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Nat Genet. 2016 Apr;48(4):374-86. doi: 10.1038/ng.3521. Epub 2016 Feb 29.

Breast cancer risk variants at 6q25 display different phenotype associations and regulate ESR1, RMND1 and CCDC170.

Dunning AM1, Michailidou K2, Kuchenbaecker KB2, Thompson D2, French JD3, Beesley J3, Healey CS1, Kar S1, Pooley KA2, Lopez-Knowles E4,5, Dicks E1, Barrowdale D2, Sinnott-Armstrong NA6, Sallari RC7, Hillman KM3, Kaufmann S3, Sivakumaran H3, Moradi Marjaneh M3, Lee JS3, Hills M5, Jarosz M4,5, Drury S4,5, Canisius S8, Bolla MK2, Dennis J2, Wang Q2, Hopper JL9, Southey MC10, Broeks A8, Schmidt MK8, Lophatananon A11, Muir K11,12, Beckmann MW13, Fasching PA13,14, Dos-Santos-Silva I15, Peto J15, Sawyer EJ16, Tomlinson I17,18, Burwinkel B19,20, Marme F21,22, Guénel P23,24, Truong T23,24, Bojesen SE25,26,27, Flyger H28, González-Neira A29, Perez JI30, Anton-Culver H31, Eunjung L32, Arndt V33, Brenner H33,34, Meindl A35, Schmutzler RK36,37,38, Brauch H34,39,40, Hamann U41, Aittomäki K42, Blomqvist C43, Ito H44, Matsuo K45, Bogdanova N46, Dörk T47, Lindblom A48, Margolin S49, Kosma VM50,51,52, Mannermaa A50,51,52, Tseng CC32, Wu AH32, Lambrechts D53,54, Wildiers H55, Chang-Claude J56,57, Rudolph A56, Peterlongo P58, Radice P59, Olson JE60, Giles GG9,61, Milne RL9,61, Haiman CA32, Henderson BE32, Goldberg MS62,63, Teo SH64,65, Yip CH65, Nord S66, Borresen-Dale AL66,67, Kristensen V66,67,68, Long J69, Zheng W69, Pylkäs K70,71, Winqvist R70,71, Andrulis IL72,73, Knight JA74,75, Devilee P76,77, Seynaeve C78, Figueroa J79, Sherman ME79, Czene K80, Darabi H80, Hollestelle A78, van den Ouweland AM81, Humphreys K80, Gao YT82, Shu XO69, Cox A83, Cross SS84, Blot W69,85, Cai Q69, Ghoussaini M1, Perkins BJ1, Shah M1, Choi JY86,87, Kang D86,87,88, Lee SC89,90, Hartman M91,92, Kabisch M41, Torres D41,93, Jakubowska A94, Lubinski J94, Brennan P95, Sangrajrang S96, Ambrosone CB97, Toland AE98, Shen CY99,100, Wu PE100, Orr N101, Swerdlow A102,103, McGuffog L2, Healey S3, Lee A2, Kapuscinski M104, John EM105, Terry MB106, Daly MB107, Goldgar DE108, Buys SS109, Janavicius R110, Tihomirova L111, Tung N112, Dorfling CM113, van Rensburg EJ113, Neuhausen SL114, Ejlertsen B115, Hansen TV116, Osorio A117,118, Benitez J117,118,119, Rando R120, Weitzel JN121, Bonanni B122, Peissel B123, Manoukian S123, Papi L124, Ottini L125, Konstantopoulou I126, Apostolou P126, Garber J127, Rashid MU41,128, Frost D2; EMBRACE, Izatt L129, Ellis S2, Godwin AK130, Arnold N131, Niederacher D132, Rhiem K133, Bogdanova-Markov N134, Sagne C135, Stoppa-Lyonnet D136,137, Damiola F135; GEMO Study Collaborators, Sinilnikova OM135,138, Mazoyer S135, Isaacs C139, Claes KB140, De Leeneer K140, de la Hoya M141, Caldes T141, Nevanlinna H142, Khan S142, Mensenkamp AR143; HEBON, Hooning MJ144, Rookus MA145, Kwong A146,147, Olah E148, Diez O149, Brunet J150, Pujana MA151, Gronwald J94, Huzarski T94, Barkardottir RB152, Laframboise R153, Soucy P154, Montagna M155, Agata S155, Teixeira MR156,157; kConFab Investigators, Park SK86,87,88, Lindor N60, Couch FJ60,158, Tischkowitz M159, Foretova L160, Vijai J161, Offit K161, Singer CF162, Rappaport C162, Phelan CM163, Greene MH164, Mai PL164, Rennert G165,166, Imyanitov EN167, Hulick PJ168, Phillips KA169, Piedmonte M170, Mulligan AM171,172, Glendon G72, Bojesen A173, Thomassen M174, Caligo MA175, Yoon