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Breast Cancer Res. 2016 Jun 21;18(1):64. doi: 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 X1, Long J1, Kuchenbaecker KB2, Droit A3, Michailidou K2, Ghoussaini M4, Kar S4, Freeman A5, Hopper JL6, Milne RL6,7, Bolla MK2, Wang Q2, Dennis J2, Agata S8, Ahmed S9, Aittomäki K10, Andrulis IL11,12, Anton-Culver H13, Antonenkova NN14, Arason A15, Arndt V16, Arun BK17, Arver B18, Bacot F19, Barrowdale D2, Baynes C9, Beeghly-Fadiel A1, Benitez J20,21, Bermisheva M22, Blomqvist C23, Blot WJ1,24, Bogdanova NV25, Bojesen SE26,27,28, Bonanni B29, Borresen-Dale AL30,31, Brand JS32, Brauch H33,34,35, Brennan P36, Brenner H16,35,37, Broeks A38, Brüning T39, Burwinkel B40,41, Buys SS42, Cai Q1, Caldes T43, Campbell I44, Carpenter J45, Chang-Claude J46,47, Choi JY48,49,50, Claes KB51, Clarke C52, Cox A53, Cross SS54, Czene K32, Daly MB55, de la Hoya M43, De Leeneer K51, Devilee P56,57, Diez O58, Domchek SM59, Doody M60, Dorfling CM61, Dörk T62, Dos-Santos-Silva I63, Dumont M64, Dwek M65, Dworniczak B66, Egan K67, Eilber U46, Einbeigi Z68, Ejlertsen B69, Ellis S2, Frost D2, Lalloo F70; EMBRACE, Fasching PA71,72, Figueroa J60, Flyger H73, Friedlander M74, Friedman E75, Gambino G76, Gao YT77, Garber J78, García-Closas M60,79, Gehrig A80, Damiola F81, Lesueur F82, Mazoyer S81, Stoppa-Lyonnet D83,84,85; behalf of GEMO Study Collaborators, Giles GG6,7, Godwin AK86, Goldgar DE87, González-Neira A20, Greene MH88, Guénel P89,90, Haeberle L71, Haiman CA91, Hallberg E92, Hamann U93, Hansen TV94, Hart S92, Hartikainen JM95,96,97, Hartman M98,99, Hassan N100,101, Healey S102, Hogervorst FB103, Verhoef S103; HEBON, Hendricks CB104,105, Hillemanns P62, Hollestelle A106, Hulick PJ107, Hunter DJ108,109, Imyanitov EN110, Isaacs C111, Ito H112, Jakubowska A113, Janavicius R114, Jaworska-Bieniek K113, Jensen UB115, John EM116,117,118, Joly Beauparlant C119, Jones M79, Kabisch M93, Kang D48,49,50, Karlan BY120, Kauppila S121, Kerin MJ122, Khan S123, Khusnutdinova E22,124, Knight JA125,126, Konstantopoulou I127, Kraft P108,109, Kwong A128,129, Laitman Y75, Lambrechts D130,131, Lazaro C132, Le Marchand L133, Lee CN98, Lee MH134, Lester J120, Li J32, Liljegren A18, Lindblom A135, Lophatananon A136, Lubinski J113, Mai PL88, Mannermaa A95,96,97, Manoukian S137, Margolin S138, Marme F40,139, Matsuo K140, McGuffog L2, Meindl A141, Menegaux F89,90, Montagna M8, Muir K136,142, Mulligan AM143,144, Nathanson KL59, Neuhausen SL145, Nevanlinna H123, Newcomb PA146,147, Nord S30, Nussbaum RL148, Offit K149,150, Olah E151, Olopade OI152, Olswold C92, Osorio A153,154, Papi L155, Park-Simon TW62, Paulsson-Karlsson Y156, Peeters S157, Peissel B158, Peterlongo P159, Peto J63, Pfeiler G160, Phelan CM161, Presneau N65, Radice P162, Rahman N163, Ramus SJ164, Rashid MU93,165, Rennert G166, Rhiem K167, Rudolph A46, Salani R168, Sangrajrang S169, Sawyer EJ170, Schmidt MK38, Schmutzler RK171,172,173,174, Schoemaker MJ79, Schürmann P62, Seynaeve C106, Shen CY175,176, Shrubsole MJ1, Shu XO1, Sigurdson A60, Singer CF177, Slager S92, Soucy P178, Southey M179, Steinemann D180, Swerdlow A79,181, Szabo CI182, Tchatchou S183, Teixeira MR184,185, Teo SH100,101, Terry MB186, Tessier DC19, Teulé A187, Thomassen M188, Tihomirova L189, Tischkowitz M190,191, Toland AE192, Tung N193, Turnbull C163, van den Ouweland AM194, van Rensburg EJ61, Ven den Berg D91, Vijai J149,150, Wang-Gohrke S195, Weitzel JN196, Whittemore AS117,118, Winqvist R197,198, Wong TY199, Wu AH91, Yannoukakos D200, Yu JC201, Pharoah PD2,9, Hall P32, Chenevix-Trench G202,203; KConFab; AOCS Investigators, Dunning AM9, Simard J64, Couch FJ204, Antoniou AC2, Easton DF2,9, Zheng W205.

