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Hum Mol Genet. 2016 Sep 1;25(17):3863-3876. doi: 10.1093/hmg/ddw223. Epub 2016 Jul 11.

An intergenic risk locus containing an enhancer deletion in 2q35 modulates breast cancer risk by deregulating IGFBP5 expression.

Wyszynski A1, Hong CC2, Lam K3, Michailidou K4, Lytle C5, Yao S2, Zhang Y2, Bolla MK4, Wang Q4, Dennis J4, Hopper JL6, Southey MC7, Schmidt MK8, Broeks A9, Muir K10,11, Lophatananon A12, Fasching PA13,14, Beckmann MW13, Peto J15, Dos-Santos-Silva I15, Sawyer EJ16, Tomlinson I9, Burwinkel B12,17, Marme F12,18, Guénel P19,20, Truong T19,20, Bojesen SE21,22, Nordestgaard BG21,22, González-Neira A23, Benitez J24,25, Neuhausen SL26, Brenner H27,28, Dieffenbach AK27,28, Meindl A29, Schmutzler RK30,31,32,33, Brauch H34,35; GENICA Network, Nevanlinna H36, Khan S36, Matsuo K37, Ito H38, Dörk T39, Bogdanova NV40, Lindblom A41, Margolin S42, Mannermaa A43,44,45, Kosma VM43,44,45; kConFab Investigators; Australian Ovarian Cancer Study Group, Wu AH46, Van Den Berg D46, Lambrechts D47,48, Wildiers H49, Chang-Claude J50,51, Rudolph A50, Radice P52, Peterlongo P53, Couch FJ54, Olson JE55, Giles GG56,6, Milne RL56,6, Haiman CA46, Henderson BE46, Dumont M57, Teo SH58,59, Wong TY60, Kristensen V61,62,63, Zheng W64, Long J64, Winqvist R65, Pylkäs K65, Andrulis IL66,67, Knight JA68,69, Devilee P70, Seynaeve C71, García-Closas M72,73, Figueroa J74, Klevebring D75, Czene K75, Hooning MJ76, van den Ouweland AM77, Darabi H75, Shu XO64, Gao YT78, Cox A79, Blot W64,80, Signorello LB81, Shah M82, Kang D83,84,85, Choi JY84,85, Hartman M86,87, Miao H86, Hamann U88, Jakubowska A89, Lubinski J89, Sangrajrang S90, McKay J91, Toland AE92, Yannoukakos D93, Shen CY94,95,96, Wu PE94,95, Swerdlow A72,97, Orr N98, Simard J57, Pharoah PD4,82, Dunning AM82, Chenevix-Trench G99, Hall P75, Bandera E100, Amos C1, Ambrosone C2, Easton DF101,102, Cole MD103.