SY64,176, Friedman E177, Laitman Y177, Borg A178, von Wachenfeldt A49, Ehrencrona H179,180, Rantala J181, Olopade OI182, Ganz PA183, Nussbaum RL184, Gayther SA32, Nathanson KL185, Domchek SM185, Arun BK186, Mitchell G187,188, Karlan BY189, Lester J189, Maskarinec G190, Woolcott C191, Scott C60, Stone J192, Apicella C9, Tamimi R193,194,195, Luben R196, Khaw KT196, Helland Å66, Haakensen V66, Dowsett M4,5, Pharoah PD1,2, Simard J154, Hall P80, García-Closas M101,102, Vachon C60, Chenevix-Trench G3, Antoniou AC2, Easton DF1,2, Edwards SL3.

Author information

1
Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Cambridge, UK.
2
Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.
3
Cancer Division, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.
4
Breast Cancer Research, Breakthrough Breast Cancer Research Centre, London, UK.
5
Academic Biochemistry, Royal Marsden Hospital, London, UK.
6
Department of Genetics, Stanford University School of Medicine, Stanford, California, USA.
7
Computer Science and Artificial Intelligence Laboratory, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.
8
Netherlands Cancer Institute, Antoni van Leeuwenhoek Hospital, Amsterdam, the Netherlands.
9
Centre for Epidemiology and Biostatistics, School of Population and Global Health, University of Melbourne, Melbourne, Victoria, Australia.
10
Department of Pathology, University of Melbourne, Melbourne, Victoria, Australia.
11
Division of Health Sciences, Warwick Medical School, Warwick University, Coventry, UK.
12
Institute of Population Health, University of Manchester, Manchester, UK.
13
Department of Gynecology and Obstetrics, University Hospital Erlangen, Friedrich Alexander University Erlangen-Nuremberg, Comprehensive Cancer Center Erlangen-Nuremberg Metropolitan Region, Erlangen, Germany.
14
Department of Medicine, Division of Hematology and Oncology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California, USA.
15
Department of Non-Communicable Disease Epidemiology, London School of Hygiene and Tropical Medicine, London, UK.
16
Research Oncology, Division of Cancer Studies, King's College London, Guy's Hospital, London, UK.
17
Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.
18
Oxford Biomedical Research Centre, University of Oxford, Oxford, UK.
19
Division of Molecular Genetic Epidemiology, German Cancer Research Center, Heidelberg, Germany.
20
Molecular Epidemiology Group, German Cancer Research Center, Heidelberg, Germany.
21
National Center for Tumor Diseases, University of Heidelberg, Heidelberg, Germany.
22
Department of Obstetrics and Gynecology, University of Heidelberg, Heidelberg, Germany.
23
Environmental Epidemiology of Cancer, Center for Research in Epidemiology and Population Health, INSERM, Villejuif, France.
24
University Paris-Sud, Villejuif, France.
25
Copenhagen General Population Study, Herlev Hospital, Copenhagen University Hospital, Herlev, Denmark.
26
Department of Clinical Biochemistry, Herlev Hospital, Copenhagen University Hospital, Herlev, Denmark.
27
Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
28
Department of Breast Surgery, Herlev Hospital, Copenhagen University Hospital, Herlev, Denmark.
29
Human Cancer Genetics Program, Spanish National Cancer Centre (CNIO), Madrid, Spain.
30
Servicio de Cirugía General y Especialidades, Hospital Monte Naranco, Oviedo, Spain.