Author information

1
Division 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.
2
Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.
3
Proteomics Center, CHU de Québec Research Center and Department of Molecular Medicine, Laval University, Quebec, Canada.
4
Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Cambridge, CB1 8RN, UK.
5
Department of Surgery, St Vincent's Hospital, Melbourne, VIC, Australia.
6
Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global health, The University of Melbourne, Melbourne, Australia.
7
Cancer Epidemiology Centre, Cancer Council Victoria, Melbourne, Australia.
8
Immunology and Molecular Oncology Unit, Istituto Oncologico Veneto IOV - IRCCS (Istituto Di Ricovero e Cura a Carattere Scientifico), Padua, Italy.
9
Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Cambridge, UK.
10
Department of Clinical Genetics, Helsinki University Hospital, University of Helsinki, Helsinki, Finland.
11
Lunenfeld-Tanenbaum Research Institute of Mount Sinai Hospital, Toronto, Canada.
12
Department of Molecular Genetics, University of Toronto, Toronto, Canada.
13
Department of Epidemiology, University of California Irvine, Irvine, CA, USA.
14
N.N. Alexandrov Research Institute of Oncology and Medical Radiology, Minsk, Belarus.
15
Department of Pathology, Landspitali University Hospital and BMC (Biomedical Centre), Faculty of Medicine, University of Iceland, Reykjavik, Iceland.
16
Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany.
17
University of Texas MD Anderson Cancer Center, Houston, TX, USA.
18
Department of Oncology, Karolinska University Hospital, Stockholm, Sweden.
19
McGill University and Génome Québec Innovation Centre, Montréal, Canada.
20
Human Cancer Genetics Program, Spanish National Cancer Research Centre, Madrid, Spain.
21
Centro de Investigación en Red de Enfermedades Raras, Valencia, Spain.
22
Institute of Biochemistry and Genetics, Ufa Scientific Center of Russian Academy of Sciences, Ufa, Russia.
23
Department of Oncology, Helsinki University Hospital, University of Helsinki, Helsinki, Finland.
24
International Epidemiology Institute, Rockville, MD, USA.
25
Department of Radiation Oncology, Hannover Medical School, Hannover, Germany.
26
Copenhagen General Population Study, Herlev Hospital, Copenhagen University Hospital, Herlev, Denmark.
27
Department of Clinical Biochemistry, Herlev Hospital, Copenhagen University Hospital, Herlev, Denmark.
28
Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
29
Division of Cancer Prevention and Genetics, Istituto Europeo di Oncologia, Milan, Italy.
30
Department of Genetics, Institute for Cancer Research, Oslo University Hospital Radiumhospitalet, Oslo, Norway.
31
K.G. Jebsen Center for Breast Cancer Research, Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway.
