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Sci Rep. 2016 Sep 7;6:32512. doi: 10.1038/srep32512.

Fine scale mapping of the 17q22 breast cancer locus using dense SNPs, genotyped within the Collaborative Oncological Gene-Environment Study (COGs).

Darabi H1, Beesley J2, Droit A3, Kar S4, Nord S5, Moradi Marjaneh M2, Soucy P6, Michailidou K7,8, Ghoussaini M4, Fues Wahl H1, Bolla MK7, Wang Q7, Dennis J7, Alonso MR9, Andrulis IL10,11, Anton-Culver H12, Arndt V13, Beckmann MW14, Benitez J15,16, Bogdanova NV17, Bojesen SE18,19,20, Brauch H21,22,23, Brenner H13,23,24, Broeks A25, Brüning T26, Burwinkel B27,28, Chang-Claude J29,30, Choi JY31,32, Conroy DM4, Couch FJ33, Cox A34, Cross SS35, Czene K1, Devilee P36,37, Dörk T38, Easton DF4,7, Fasching PA14,39, Figueroa J40,41, Fletcher O42,43, Flyger H44, Galle E45,46, García-Closas M41, Giles GG47,48, Goldberg MS49,50, González-Neira A15, Guénel P51, Haiman CA52, Hallberg E53, Hamann U54, Hartman M55,56, Hollestelle A57, Hopper JL48, Ito H58, Jakubowska A59, Johnson N42,43, Kang D31,32,60, Khan S61, Kosma VM62,63,64, Kriege M57, Kristensen V5,65,66, Lambrechts D45,46, Le Marchand L67, Lee SC68,69, Lindblom A70, Lophatananon A71, Lubinski J59, Mannermaa A62,63,64, Manoukian S72, Margolin S73, Matsuo K74, Mayes R4, McKay J75, Meindl A76, Milne RL47,48, Muir K71,77, Neuhausen SL78, Nevanlinna H61, Olswold C53, Orr N42, Peterlongo P79, Pita G9, Pylkäs K80,81, Rudolph A29, Sangrajrang S82, Sawyer EJ83, Schmidt MK25, Schmutzler RK84,85,86, Seynaeve C57, Shah M4, Shen CY87,88, Shu XO89, Southey MC90, Stram DO52, Surowy H27,28, Swerdlow A43,91, Teo SH92,93, Tessier DC94, Tomlinson I95, Torres D54,96, Truong T51, Vachon CM53, Vincent D94, Winqvist R80,81, Wu AH52, Wu PE88, Yip CH93, Zheng W89, Pharoah PD4,7, Hall P1, Edwards SL2, Simard J6, French JD2, Chenevix-Trench G2, Dunning AM4.