31
Department of Epidemiology, University of California-Irvine, Irvine, California, USA.
32
Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California, USA.
33
Division of Clinical Epidemiology and Aging Research, German Cancer Research Center, Heidelberg, Germany.
34
German Cancer Consortium, German Cancer Research Center, Heidelberg, Germany.
35
Department of Gynaecology and Obstetrics, Technical University of Munich, Munich, Germany.
36
Division of Molecular Gyneco-Oncology, Department of Gynaecology and Obstetrics, University Hospital of Cologne, Cologne, Germany.
37
Centre of Familial Breast and Ovarian Cancer, University Hospital of Cologne, Cologne, Germany.
38
Center for Integrated Oncology, University Hospital, Cologne, Germany.
39
Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart, Germany.
40
University of Tübingen, Tübingen, Germany.
41
Molecular Genetics of Breast Cancer, German Cancer Research Center, Heidelberg, Germany.
42
Department of Clinical Genetics, Helsinki University Central Hospital, Helsinki, Finland.
43
Department of Oncology, Helsinki University Central Hospital, University of Helsinki, Helsinki, Finland.
44
Division of Epidemiology and Prevention, Aichi Cancer Center Research Institute, Aichi, Japan.
45
Division of Molecular Medicine, Aichi Cancer Center Research Institute, Nagoya, Japan.
46
Radiation Oncology Research Unit, Hannover Medical School, Hannover, Germany.
47
Gynaecology Research Unit, Hannover Medical School, Hannover, Germany.
48
Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.
49
Department of Oncology-Pathology, Karolinska University Hospital, Stockholm, Sweden.
50
Cancer Center, Kuopio University Hospital, Kuopio, Finland.
51
Institute of Clinical Medicine, Pathology and Forensic Medicine, University of Eastern Finland, Kuopio, Finland.
52
Imaging Center, Department of Clinical Pathology, Kuopio University Hospital, Kuopio, Finland.
53
Vesalius Research Center, Leuven, Belgium.
54
Laboratory for Translational Genetics, Department of Oncology, University of Leuven, Leuven, Belgium.
55
Multidisciplinary Breast Center, Department of General Medical Oncology, University Hospitals Leuven, Leuven, Belgium.
56
Division of Cancer Epidemiology, German Cancer Research Center, Heidelberg, Germany.
57
University Cancer Center Hamburg (UCCH), University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
58
IFOM, Fondazione Istituto FIRC di Oncologia Molecolare, Milan, Italy.
59
Unit of Molecular Basis of Genetic Risk and Genetic Testing, Department of Preventive and Predictive Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
60
Department of Health Sciences Research, Mayo Clinic, Rochester, Minnesota, USA.
61
Cancer Epidemiology Centre, Cancer Council Victoria, Melbourne, Victoria, Australia.
62
Department of Medicine, McGill University, Montreal, Quebec, Canada.
63
Division of Clinical Epidemiology, Royal Victoria Hospital, McGill University, Montreal, Quebec, Canada.
64
Cancer Research Initiatives Foundation, Sime Darby Medical Centre, Subang Jaya, Malaysia.
65
Breast Cancer Research Unit, University Malaya Cancer Research Institute, University Malaya Medical Centre, Kuala Lumpur, Malaysia.
66
Department of Genetics, Institute for Cancer Research, Oslo University Hospital, Radiumhospitalet, Oslo, Norway.
67
Institute of Clinical Medicine, University of Oslo, Oslo, Norway.
68
Department of Clinical Molecular Biology, Oslo University Hospital, University of Oslo, Oslo, Norway.
69
Division of Epidemiology, Department of Medicine, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, Tennessee, USA.
70
Laboratory of Cancer Genetics and Tumor Biology, Department of Clinical Chemistry and Biocenter Oulu, University of Oulu, NordLab Oulu University Hospital, Oulu, Finland.
71
Laboratory of Cancer Genetics and Tumor Biology, Northern Finland Laboratory Centre NordLab, Oulu, Finland.
72
Lunenfeld-Tanenbaum Research Institute of Mount Sinai Hospital, Toronto, Ontario, Canada.
73
Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada.
