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Am J Hum Genet. 2015 Jul 2;97(1):22-34. doi: 10.1016/j.ajhg.2015.05.002. Epub 2015 Jun 11.

Polymorphisms in a Putative Enhancer at the 10q21.2 Breast Cancer Risk Locus Regulate NRBF2 Expression.

Darabi H1, McCue K2, Beesley J2, Michailidou K3, Nord S4, Kar S5, Humphreys K1, Thompson D3, Ghoussaini M5, Bolla MK3, Dennis J3, Wang Q3, Canisius S6, Scott CG7, Apicella C8, Hopper JL8, Southey MC9, Stone J10, Broeks A6, Schmidt MK6, Scott RJ11, Lophatananon A12, Muir K13, Beckmann MW14, Ekici AB15, Fasching PA16, Heusinger K14, Dos-Santos-Silva I17, Peto J17, Tomlinson I18, Sawyer EJ19, Burwinkel B20, Marme F21, Guénel P22, Truong T22, Bojesen SE23, Flyger H24, Benitez J25, González-Neira A26, Anton-Culver H27, Neuhausen SL28, Arndt V29, Brenner H30, Engel C31, Meindl A32, Schmutzler RK33; German Consortium of Hereditary Breast and Ovarian Cancer, Arnold N34, Brauch H35, Hamann U36, Chang-Claude J37, Khan S38, Nevanlinna H38, Ito H39, Matsuo K40, Bogdanova NV41, Dörk T42, Lindblom A43, Margolin S44; kConFab/AOCS Investigators, Kosma VM45, Mannermaa A45, Tseng CC46, Wu AH46, Floris G47, Lambrechts D48, Rudolph A37, Peterlongo P49, Radice P50, Couch FJ51, Vachon C7, Giles GG52, McLean C53, Milne RL52, Dugué PA54, Haiman CA46, Maskarinec G55, Woolcott C56, Henderson BE46, Goldberg MS57, Simard J58, Teo SH59, Mariapun S59, Helland Å60, Haakensen V61, Zheng W62, Beeghly-Fadiel A62, Tamimi R63, Jukkola-Vuorinen A64, Winqvist R65, Andrulis IL66, Knight JA67, Devilee P68, Tollenaar RA69, Figueroa J70, García-Closas M71, Czene K1, Hooning MJ72, Tilanus-Linthorst M73, Li J74, Gao YT75, Shu XO62, Cox A76, Cross SS77, Luben R78, Khaw KT79, Choi JY80, Kang D81, Hartman M82, Lim WY83, Kabisch M36, Torres D84, Jakubowska A85, Lubinski J85, McKay J86, Sangrajrang S87, Toland AE88, Yannoukakos D89, Shen CY90, Yu JC91, Ziogas A27, Schoemaker MJ92, Swerdlow A93, Borresen-Dale AL94, Kristensen V95, French JD2, Edwards SL2, Dunning AM5, Easton DF96, Hall P1, Chenevix-Trench G97.

