Hospital, 70210 Kuopio, Finland.
137
Institute of Clinical Medicine, Pathology and Forensic Medicine, University of Eastern Finland, 70210 Kuopio, Finland.
138
Department of Clinical Molecular Biology, Oslo University Hospital, University of Oslo, 1478 Oslo, Norway.
139
The Hong Kong Hereditary Breast Cancer Family Registry, Cancer Genetics Center, Hong Kong Sanatorium and Hospital, Hong Kong, China.
140
Department of Surgery, The University of Hong Kong, Hong Kong, China.
141
Vesalius Research Center, VIB, 3000 Leuven, Belgium.
142
Laboratory for Translational Genetics, Department of Oncology, University of Leuven, 3000 Leuven, Belgium.
143
Department of Molecular Medicine and Surgery, Karolinska Institutet, SE-171 77 Stockholm, Sweden.
144
Division of Health Sciences, Warwick Medical School, Warwick University, Coventry CV4 7AL, UK.
145
Department of Gynecologic Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
146
Unit of Medical Genetics, Department of Preventive and Predictive Medicine, Fondazione IRCCS (Istituto Di Ricovero e Cura a Carattere Scientifico) Istituto Nazionale Tumori (INT), 20133 Milan, Italy.
147
University of Hawaii Cancer Center, Honolulu, Hawaii 96813, USA.
148
Department of Oncology - Pathology, Karolinska Institutet, SE-171 77 Stockholm, Sweden.
149
National Center for Tumour Diseases, University of Heidelberg, 69117 Heidelberg, Germany.
150
Department of Gynaecology, Radboud University Medical Centre, 6500 Nijmegen, The Netherlands.
151
Department of Preventive Medicine, Kyushu University Faculty of Medical Sciences, Fukuoka 812-8582, Japan.
152
Anatomical Pathology, The Alfred Hospital, Melbourne, Victoria 3004, Australia.
153
Institute of Cancer Sciences, University of Glasgow, Wolfson Wohl Cancer Research Centre, Beatson Institute for Cancer Research, Glasgow G61 1BD, UK.
154
Division of Gynaecology and Obstetrics, Technische Universität München, 81675 Munich, Germany.
155
Department of Human Genetics, Radboud University Medical Centre, 6500 Nijmegen, The Netherlands.
156
Immunology and Molecular Oncology Unit, Instituto Oncologico Veneto IOV, IRCCS, 35128 Padua, Italy.
157
Department of Cancer Prevention and Control, Roswell Park Cancer Institute, Buffalo, New York 14263, USA.
158
Institute of Population Health, University of Manchester, Manchester M13 9PL, UK.
159
Laboratory Medicine Program, University Health Network, Toronto, Ontario M5G 1L7, Canada.
160
Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario M5G 1L7, Canada.
161
The University of Texas School of Public Health, Houston, Texas 77030, USA.
162
Department of Population Sciences, Beckman Research Institute of City of Hope, Duarte, California 91010, USA.
163
Department of Medicine and Genetics, University of California, San Francisco, California 94143, USA.
164
Department of Gynecological Oncology, Roswell Park Cancer Institute, Buffalo, New York 14263, USA.
165
Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York 10065, USA.
166
Department of Molecular Genetics, National Institute of Oncology, 1122 Budapest, Hungary.
167
Center for Clinical Cancer Genetics and Global Health, University of Chicago Medical Center, Chicago, Illinois 60637, USA.
168
The Ohio State University and the James Cancer Center, Columbus, Ohio 43210, USA.
169
Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York 10017, USA.
170
Human Genetics Group, Human Cancer Genetics Program, Spanish National Cancer Centre (CNIO), 28019 Madrid, Spain.
171
Biomedical Network on Rare Diseases (CIBERER), 28029 Madrid, Spain.
172
Department of Surgery, Seoul National University College of Medicine, Seoul, 03080 Korea.
173
Department of Obstetrics and Gynecology, Oregon Health and Science University, Portland, Oregon 97239, USA.
174
Knight Cancer Institute, Oregon Health and Science University, Portland, Oregon 97239, USA.
175
IFOM, The FIRC (Italian Foundation for Cancer Research) Institute of Molecular Oncology, 16 20139 Milan, Italy.
176
Department of Obstetrics and Gynecology, Comprehensive Cancer Center, Medical University of Vienna, 1090 Vienna, Austria.
177
Department of Cancer Epidemiology, Moffitt Cancer Center, Tampa, Florida 33606, USA.
178
Channing Division of Network Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA.
179
Department of Epidemiology, Harvard TH Chan School of Public Health, Boston, Massachusetts 02115, USA.
180
Laboratory of Cancer Genetics and Tumour Biology, Northern Finland Laboratory Centre NordLab, FI-90014 Oulu, Finland.
181
Laboratory of Cancer Genetics and Tumour Biology, Department of Clinical Chemistry and Biocenter Oulu, University of Oulu, FI-90014 Oulu, Finland.
182
Unit of Molecular Bases of Genetic Risk and Genetic Testing, Department of Preventive and Predictive Medicine, Fondazione IRCCS (Istituto Di Ricovero e Cura a Carattere Scientifico) Istituto Nazionale dei Tumori (INT), 20133 Milan, Italy.
183
Department of Clinical Genetics, Karolinska University Hospital, 171 76 Stockholm, Sweden.
184
Department of Basic Sciences, Shaukat Khanum Memorial Cancer Hospital and Research Centre (SKMCH &RC), Lahore 54000, Pakistan.
185
Clalit National Israeli Cancer Control Center and Department of Community Medicine and Epidemiology, Carmel Medical Center and B. Rappaport Faculty of Medicine, Haifa 34362, Israel.