74
Prosserman Centre for Health Research, Lunenfeld-Tanenbaum Research Institute of Mount Sinai Hospital, Toronto, Ontario, Canada.
75
Division of Epidemiology, Dalla Lana School of Public Health, University of Toronto, Toronto, Ontario, Canada.
76
Department of Pathology, Leiden University Medical Center, Leiden, the Netherlands.
77
Department of Human Genetics, Leiden University Medical Center, Leiden, the Netherlands.
78
Department of Medical Oncology, Erasmus University Medical Center, Rotterdam, the Netherlands.
79
Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, Maryland, USA.
80
Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
81
Department of Clinical Genetics, Erasmus University Medical Center, Rotterdam, the Netherlands.
82
Department of Epidemiology, Shanghai Cancer Institute, Shanghai, China.
83
Sheffield Cancer Research, Department of Oncology, University of Sheffield, Sheffield, UK.
84
Academic Unit of Pathology, Department of Neuroscience, University of Sheffield, Sheffield, UK.
85
International Epidemiology Institute, Rockville, Maryland, USA.
86
Department of Preventive Medicine, Seoul National University College of Medicine, Seoul, Korea.
87
Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, Korea.
88
Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea.
89
Department of Haematology-Oncology, National University Health System, Singapore.
90
Cancer Science Institute of Singapore, National University of Singapore, Singapore.
91
Saw Swee Hock School of Public Health, National University of Singapore, Singapore.
92
Department of Surgery, National University Health System, Singapore.
93
Institute of Human Genetics, Pontificia Universidad Javerianar, Bogota, Colombia.
94
Department of Genetics and Pathology, Pomeranian Medical University, Szczecin, Poland.
95
International Agency for Research on Cancer, Lyon, France.
96
National Cancer Institute, Bangkok, Thailand.
97
Roswell Park Cancer Institute, Buffalo, New York, USA.
98
Department of Molecular Virology, Immunology and Medical Genetics, Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio, USA.
99
School of Public Health, China Medical University, Taichung, Taiwan.
100
Taiwan Biobank, Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan.
101
Division of Cancer Studies, Breakthrough Breast Cancer Research Centre, Institute of Cancer Research, London, UK.
102
Division of Genetics and Epidemiology, Institute of Cancer Research, London, UK.
103
Division of Breast Cancer Research, Institute of Cancer Research, London, UK.
104
Centre for Epidemiology and Biostatistics, University of Melbourne, Melbourne, Victoria, Australia.
105
Department of Epidemiology, Cancer Prevention Institute of California, Fremont, California, USA.
106
Department of Epidemiology, Mailman School of Public Health, Columbia University, New York, New York, USA.
107
Department of Clinical Genetics, Fox Chase Cancer Center, Philadelphia, Pennsylvania, USA.
108
Department of Dermatology, Huntsman Cancer Institute, University of Utah School of Medicine, Salt Lake City, Utah, USA.
109
Department of Medicine, Huntsman Cancer Institute, University of Utah School of Medicine, Salt Lake City, Utah, USA.
110
State Research Institute Centre for Innovative Medicine, Vilnius, Lithuania.
111
Latvian Biomedical Research and Study Centre, Riga, Latvia.
112
Department of Medical Oncology, Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA.
113
Department of Genetics, University of Pretoria, Pretoria, South Africa.
114
Department of Population Sciences, Beckman Research Institute of City of Hope, Duarte, California, USA.
115
Department of Oncology, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark.
116
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark.
117
Human Genetics Group, Spanish National Cancer Centre (CNIO), Madrid, Spain.
118
Biomedical Network on Rare Diseases (CIBERER), Madrid, Spain.
119
Human Genotyping (CEGEN) Unit, Human Cancer Genetics Program, Spanish National Cancer Research Centre (CNIO), Madrid, Spain.
120
City of Hope Clinical Cancer Genomics Community Research Network, Duarte, California, USA.
121
Clinical Cancer Genetics, City of Hope, Duarte, California, USA.
122
Division of Cancer Prevention and Genetics, Istituto Europeo di Oncologia, Milan, Italy.