Author information

1
Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm 17177, Sweden.
2
Department of Genetics, QIMR Berghofer Medical Research Institute, Brisbane, QLD 4006, Australia.
3
Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge CB1 8RN, UK.
4
Department of Genetics, Institute for Cancer Research, Oslo University Hospital, Radiumhospitalet, 0310 Oslo, Norway; K.G. Jebsen Center for Breast Cancer Research, Institute for Clinical Medicine, Faculty of Medicine, University of Oslo, Kirkeveien 166, 0450 Oslo, Norway.
5
Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Cambridge CB1 8RN, UK.
6
Netherlands Cancer Institute, Antoni van Leeuwenhoek Hospital, 1066 CX Amsterdam, the Netherlands.
7
Department of Health Sciences Research, Mayo Clinic, Rochester, MN 55905, USA.
8
Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, VIC 3010, Australia.
9
Department of Pathology, The University of Melbourne, Melbourne, VIC 3010, Australia.
10
Centre for Genetic Origins of Health and Disease, University of Western Australia, Crawley, WA 6009, Australia.
11
Discipline of Medical Genetics, School of Biomedical Sciences and Pharmacy, Faculty of Health, University of Newcastle, Newcastle, NSW 2308, Australia; Division of Molecular Medicine, Pathology North, John Hunter Hospital and The Hunter Medical Research Institute, Newcastle, NSW 2305, Australia.
12
Division of Health Sciences, Warwick Medical School, Warwick University, Coventry CV4 7AL, UK.
13
Division of Health Sciences, Warwick Medical School, Warwick University, Coventry CV4 7AL, UK; Institute of Population Health, University of Manchester, Manchester M13 9PL, UK.
14
University Breast Center Franconia, Department of Gynecology and Obstetrics, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nuremberg, Comprehensive Cancer Center Erlangen-EMN, 91054 Erlangen, Germany.
15
Institute of Human Genetics, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nuremberg, Comprehensive Cancer Center Erlangen-EMN, 91054 Erlangen, Germany.
16
University Breast Center Franconia, Department of Gynecology and Obstetrics, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nuremberg, Comprehensive Cancer Center Erlangen-EMN, 91054 Erlangen, Germany; Department of Medicine Division of Hematology and Oncology, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA.
17
Department of Non-Communicable Disease Epidemiology, London School of Hygiene and Tropical Medicine, London WC1E 7HT, UK.
18
Wellcome Trust Centre for Human Genetics and Oxford Biomedical Research Centre, University of Oxford, Oxford OX3 7BN, UK.
19
Research Oncology, Division of Cancer Studies, King's College London, Guy's Hospital, London SE1 9RT, UK.
20
National Center for Tumor Diseases, University of Heidelberg, 69120 Heidelberg, Germany; Division of Molecular Genetic Epidemiology, German Cancer Research Centre (DZFK), 69047 Heidelberg, Germany.
21
National Center for Tumor Diseases, University of Heidelberg, 69120 Heidelberg, Germany; Department of Obstetrics and Gynecology, University of Heidelberg, 69120 Heidelberg, Germany.
22
University Paris-Sud, UMRS 1018, 94807 Villejuif, France; INSERM (National Institute of Health and Medical Research), CESP (Center for Research in Epidemiology and Population Health), U1018, Environmental Epidemiology of Cancer, 94807 Villejuif, France.
23
Copenhagen General Population Study, Herlev Hospital, Copenhagen University Hospital, 2730 Herlev, Denmark; Department of Clinical Biochemistry, Herlev Hospital, Copenhagen University Hospital, 2730 Herlev, Denmark; Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark.
24
Department of Breast Surgery, Herlev Hospital, Copenhagen University Hospital, 2730 Herlev, Denmark.
25
Human Genotyping (CEGEN) Unit, Human Cancer Genetics Program, Spanish National Cancer Research Centre (CNIO), Madrid 28029, Spain; Human Genetics Group, Spanish National Cancer Centre (CNIO), Madrid 28029, Spain; Biomedical Network on Rare Diseases (CIBERER), Madrid 28029, Spain.
26
Human Genotyping (CEGEN) Unit, Human Cancer Genetics Program, Spanish National Cancer Research Centre (CNIO), Madrid 28029, Spain.
27
Department of Epidemiology, University of California Irvine, Irvine, CA 92697, USA.
28
Beckman Research Institute of City of Hope, Duarte, CA 91010, USA.
29
Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany.
30
Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany; Division of Preventive Oncology, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany; German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany.
31
Institute for Medical Informatics, Statistics and Epidemiology, University of Leipzig, 04107 Leipzig, Germany.
32
Division of Gynaecology and Obstetrics, Technische Universität München, 81675 Munich, Germany.
33
Center for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne 50932, Germany; Center for Hereditary Breast and Ovarian Cancer, Medical Faculty, University Hospital Cologne, Cologne 50937, Germany; Center for Integrated Oncology (CIO), Medical Faculty, University Hospital Cologne, Cologne 50937, Germany.
34
Department of Gynaecology and Obstetrics, University Hospital of Schleswig-Holstein, Campus Kiel, Christian-Albrechts University Kiel, 24105 Kiel, Germany.
35
German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany; Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology, 70376 Stuttgart, Germany; University of Tübingen, 72074 Tübingen, Germany.
36
Molecular Genetics of Breast Cancer, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany.
37
Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany.
38
Department of Obstetrics and Gynecology, University of Helsinki and Helsinki University Hospital, Helsinki, 00029 HUS, Finland.
39
Division of Epidemiology and Prevention, Aichi Cancer Center Research Institute, Nagoya, Aichi 464-8681, Japan.
40
Department of Preventive Medicine, Kyushu University Faculty of Medical Sciences, Fukuoka 812-8582, Japan.
41
Department of Radiation Oncology, Hannover Medical School, 30625 Hannover, Germany.
42
Gynaecology Research Unit, Hannover Medical School, 30625 Hannover, Germany.
43
Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm 17177, Sweden.
44
Department of Oncology - Pathology, Karolinska Institutet, Stockholm 17177, Sweden.
45
School of Medicine, Institute of Clinical Medicine, Pathology and Forensic Medicine, University of Eastern Finland, Kuopio 70211, Finland; Imaging Center, Department of Clinical Pathology, Kuopio University Hospital, Kuopio 70211, Finland; Cancer Center of Eastern Finland, University of Eastern Finland, Kuopio 70211, Finland.
46
Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA.
47
University Hospital Gashuisberg, 3000 Leuven, Belgium.
48
Vesalius Research Center (VRC), VIB, Leuven 3000, Belgium; Laboratory for Translational Genetics, Department of Oncology, University of Leuven, Leuven 3000, Belgium.
49