32
Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
33
Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology, Stuttgart, Germany.
34
University of Tübingen, Tübingen, Germany.
35
German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany.
36
International Agency for Research on Cancer, Lyon, France.
37
Division of Preventive Oncology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
38
Netherlands Cancer Institute, Antoni van Leeuwenhoek Hospital, Amsterdam, The Netherlands.
39
Institute for Prevention and Occupational Medicine of the German Social Accident Insurance, Institute of the Ruhr University Bochum, Bochum, Germany.
40
Department of Obstetrics and Gynecology, University of Heidelberg, Heidelberg, Germany.
41
Molecular Epidemiology Group, German Cancer Research Center (DKFZ), Heidelberg, Germany.
42
Department of Medicine, Huntsman Cancer Institute, University of Utah School of Medicine, Salt Lake City, UT, USA.
43
Molecular Oncology Laboratory, Hospital Clinico San Carlos, IdISSC (El Instituto de Investigación Sanitaria del Hospital Clínico San Carlos), Madrid, Spain.
44
Cancer Genetics Laboratory, Peter MacCallum Cancer Centre, Melbourne, Australia.
45
Australian Breast Cancer Tissue Bank, Westmead Millennium Institute, University of Sydney, Sydney, Australia.
46
Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
47
University Cancer Center Hamburg (UCCH), University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
48
Department of Preventive Medicine, Seoul National University College of Medicine, Seoul, South Korea.
49
Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, South Korea.
50
Cancer Research Institute, Seoul National University, Seoul, South Korea.
51
Center for Medical Genetics, Ghent University, Ghent, Belgium.
52
Westmead Millenium Institute for Medical Research, University of Sydney, Sydney, Australia.
53
Sheffield Cancer Research, Department of Oncology, University of Sheffield, Sheffield, UK.
54
Academic Unit of Pathology, Department of Neuroscience, University of Sheffield, Sheffield, UK.
55
Department of Clinical Genetics, Fox Chase Cancer Center, Philadelphia, PA, USA.
56
Department of Pathology, Leiden University Medical Center, Leiden, The Netherlands.
57
Department of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands.
58
Oncogenetics Group, University Hospital Vall d'Hebron, Vall d'Hebron Institute of Oncology (VHIO) and Universitat Autònoma de Barcelona, Barcelona, Spain.
59
Department of Medicine, Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
60
Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD, USA.
61
Department of Genetics, University of Pretoria, Pretoria, South Africa.
62
Clinics of Obstetrics and Gynaecology, Hannover Medical School, Hannover, Germany.
63
Department of Non-Communicable Disease Epidemiology, London School of Hygiene and Tropical Medicine, London, UK.
64
Genomics Center, Centre Hospitalier Universitaire de Québec Research Center, Laval University, Québec City, Canada.
65
Department of Biomedical Sciences, Faculty of Science and Technology, University of Westminster, London, UK.
66
Institute of Human Genetics, Muenster, Germany.
67
Division of Population Sciences, Moffitt Cancer Center & Research Institute, Tampa, FL, USA.
68
Department of Oncology, Sahlgrenska University Hospital, Gothenburg, Sweden.
69
Department of Oncology, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark.
70
Genetic Medicine, Manchester Academic Health Sciences Centre, Central Manchester University Hospitals NHS Foundation Trust, Manchester, UK.
71
Department of Gynaecology and Obstetrics, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nuremberg, Comprehensive Cancer Center Erlangen-EMN, Erlangen, Germany.
72
David Geffen School of Medicine, Department of Medicine Division of Hematology and Oncology, University of California at Los Angeles, Los Angeles, CA, USA.
73
Department of Breast Surgery, Herlev Hospital, Copenhagen University Hospital, Herlev, Denmark.
74
ANZ GOTG Coordinating Centre, Australia New Zealand GOG, Camperdown, NSW, Australia.
75
Susanne Levy Gertner Oncogenetics Unit, Sheba Medical Center, Tel-Hashomer, Israel.