123
Unit of Medical Genetics, Department of Preventive and Predictive Medicine, Fondazione Istituto di Ricovero e Cura a Carattere Scientifico, Istituto Nazionale Tumori, Milan, Italy.
124
Unit of Medical Genetics, Department of Biomedical, Experimental and Clinical Sciences, University of Florence, Florence, Italy.
125
Department of Molecular Medicine, University La Sapienza, Rome, Italy.
126
Molecular Diagnostics Laboratory, INRASTES (Institute of Nuclear and Radiological Sciences and Technology), National Centre for Scientific Research 'Demokritos', Aghia Paraskevi Attikis, Athens, Greece.
127
Cancer Risk and Prevention Clinic, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.
128
Department of Basic Sciences, Shaukat Khanum Memorial Cancer Hospital and Research Centre, Lahore, Pakistan.
129
Clinical Genetics, Guy's and St. Thomas' National Health Service (NHS) Foundation Trust, London, UK.
130
Department of Pathology and Laboratory Medicine, University of Kansas Medical Center, Kansas City, Kansas, USA.
131
Department of Gynaecology and Obstetrics, University Hospital of Schleswig-Holstein, Campus Kiel, Christian Albrechts University Kiel, Kiel, Germany.
132
University Düsseldorf, Dusseldorf, Germany.
133
Centre of Familial Breast and Ovarian Cancer, Department of Gynaecology and Obstetrics and Centre for Integrated Oncology, Center for Molecular Medicine Cologne, University Hospital of Cologne, Cologne, Germany.
134
Institute of Human Genetics, Münster, Germany.
135
INSERM U1052, CNRS UMR 5286, Université Lyon, Centre de Recherche en Cancérologie de Lyon, Lyon, France.
136
Institut Curie, Department of Tumour Biology, Paris, France.
137
Université Paris Descartes, Sorbonne Paris Cité, Paris, France.
138
Unité Mixte de Génétique Constitutionnelle des Cancers Fréquents, Hospices Civils de Lyon-Centre Léon Bérard, Lyon, France.
139
Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC, USA.
140
Center for Medical Genetics, Ghent University, Ghent, Belgium.
141
Molecular Oncology Laboratory, Hospital Clinico San Carlos, IdISSC (El Instituto de Investigación Sanitaria del Hospital Clínico San Carlos), Madrid, Spain.
142
Department of Obstetrics and Gynecology, University of Helsinki and Helsinki University Central Hospital, Helsinki, Finland.
143
Department of Human Genetics, Radboud University Nijmegen Medical Centre, Nijmegen, the Netherlands.
144
Department of Medical Oncology, Family Cancer Clinic, Erasmus University Medical Center, Rotterdam, the Netherlands.
145
Department of Epidemiology, Netherlands Cancer Institute, Amsterdam, the Netherlands.
146
Hong Kong Hereditary Breast Cancer Family Registry, Cancer Genetics Center, Hong Kong Sanatorium and Hospital, Hong Kong.
147
Department of Surgery, University of Hong Kong, Hong Kong.
148
Department of Molecular Genetics, National Institute of Oncology, Budapest, Hungary.
149
Oncogenetics Laboratory, Vall d'Hebron Institute of Oncology (VHIO), Vall d'Hebron University Hospital, Barcelona, Spain.
150
Genetic Counseling Unit, Hereditary Cancer Program, IDIBGI (Institut d'Investigació Biomèdica de Girona), Catalan Institute of Oncology, Girona, Spain.
151
Breast Cancer and Systems Biology Unit, IDIBELL (Bellvitge Biomedical Research Institute), Catalan Institute of Oncology, Barcelona, Spain.
152
Department of Pathology, Landspitali University Hospital and Biomedical Centre (BMC), Faculty of Medicine, University of Iceland, Reykjavik, Iceland.
153
Medical Genetic Division, Centre Hospitalier Universitaire de Québec and Laval University, Quebec City, Quebec, Canada.
154
Centre Hospitalier Universitaire de Québec and Laval University, Quebec City, Quebec, Canada.
155
Immunology and Molecular Oncology Unit, Istituto Oncologico Veneto (IOV), IRCCS (Istituto di Ricovero e Cura a Carattere Scientifico), Padua, Italy.