IFOM, the FIRC (Italian Foundation for Cancer Research) Institute of Molecular Oncology, 20139 Milan, Italy.
50
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.
51
Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN 55905, USA.
52
Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, VIC 3010, Australia; Cancer Epidemiology Centre, Cancer Council Victoria, Melbourne, VIC 3053, Australia.
53
Anatomical Pathology, The Alfred Hospital, Melbourne, VIC 3004, Australia.
54
Cancer Epidemiology Centre, Cancer Council Victoria, Melbourne, VIC 3053, Australia.
55
Cancer Epidemiology Program, University of Hawaii Cancer Center, Honolulu, HI 96813, USA.
56
Departments of Obstetrics & Gynaecology and Pediatrics, Dalhousie University, Halifax, NS B3H 4R2, Canada.
57
Department of Medicine, McGill University, Montreal, QC H3A 1W7, Canada; Division of Clinical Epidemiology, McGill University Health Centre, Royal Victoria Hospital, Montreal, QC H3H 2R9, Canada.
58
Centre Hospitalier Universitaire de Québec Research Center and Laval University, Quebec City, QC G1V 4G2, Canada.
59
Breast Cancer Research Unit, University Malaya Cancer Research Institute, University Malaya Medical Centre (UMMC), 50603 Kuala Lumpur, Malaysia; Cancer Research Initiatives Foundation, Sime Darby Medical Centre, 47500 Subang Jaya, Malaysia.
60
Department of Oncology, Oslo University Hospital, Radiumhospitalet, 0310 Oslo, Norway.
61
Department of Genetics, Oslo University Hospital, Radiumhospitalet, 0310 Oslo, Norway.
62
Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, TN 37203, USA.
63
Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA; Program in Molecular and Genetic Epidemiology, Harvard School of Public Health, Boston, MA 02115, USA; Department of Epidemiology, Harvard School of Public Health, Boston, MA 02115, USA.
64
Department of Oncology, Oulu University Hospital and University of Oulu, 90014 Oulu, Finland.
65
Laboratory of Cancer Genetics and Tumor Biology, Department of Clinical Chemistry and Biocenter Oulu, University of Oulu, 90014 Oulu, Finland; Laboratory of Cancer Genetics and Tumor Biology, Northern Finland Laboratory Centre NordLab, 90220 Oulu, Finland.
66
Lunenfeld-Tanenbaum Research Institute of Mount Sinai Hospital, Toronto, ON M5G 1X5, Canada; Departments of Molecular Genetics and Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON M5S 3G3, Canada.
67
Prosserman Centre for Health Research, Lunenfeld-Tanenbaum Research Institute of Mount Sinai Hospital, Toronto, ON M5G 1X5, Canada; Division of Epidemiology, Dalla Lana School of Public Health, University of Toronto, Toronto, ON M5S 3G3, Canada.
68
Department of Human Genetics, Leiden University Medical Center, 2333 ZA Leiden, the Netherlands; Department of Pathology, Leiden University Medical Center, 2333 ZA Leiden, the Netherlands.
69
Department of Surgical Oncology, Leiden University Medical Center, 2333 ZC Leiden, the Netherlands.
70
Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, Rockville, MD 20850, USA.
71
Division of Genetics and Epidemiology, Institute of Cancer Research, Sutton SM2 5NG, UK; Division of Cancer Studies, Breakthrough Breast Cancer Research Centre, London SW3 6JB, UK.
72
Department of Medical Oncology, Erasmus MC Cancer Institute, 3008 AE Rotterdam, the Netherlands.
73
Department of Surgical Oncology, Erasmus University Medical Center, 3075 EA Rotterdam, the Netherlands.
74
Human Genetics Division, Genome Institute of Singapore, Singapore 138672, Singapore.
75
Department of Epidemiology, Shanghai Cancer Institute, Xuhui, Shanghai 200031, China.
76
Sheffield Cancer Research Centre, Department of Oncology, University of Sheffield, Sheffield S10 2RX, UK.
77
Academic Unit of Pathology, Department of Neuroscience, University of Sheffield, Sheffield S10 2HQ, UK.
78
Clinical Gerontology, Department of Public Health and Primary Care, University of Cambridge, Cambridge CB1 8RN, UK.
79
Department of Public Health and Primary Care, University of Cambridge, Cambridge CB2 1TN, UK.
80
Department of Biomedical Science, Seoul National University College of Medicine, Seoul 110-799, Korea; Department of Surgery, Seoul National University College of Medicine, Seoul 110-799, Korea.
81
Department of Biomedical Science, Seoul National University College of Medicine, Seoul 110-799, Korea; Department of Surgery, Seoul National University College of Medicine, Seoul 110-799, Korea; Department of Preventive Medicine, Seoul National University College of Medicine, Seoul 110-799, Korea.
82
Saw Swee Hock School of Public Health, National University of Singapore and Department of Surgery, National University Health System, Singapore 117597, Singapore.
83
Saw Swee Hock School of Public Health, National University of Singapore and Department of Surgery, National University Health System, Singapore 117597, Singapore; Department of Surgery, Yong Loo Lin School of Medicine, National University of Singapore and National University Health System, Singapore 119228, Singapore.
84
Molecular Genetics of Breast Cancer, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany; Institute of Human Genetics, Pontificia Universidad Javeriana, Bogota 12362, Columbia.
85
Department of Genetics and Pathology, Pomeranian Medical University, 70-115 Szczecin, Poland.
86
International Agency for Research on Cancer, 69372 Lyon, CEDEX 08, France.
87
National Cancer Institute, Bangkok 10400, Thailand.
88
Department of Molecular Virology, Immunology and Medical Genetics, Comprehensive Cancer Center, The Ohio State University, Columbus, OH 43210, USA.
89
Molecular Diagnostics Laboratory, IRRP, National Centre for Scientific Research "Demokritos," Aghia Paraskevi Attikis, 153 10 Athens, Greece.
90
Taiwan Biobank, Institute of Biomedical Sciences, Academia Sinica, Taipei 115, Taiwan; School of Public Health, China Medical University, Taichung 40402, Taiwan.
91
Department of Surgery, Tri-Service General Hospital, Taipei 114, Taiwan.
92
Division of Genetics and Epidemiology, Institute of Cancer Research, Sutton SM2 5NG, UK.
93
Division of Genetics and Epidemiology, Institute of Cancer Research, Sutton SM2 5NG, UK; Division of Breast Cancer Research, Institute of Cancer Research, Sutton SM2 5NG, UK.
94
Department of Genetics, Institute for Cancer Research, Oslo University Hospital, Radiumhospitalet, 0310 Oslo, Norway; Institute of Clinical Medicine, University of Oslo (UiO), Oslo 0316, Norway.
95
Department of Genetics, Institute for Cancer Research, Oslo University Hospital, Radiumhospitalet, 0310 Oslo, Norway; Institute of Clinical Medicine, University of Oslo (UiO), Oslo 0316, Norway; Department of Clinical Molecular Biology (EpiGen), University of Oslo (UiO), Oslo 0316, Norway.
96
Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge CB1 8RN, UK; Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Cambridge CB1 8RN, UK.
97
Department of Genetics, QIMR Berghofer Medical Research Institute, Brisbane, QLD 4006, Australia. Electronic address: georgia.trench@qimr.edu.au.