Author information

1
Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
2
Department of Genetics, QIMR Berghofer Medical Research Institute, Brisbane, Australia.
3
Département de Médecine Moléculaire, Faculté de Médecine, Centre Hospitalier Universitaire de Québec Research Center, Laval University, Québec City, Canada.
4
Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Cambridge, UK.
5
Department of Cancer Genetics, Institute for Cancer Research, Oslo University Hospital Radiumhospitalet, Oslo, Norway.
6
Genomics Center, Centre Hospitalier Universitaire de Québec Research Center, Laval University, Québec City, Canada.
7
Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.
8
Department of Electron Microscopy/Molecular Pathology, The Cyprus Institute of Neurology and Genetics, Nicosia, Cyprus.
9
Human Genotyping-CEGEN Unit, Human Cancer Genetic Program, Spanish National Cancer Research Centre, Madrid, Spain.
10
Lunenfeld-Tanenbaum Research Institute of Mount Sinai Hospital, Toronto, Canada.
11
Department of Molecular Genetics, University of Toronto, Toronto, Canada.
12
Department of Epidemiology, University of California Irvine, Irvine, CA, USA.
13
Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany.
14
Department of Gynaecology and Obstetrics, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nuremberg, Comprehensive Cancer Center Erlangen-EMN, Erlangen, Germany.
15
Human Cancer Genetics Program, Spanish National Cancer Research Centre, Madrid, Spain.
16
Centro de Investigación en Red de Enfermedades Raras, Valencia, Spain.
17
Department of Radiation Oncology, Hannover Medical School, Hannover, Germany.
18
Copenhagen General Population Study, Herlev and Gentofte Hospital, Copenhagen University Hospital, Herlev, Denmark.
19
Department of Clinical Biochemistry, Herlev and Gentofte Hospital, Copenhagen University Hospital, Herlev, Denmark.
20
Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
21
Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology, Stuttgart, Germany.
22
University of Tübingen, Tübingen, Germany.
23
German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany.
24
Division of Preventive Oncology, German Cancer Research Center (DKFZ) and National Center for Tumor Diseases (NCT), Heidelberg, Germany.
25
Netherlands Cancer Institute, Antoni van Leeuwenhoek hospital, Amsterdam, The Netherlands.
26
Institute for Prevention and Occupational Medicine of the German Social Accident Insurance, Institute of the Ruhr University Bochum, Bochum, Germany.
27
Department of Obstetrics and Gynecology, University of Heidelberg, Heidelberg, Germany.
28
Molecular Epidemiology Group, German Cancer Research Center (DKFZ), Heidelberg, Germany.
29
Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
30
University Cancer Center Hamburg (UCCH), University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
31
Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, Korea.
32
Cancer Research Institute, Seoul National University, Seoul, Korea.
33
Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA.
34
Sheffield Cancer Research, Department of Oncology and Metabolism, University of Sheffield, Sheffield, UK.
35
Academic Unit of Pathology, Department of Neuroscience, University of Sheffield, Sheffield, UK.
36
Department of Pathology, Leiden University Medical Center, Leiden, The Netherlands.
37
Department of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands.
38
Gynaecology Research Unit, Hannover Medical School, Hannover, Germany.
39
David Geffen School of Medicine, Department of Medicine Division of Hematology and Oncology, University of California at Los Angeles, Los Angeles, CA, USA.
40
Usher Institute of Population Health Sciences and Informatics, The University of Edinburgh Medical School, Edinburgh, UK.
41
Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD, USA.
42
Breakthrough Breast Cancer Research Centre, The Institute of Cancer Research, London, UK.
43
Division of Breast Cancer Research, The Institute of Cancer Research, London, UK.
44
Department of Breast Surgery, Herlev and Gentofte Hospital, Copenhagen University Hospital, Herlev, Denmark.
45
Vesalius Research Center, Leuven, Belgium.
46
Laboratory for Translational Genetics, Department of Oncology, University of Leuven, Leuven, Belgium.
47
Cancer Epidemiology Centre, Cancer Council Victoria, Melbourne, Australia.
48
Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global health, The University of Melbourne, Melbourne, Australia.
49
Department of Medicine, McGill University, Montreal, Canada.
50
Division of Clinical Epidemiology, Royal Victoria Hospital, McGill University, Montreal, Canada.
51
Cancer &Environment Group, Center for Research in Epidemiology and Population Health (CESP), INSERM, University Paris-Sud, University Paris-Saclay, Villejuif, France.
52
Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
53
Department of Health Sciences Research, Mayo Clinic, Rochester, MN, USA.
54
Molecular Genetics of Breast Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany.
55
Saw Swee Hock School of Public Health, National University of Singapore, Singapore, Singapore.
56
Department of Surgery, National University Health System, Singapore, Singapore.
57
Department of Medical Oncology, Family Cancer Clinic, Erasmus MC Cancer Institute, Rotterdam, The Netherlands.
58
Division of Epidemiology and Prevention, Aichi Cancer Center Research Institute, Nagoya, Japan.
59
Department of Genetics and Pathology, Pomeranian Medical University, Szczecin, Poland.
60
Department of Preventive Medicine, Seoul National University College of Medicine, Seoul, Korea.
61
Department of Obstetrics and Gynecology, Helsinki University Hospital, University of Helsinki, Helsinki, Finland.
62
Cancer Center of Eastern Finland, University of Eastern Finland, Kuopio, Finland.
63
Institute of Clinical Medicine, Pathology and Forensic Medicine, University of Eastern Finland, Kuopio, Finland.
64
Imaging Center, Department of Clinical Pathology, Kuopio University Hospital, Kuopio, Finland.
65
K.G. Jebsen Center for Breast Cancer Research, Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway.
66
Department of Clinical Molecular Biology, Oslo University Hospital, University of Oslo, Oslo, Norway.
67
University of Hawaii Cancer Center, Honolulu, HI, USA.
68
Department of Hematology-Oncology, National University Health System, Singapore, Singapore.
69
Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore.
70
Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.
71
Division of Health Sciences, Warwick Medical School, Warwick University, Coventry, UK.
72
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), Milan, Italy.
73
Department of Oncology - Pathology, Karolinska Institutet, Stockholm, Sweden.
74
Division of Molecular Medicine, Aichi Cancer Center Research Institute, Nagoya, Japan.
75
International Agency for Research on Cancer, Lyon, France.
76
Division of Gynaecology and Obstetrics, Technische Universität München, Munich, Germany.
77
Institute of Population Health, University of Manchester, Manchester, UK.
78
Department of Population Sciences, Beckman Research Institute of City of Hope, Duarte, CA, USA.
79
IFOM, The FIRC (Italian Foundation for Cancer Research) Institute of Molecular Oncology, Milan, Italy.
80
Laboratory of Cancer Genetics and Tumor Biology, Cancer and Translational Medicine Research Unit, Biocenter Oulu, University of Oulu, Oulu, Finland.
81
Laboratory of Cancer Genetics and Tumor Biology, Northern Finland Laboratory Centre Oulu, Oulu, Finland.
82
National Cancer Institute, Bangkok, Thailand.
83
Research Oncology, Guy's Hospital, King's College London, London, UK.
84
Center for Hereditary Breast and Ovarian Cancer, University Hospital of Cologne, Cologne, Germany.
85
Center for Integrated Oncology (CIO), University Hospital of Cologne, Cologne, Germany.
86
Center for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany.
87
Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan.
88
Taiwan Biobank, Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan.
89
Division of Epidemiology, Department of Medicine, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, TN, USA.
90
Department of Pathology, The University of Melbourne, Melbourne, Australia.
91
Division of Genetics and Epidemiology, The Institute of Cancer Research, London, UK.
92
Cancer Research Initiatives Foundation, Subang Jaya, Selangor, Malaysia.
93
Breast Cancer Research Unit, Cancer Research Institute, University Malaya Medical Centre, Kuala Lumpur, Malaysia.
94
McGill University and Génome Québec Innovation Centre, Montréal, Canada.
95
Wellcome Trust Centre for Human Genetics and Oxford NIHR Biomedical Research Centre, University of Oxford, Oxford, UK.
96
Institute of Human Genetics, Pontificia Universidad Javeriana, Bogota, Colombia.