156
Department of Genetics, Portuguese Oncology Institute, Porto, Portugal.
157
Biomedical Sciences Institute (ICBAS), Porto University, Porto, Portugal.
158
Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota, USA.
159
Program in Cancer Genetics, McGill University, Montreal, Quebec, Canada.
160
Masaryk Memorial Cancer Institute and Medical Faculty, Masaryk University, Brno, Czech Republic.
161
Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
162
Department of Obstetrics and Gynecology, Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria.
163
Department of Cancer Epidemiology, Moffitt Cancer Center, Tampa, Florida, USA.
164
Clinical Genetics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, US National Institutes of Health, Rockville, Maryland, USA.
165
Department of Community Medicine and Epidemiology, Carmel Medical Center and B. Rappaport Faculty of Medicine, Haifa, Israel.
166
Clalit National Israeli Cancer Control Center, Haifa, Israel.
167
N.N. Petrov Institute of Oncology, St. Petersburg, Russia.
168
Center for Medical Genetics, NorthShore University Health System, Evanston, Illinois, USA.
169
Division of Cancer Medicine, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia.
170
NRG Oncology, Statistics and Data Management Center, Roswell Park Cancer Institute, Buffalo, New York, USA.
171
Laboratory Medicine Program, University Health Network, Toronto, Ontario, Canada.
172
Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada.
173
Department of Clinical Genetics, Vejle Hospital, Vejle, Denmark.
174
Department of Clinical Genetics, Odense University Hospital, Odense, Denmark.
175
Section of Genetic Oncology, Department of Laboratory Medicine, University of Pisa and University Hospital of Pisa, Pisa, Italy.
176
University Malaya Cancer Research Institute, Faculty of Medicine, University Malaya Medical Centre, University Malaya, Kuala Lumpur, Malaysia.
177
Susanne Levy Gertner Oncogenetics Unit, Sheba Medical Center, Tel-Hashomer, Israel.
178
Department of Oncology, Lund University, Lund, Sweden.
179
Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden.
180
Department of Clinical Genetics, Lund University Hospital, Lund, Sweden.
181
Department of Clinical Genetics, Karolinska University Hospital, Stockholm, Sweden.
182
Center for Clinical Cancer Genetics and Global Health, University of Chicago Medical Center, Chicago, Illinois, USA.
183
Division of Cancer Prevention and Control Research, Jonsson Comprehensive Cancer Center, University of California Los Angeles School of Medicine and School of Public Health, Los Angeles, California, USA.
184
Department of Medicine and Genetics, University of California, San Francisco, San Francisco, California, USA.
185
Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
186
University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
187
Familial Cancer Centre, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia.
188
Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, Victoria, Australia.
189
Women's Cancer Program at the Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA.
190
University of Hawaii Cancer Center, Honolulu, Hawaii, USA.
191
Department of Obstetrics, Gynaecology and Pediatrics, Dalhousie University, Halifax, Nova Scotia, Canada.
192
Centre for Genetic Origins of Health and Disease, University of Western Australia, Perth, Western Australia, Australia.
193
Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA.
194
Department of Epidemiology, Harvard School of Public Health, Boston, Massachusetts, USA.
195
Program in Genetic Epidemiology and Statistical Genetics, Harvard School of Public Health, Boston, Massachusetts, USA.
196
Clinical Gerontology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.

Abstract

We analyzed 3,872 common genetic variants across the ESR1 locus (encoding estrogen receptor α) in 118,816 subjects from three international consortia. We found evidence for at least five independent causal variants, each associated with different phenotype sets, including estrogen receptor (ER(+) or ER(-)) and human ERBB2 (HER2(+) or HER2(-)) tumor subtypes, mammographic density and tumor grade. The best candidate causal variants for ER(-) tumors lie in four separate enhancer elements, and their risk alleles reduce expression of ESR1, RMND1 and CCDC170, whereas the risk alleles of the strongest candidates for the remaining independent causal variant disrupt a silencer element and putatively increase ESR1 and RMND1 expression.

PMID:
26928228
PMCID:
PMC4938803
DOI:
10.1038/ng.3521
[Indexed for MEDLINE]
Free PMC Article

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