76
Section of Genetic Oncology, Deparment of Laboratory Medicine, University and University Hospital of Pisa, Pisa, Italy.
77
Department of Epidemiology, Shanghai Cancer Institute, Shanghai, China.
78
Cancer Risk and Prevention Clinic, Dana-Farber Cancer Institute, Boston, MA, USA.
79
Division of Genetics and Epidemiology, The Institute of Cancer Research, London, UK.
80
Institute of Human Genetics, University Würzburg, Wurzburg, Germany.
81
INSERM U1052, CNRS UMR5286, Université Lyon, Centre de Recherche en Cancérologie de Lyon, Lyon, France.
82
Genetic Epidemiology of Cancer team, Inserm, U900, Institut Curie, Mines ParisTech, 75248, Paris, France.
83
Department of Tumour Biology, Institut Curie, Paris, France.
84
Institut Curie, INSERM U830, Paris, France.
85
Université Paris Descartes, Sorbonne Paris Cité, Paris, France.
86
Department of Pathology and Laboratory Medicine, University of Kansas Medical Center, Kansas City, KS, USA.
87
Department of Dermatology, Huntsman Cancer Institute, University of Utah School of Medicine, Salt Lake City, UT, USA.
88
Clinical Genetics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Rockville, MD, USA.
89
Environmental Epidemiology of Cancer, Center for Research in Epidemiology and Population Health, INSERM, Villejuif, France.
90
University Paris-Sud, Villejuif, France.
91
Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
92
Department of Health Sciences Research, Mayo Clinic, Rochester, MN, USA.
93
Molecular Genetics of Breast Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany.
94
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark.
95
Cancer Center, Kuopio University Hospital, Kuopio, Finland.
96
Institute of Clinical Medicine, Pathology and Forensic Medicine, University of Eastern Finland, Kuopio, Finland.
97
Imaging Center, Department of Clinical Pathology, Kuopio University Hospital, Kuopio, Finland.
98
Saw Swee Hock School of Public Health, National University of Singapore, Singapore, Singapore.
99
Department of Surgery, National University Health System, Singapore, Singapore.
100
Cancer Research Initiatives Foundation, Subang Jaya, Selangor, Malaysia.
101
Breast Cancer Research Unit, Cancer Research Institute, University Malaya Medical Centre, Kuala Lumpur, Malaysia.
102
Cancer Division, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia.
103
Family Cancer Clinic, Netherlands Cancer Institute, Amsterdam, The Netherlands.
104
Suburban Hospital, Bethesda, MD, USA.
105
Care of City of Hope Clinical Cancer Genetics Community Research Network, Duarte, CA, USA.
106
Department of Medical Oncology, Family Cancer Clinic, Erasmus MC Cancer Institute, Rotterdam, The Netherlands.
107
Center for Medical Genetics, NorthShore University HealthSystem, Evanston, IL, USA.
108
Program in Genetic Epidemiology and Statistical Genetics, Harvard School of Public Health, Boston, MA, USA.
109
Department of Epidemiology, Harvard School of Public Health, Boston, MA, USA.
110
N.N. Petrov Institute of Oncology, St. Petersburg, Russia.
111
Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC, USA.
112
Division of Epidemiology and Prevention, Aichi Cancer Center Research Institute, Aichi, Japan.
113
Department of Genetics and Pathology, Pomeranian Medical University, Szczecin, Poland.
114
State Research Institute Centre for Innovative Medicine, Vilnius, Lithuania.
115
Department of Clinical Genetics, Aarhus University Hospital, Aarhus, N, Denmark.
116
Department of Epidemiology, Cancer Prevention Institute of California, Fremont, CA, USA.
117
Department of Health Research and Policy - Epidemiology, Stanford University School of Medicine, Stanford, CA, USA.
118
Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA, USA.
119
Genomics Center, Centre Hospitalier Universitaire de Québec Research Center and Laval University, Quebec City, QC, Canada.
120
Women's Cancer Program at the Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
121
Department of Pathology, Oulu University Hospital, University of Oulu, Oulu, Finland.