Abstract

Genome-wide association studies have identified SNPs near ZNF365 at 10q21.2 that are associated with both breast cancer risk and mammographic density. To identify the most likely causal SNPs, we fine mapped the association signal by genotyping 428 SNPs across the region in 89,050 European and 12,893 Asian case and control subjects from the Breast Cancer Association Consortium. We identified four independent sets of correlated, highly trait-associated variants (iCHAVs), three of which were located within ZNF365. The most strongly risk-associated SNP, rs10995201 in iCHAV1, showed clear evidence of association with both estrogen receptor (ER)-positive (OR = 0.85 [0.82-0.88]) and ER-negative (OR = 0.87 [0.82-0.91]) disease, and was also the SNP most strongly associated with percent mammographic density. iCHAV2 (lead SNP, chr10: 64,258,684:D) and iCHAV3 (lead SNP, rs7922449) were also associated with ER-positive (OR = 0.93 [0.91-0.95] and OR = 1.06 [1.03-1.09]) and ER-negative (OR = 0.95 [0.91-0.98] and OR = 1.08 [1.04-1.13]) disease. There was weaker evidence for iCHAV4, located 5' of ADO, associated only with ER-positive breast cancer (OR = 0.93 [0.90-0.96]). We found 12, 17, 18, and 2 candidate causal SNPs for breast cancer in iCHAVs 1-4, respectively. Chromosome conformation capture analysis showed that iCHAV2 interacts with the ZNF365 and NRBF2 (more than 600 kb away) promoters in normal and cancerous breast epithelial cells. Luciferase assays did not identify SNPs that affect transactivation of ZNF365, but identified a protective haplotype in iCHAV2, associated with silencing of the NRBF2 promoter, implicating this gene in the etiology of breast cancer.

PMID:
26073781
PMCID:
PMC4572510
DOI:
10.1016/j.ajhg.2015.05.002
[Indexed for MEDLINE]
Free PMC Article

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