186
Centre of Familial Breast and Ovarian Cancer, Department of Gynaecology and Obstetrics and Centre for Integrated Oncology (CIO), Center for Molecular Medicine Cologne (CMMC), University Hospital of Cologne, 50931 Cologne, Germany.
187
Department of Chronic Disease Epidemiology, Yale School of Public Health, New Haven, Connecticut 06510, USA.
188
Division of Gynecologic Oncology, NorthShore University HealthSystem, Evanston, Illinois 60201, USA.
189
Program in Epidemiology, Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington 98109, USA.
190
Department of Epidemiology, University of Washington, Seattle, Washington 98109, USA.
191
National Cancer Institute, Bangkok 10400, Thailand.
192
Research Oncology, Guy's Hospital, King's College London, London SE1 9RT, UK.
193
Department of Community and Family Medicine, Duke University Medical Center, Durham, North Carolina 27710, USA.
194
Cancer Control and Population Sciences, Duke Cancer Institute, Durham, North Carolina 27710, USA.
195
Netherlands Cancer Institute, Antoni van Leeuwenhoek Hospital, 1066 CX Amsterdam, The Netherlands.
196
Division of Molecular Gyneco-Oncology, Department of Gynaecology and Obstetrics, University Hospital of Cologne, 50676 Cologne, Germany.
197
Center for Integrated Oncology, University Hospital of Cologne, 50676 Cologne, Germany.
198
Center for Molecular Medicine, University Hospital of Cologne, 50676 Cologne, Germany.
199
Center of Familial Breast and Ovarian Cancer, University Hospital of Cologne, 50676 Cologne, Germany.
200
Taiwan Biobank, Institute of Biomedical Sciences, Academia Sinica, Taipei 115, Taiwan.
201
School of Public Health, China Medical University, Taichung 404, Taiwan.
202
Department of Health Research and Policy - Epidemiology, Stanford University School of Medicine, Stanford California 94305, USA.
203
Unité Mixte de Génétique Constitutionnelle des Cancers Fréquents, Hospices Civils de Lyon - Centre Léon Bérard, Lyon 69008, France.
204
INSERM U1052, CNRS UMR5286, Université Lyon 1, Centre de Recherche en Cancérologie de Lyon, Lyon 69003, France.
205
Department of Pathology, University of Melbourne, Parkville, Victoria 3010, Australia.
206
Division of Clinical Genetics, Department of Clinical and Experimental Medicine, Linköping University, 581 83 Linköping, Sweden.
207
Institut Curie, Department of Tumour Biology, Paris, France; Institut Curie, INSERM U830, 75248 Paris, France.
208
Université Paris Descartes, Sorbonne Paris Cité, 75270 Paris, France.
209
Institute of Human Genetics, Department of Human Genetics, University Hospital Heidelberg, 69120 Heidelberg, Germany.
210
Department of Genetics, Portuguese Oncology Institute, Porto 4200-072, Portugal.
211
Biomedical Sciences Institute (ICBAS), Porto University, Porto 4099-002, Portugal.
212
Department of Epidemiology, Mailman School of Public Health, Columbia University, New York 10027, USA.
213
Department of Clinical Genetics, Odense University Hospital, 5000 Odense C, Denmark.
214
UO Anatomia Patologica, Ospedale di Circolo-Università dell'Insubria, 21100 Varese, Italy.
215
Latvian Biomedical Research and Study Centre, Riga LV-1067, Latvia.
216
Immunology and Molecular Oncology Unit, Istituto Oncologico Veneto IOV - IRCCS (Istituto Di Ricovero e Cura a Carattere Scientifico), 64 - 35128 Padua, Italy.
217
Department of Molecular Virology, Immunology and Medical Genetics, The Ohio State University, Columbus, Ohio 43210, USA.
218
Wellcome Trust Centre for Human Genetics and Oxford Biomedical Research Centre, University of Oxford, Oxford OX3 7BN, UK.
219
Institute of Human Genetics, Pontificia Universidad Javeriana, Cra. 7 #40-62 Bogota, Colombia.
220
Department of Medical Oncology, Beth Israel Deaconess Medical Center, Boston, Massachusetts 02215, USA.
221
Department of Clinical Genetics, Erasmus University Medical Center, 3015 CE Rotterdam, The Netherlands.
222
Department of Gynecology, Family Cancer Clinic, Erasmus MC Cancer Institute, 3015 CE Rotterdam, The Netherlands.
223
Division of Gynecological Oncology, Department of Oncology, University Hospitals Leuven, B-3000 Leuven, Belgium.
224
Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda Maryland 20892, USA.
225
Multidisciplinary Breast Center, Department of General Medical Oncology, University Hospitals Leuven, B-3000 Leuven, Belgium.
226
Molecular Diagnostics Laboratory, IRRP, National Centre for Scientific Research 'Demokritos', Athens 153 10, Greece.
227
Cancer Research Initiatives Foundation, Sime Darby Medical Centre, 47500 Subang Jaya, Malaysia.
228
University Malaya Cancer Research Institute, Faculty of Medicine, University Malaya Medical Centre, University Malaya, 59100 Kuala Lumpur, Malaysia.
229
Department of Surgery, Tri-Service General Hospital, National Defense Medical Center, Taipei, 114 Taiwan.
230
Shanghai Center for Disease Control and Prevention, Shanghai, China.
231
Cancer Epidemiology Program, Division of Population Sciences, H. Lee Moffitt Cancer Center &Research Institute, Tampa, Florida 33612, USA.
232
Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota 55905, 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.

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