122
School of Medicine, National University of Ireland, Galway, Ireland.
123
Department of Obstetrics and Gynecology, Helsinki University Hospital, University of Helsinki, Helsinki, Finland.
124
Department of Genetics and Fundamental Medicine, Bashkir State University, Ufa, Russia.
125
Prosserman Centre for Health Research, Lunenfeld-Tanenbaum Research Institute of Mount Sinai Hospital, Toronto, Canada.
126
Division of Epidemiology, Dalla Lana School of Public Health, University of Toronto, Toronto, Canada.
127
Molecular Diagnostics Laboratory, IRRP, National Centre for Scientific Research "Demokritos", Athens, Greece.
128
The Hong Kong Hereditary Breast Cancer Family Registry, Cancer Genetics Center, Hong Kong Sanatorium and Hospital, Hong Kong, China.
129
Department of Surgery, The University of Hong Kong, Hong Kong, China.
130
Vesalius Research Center, Leuven, Belgium.
131
Laboratory for Translational Genetics, Department of Oncology, University of Leuven, Leuven, Belgium.
132
Molecular Diagnostic Unit, Hereditary Cancer Program, IDIBELL (Bellvitge Biomedical Research Institute), Catalan Institute of Oncology, Barcelona, Spain.
133
University of Hawaii Cancer Center, Honolulu, HI, USA.
134
Department of Surgery, Soonchunhyang University and Hospital, Seoul, South Korea.
135
Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.
136
Division of Health Sciences, Warwick Medical School, Warwick University, Coventry, UK.
137
Unit 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.
138
Department of Oncology - Pathology, Karolinska Institutet, Stockholm, Sweden.
139
National Center for Tumor Diseases, University of Heidelberg, Heidelberg, Germany.
140
Department of Preventive Medicine, Kyushu University Faculty of Medical Sciences, Fukuoka, Japan.
141
Division of Gynaecology and Obstetrics, Technische Universität München, Munich, Germany.
142
Institute of Population Health, University of Manchester, Manchester, UK.
143
Laboratory Medicine Program, University Health Network, Toronto, ON, Canada.
144
Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada.
145
Beckman Research Institute of City of Hope, Duarte, CA, USA.
146
Carbone Cancer Center, University of Wisconsin, Madison, WI, USA.
147
Cancer Prevention Program, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
148
Department of Medicine and Genetics, University of California, San Francisco, San Francisco, CA, USA.
149
Clinical Genetics Research Lab, Department of Cancer Biology and Genetics, Memorial Sloan-Kettering Cancer Center, New York, NY, USA.
150
Clinical Genetics Service, Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY, USA.
151
Department of Molecular Genetics, National Institute of Oncology, Budapest, Hungary.
152
Center for Clinical Cancer Genetics and Global Health, University of Chicago Medical Center, Chicago, IL, USA.
153
Human Genetics Group, Human Cancer Genetics Program, Spanish National Cancer Centre (CNIO), Madrid, Spain.
154
Biomedical Network on Rare Diseases (CIBERER), Madrid, Spain.
155
Unit of Medical Genetics, Department of Biomedical, Experimental and Clinical Sciences, University of Florence, Florence, Italy.
156
Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden.
157
University Hospital Gashuisberg, Leuven, Belgium.
158
Unit 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.
159
IFOM, Fondazione Istituto FIRC (Italian Foundation of Cancer Research) di Oncologia Molecolare, Milan, Italy.
160
Department of Obstetrics and Gynecology, and Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria.
161
Department of Cancer Epidemiology, Moffitt Cancer Center, Tampa, FL, USA.
162
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 Tumori (INT), Milan, Italy.
163
Section of Cancer Genetics, The Institute of Cancer Research, London, UK.
164
Department of Preventive Medicine, Keck School of Medicine, University of Southern California Norris Comprehensive Cancer Center, Los Angeles, CA, USA.
165
Department of Basic Sciences, Shaukat Khanum Memorial Cancer Hospital and Research Centre (SKMCH & RC), Lahore, Pakistan.