Abstract

Genome-wide association studies have found SNPs at 17q22 to be associated with breast cancer risk. To identify potential causal variants related to breast cancer risk, we performed a high resolution fine-mapping analysis that involved genotyping 517 SNPs using a custom Illumina iSelect array (iCOGS) followed by imputation of genotypes for 3,134 SNPs in more than 89,000 participants of European ancestry from the Breast Cancer Association Consortium (BCAC). We identified 28 highly correlated common variants, in a 53 Kb region spanning two introns of the STXBP4 gene, that are strong candidates for driving breast cancer risk (lead SNP rs2787486 (OR = 0.92; CI 0.90-0.94; P = 8.96 × 10(-15))) and are correlated with two previously reported risk-associated variants at this locus, SNPs rs6504950 (OR = 0.94, P = 2.04 × 10(-09), r(2) = 0.73 with lead SNP) and rs1156287 (OR = 0.93, P = 3.41 × 10(-11), r(2) = 0.83 with lead SNP). Analyses indicate only one causal SNP in the region and several enhancer elements targeting STXBP4 are located within the 53 kb association signal. Expression studies in breast tumor tissues found SNP rs2787486 to be associated with increased STXBP4 expression, suggesting this may be a target gene of this locus.

PMID:
27600471
PMCID:
PMC5013272
DOI:
10.1038/srep32512
[Indexed for MEDLINE]
Free PMC Article

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