166
Clalit National Israeli Cancer Control Center and Department of Community Medicine and Epidemiology, Carmel Medical Center and B. Rappaport Faculty of Medicine, Haifa, Israel.
167
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, Cologne, Germany.
168
Obstetrics and Gynecology, Ohio State University College of Medicine, Columbus, OH, USA.
169
National Cancer Institute, Bangkok, Thailand.
170
Research Oncology, Guy's Hospital, King's College London, London, UK.
171
Division of Molecular Gyneco-Oncology, Department of Gynaecology and Obstetrics, University Hospital of Cologne, Cologne, Germany.
172
Center of Familial Breast and Ovarian Cancer, University Hospital of Cologne, Cologne, Germany.
173
Center for Integrated Oncology, University Hospital of Cologne, Cologne, Germany.
174
Center for Molecular Medicine, University Hospital of Cologne, Cologne, Germany.
175
School of Public Health, China Medical University, Taichung, Taiwan.
176
Taiwan Biobank, Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan.
177
Department of Obstetrics and Gynecology, Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria.
178
Centre Hospitalier Universitaire de Québec Research Center and Laval University, Quebec City, QC, Canada.
179
Genetic Epidemiology Laboratory, Department of Pathology, University of Melbourne, Parkville, VIC, Australia.
180
Hannover Medical School, Hannover, Germany.
181
Division of Breast Cancer Research, The Institute of Cancer Research, London, UK.
182
National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA.
183
Lunenfeld-Tanenbaum Research Institute of Mount Sinai Hospital, Toronto, ON, Canada.
184
Department of Genetics, Portuguese Oncology Institute, Porto, Portugal.
185
Biomedical Sciences Institute (ICBAS), Porto University, Porto, Portugal.
186
Department of Epidemiology, Mailman School of Public Health, Columbia University, New York, NY, USA.
187
Genetic Counseling Unit, Hereditary Cancer Program, IDIBELL (Bellvitge Biomedical Research Institute), Catalan Institute of Oncology, Barcelona, Spain.
188
Department of Clinical Genetics, Odense University Hospital, Odense, C, Denmark.
189
Latvian Biomedical Research and Study Centre, Riga, Latvia.
190
Program in Cancer Genetics, Departments of Human Genetics and Oncology, McGill University, Montreal, QC, Canada.
191
Currently at Medical School Cambridge University, Cambridge, UK.
192
Department of Molecular Virology, Immunology and Medical Genetics, Comprehensive Cancer Center, The Ohio State University, Columbus, OH, USA.
193
Department of Medical Oncology, Beth Israel Deaconess Medical Center, Boston, MA, USA.
194
Department of Clinical Genetics, Erasmus University Medical Center, Rotterdam, The Netherlands.
195
Department of Obstetrics and Gynecology, University of Ulm, Ulm, Germany.
196
Clinical Cancer Genetics, for the City of Hope Clinical Cancer Genetics Community Research Network, Duarte, CA, USA.
197
Laboratory of Cancer Genetics and Tumor Biology, Department of Clinical Chemistry and Biocenter Oulu, University of Oulu, Oulu, Finland.
198
Laboratory of Cancer Genetics and Tumor Biology, Northern Finland Laboratory Centre NordLab, Oulu, Finland.
199
Singapore Eye Research Institute, National University of Singapore, Singapore, Singapore.
200
Department of Medical Oncology, Papageorgiou Hospital, Aristotle University of Thessaloniki School of Medicine, Thessaloniki, Greece.
201
Department of Surgery, National Taiwan University Hospital, Taipei, Taiwan.
202
Department of Genetics, QIMR Berghofer Medical Research Institute, Brisbane, Australia.
203
Peter MacCallum Cancer Center, The University of Melbourne, Melbourne, Australia.
204
Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA.
205
Division 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

PMID:
27459855
PMCID:
PMC4962376
DOI:
10.1186/s13058-016-0718-0
[Indexed for MEDLINE]
Free PMC Article

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