Author information

1
Department of Biomedical Data Science, Geisel School of Medicine at Dartmouth, Hanover, NH 03755, USA.
2
Department of Cancer Prevention and Control, Roswell Park Cancer Institute, Buffalo, NY 14263, USA.
3
Dartmouth College, Hanover, NH 03755 USA.
4
Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, CB1 8RN, UK.
5
Molecular Biology Core Facility, Dartmouth College, Hanover, NH 03755 USA.
6
Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, Victoria 3010, Australia.
7
Department of Pathology, The University of Melbourne, Melbourne, Victoria 3010, Australia.
8
Netherlands Cancer Institute, Antoni van Leeuwenhoek hospital, 1066 CX Amsterdam, The Netherlands.
9
Wellcome Trust Centre for Human Genetics and Oxford Biomedical Research Centre, University of Oxford, OX3 7BN, UK.
10
Division of Health Sciences, Warwick Medical school, Warwick University, Coventry, CV4 7AL, UK.
11
Institute of Population Health, University of Manchester, Manchester, M13 9PL, UK.
12
Department of Obstetrics and Gynecology, University of Heidelberg, 69120 Heidelberg, Germany.
13
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.
14
David Geffen School of Medicine, Department of Medicine Division of Hematology and Oncology, University of California at Los Angeles, Los Angeles, CA 90095, USA.
15
Department of Non-Communicable Disease Epidemiology, London School of Hygiene and Tropical Medicine, London, WC1E 7HT, UK.
16
Research Oncology, Division of Cancer Studies, King's College London, Guy's Hospital, London, SE1 9RT, UK.
17
Molecular Epidemiology Group, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany.
18
National Center for Tumor Diseases, University of Heidelberg, 69120 Heidelberg, Germany.
19
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.
20
University Paris-Sud, UMRS 1018, 94807 Villejuif, France.
21
Copenhagen General Population Study, Herlev Hospital, Copenhagen University Hospital, 2730 Herlev, Denmark.
22
Department of Clinical Biochemistry, Herlev Hospital, Copenhagen University Hospital, 2730 Herlev, Denmark.
23
Human Genotyping-CEGEN Unit, Human Cancer Genetics Program, Spanish National Cancer Research Centre (CNIO), 28029 Madrid, Spain.
24
Human Genetics Group, Human Cancer Genetics Program, Spanish National Cancer Research Centre (CNIO), 28029 Madrid, Spain.
25
Centro de Investigación en Red de Enfermedades Raras (CIBERER), 46010 Valencia, Spain.
26
Beckman Research Institute of City of Hope, Duarte, CA 91010, USA.
27
Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany.
28
German Cancer Consortium (DKTK), 69120 Heidelberg, Germany.
29
Division of Gynaecology and Obstetrics, Technische Universität München, 81675 Munich, Germany.
30
Division of Molecular Gyneco-Oncology, Department of Gynaecology and Obstetrics, University Hospital of Cologne, 50931 Cologne, Germany.
31
Center of Familial Breast and Ovarian Cancer, University Hospital of Cologne, 50931 Cologne, Germany.
32
Center for Integrated Oncology (CIO), University Hospital of Cologne, 50931 Cologne, Germany.
33
Center for Molecular Medicine Cologne (CMMC), University of Cologne, 50931 Cologne, Germany.
34
Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology, 70376 Stuttgart, Germany.
35
University of Tübingen, 72074 Tübingen, Germany.
36
Department of Obstetrics and Gynecology, University of Helsinki and Helsinki University Central Hospital, Helsinki, FI-00029 HUS, Finland.
37
Department of Preventive Medicine, Kyushu University Faculty of Medical Sciences, Fukuoka, Japan.
38
Division of Epidemiology and Prevention, Aichi Cancer Center Research Institute, Nagoya, Aichi, 464-8681, Japan.
39
Department of Obstetrics and Gynaecology, Hannover Medical School, 30625 Hannover, Germany.
40
Department of Radiation Oncology, Hannover Medical School, 30625 Hannover, Germany.
41
Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm SE-17177, Sweden.
42
Department of Oncology - Pathology, Karolinska Institutet, Stockholm SE-17177, Sweden.
43
School of Medicine, Institute of Clinical Medicine, Pathology and Forensic Medicine, University of Eastern Finland, FI-70211 Kuopio, Finland.
44
Cancer Center of Eastern Finland, University of Eastern Finland, FI-70211 Kuopio, Finland.
45
Imaging Center, Department of Clinical Pathology, Kuopio University Hospital, 70210 Kuopio, Finland.
46
Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA.
47
Vesalius Research Center (VRC), VIB, 3000 Leuven, Belgium.
48
Laboratory for Translational Genetics, Department of Oncology, University of Leuven, 3000 Leuven, Belgium.
49
Multidisciplinary Breast Center, Department of General Medical Oncology, University Hospitals Leuven, B-3000 Leuven, Belgium.
50
Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany.
51
University Cancer Center Hamburg (UCCH), University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany.
52
Unit of Molecular Bases of Genetic Risk and Genetic Testing, Department of Preventive and Predictive Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori (INT), 20133 Milan, Italy.
53
IFOM, Fondazione Istituto FIRC di Oncologia Molecolare, 20139 Milan, Italy.
54
Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN 55905, USA.
55
Department of Health Sciences Research, Mayo Clinic, Rochester, MN 55905, USA.
56
Cancer Epidemiology Centre, Cancer Council Victoria, Melbourne, Victoria 3004, Australia.
57
Centre Hospitalier Universitaire de Québec Research Center and Laval University, QC, G1V 4G2, Canada.
58
Cancer Research Initiatives Foundation, Sime Darby Medical Centre, 47500 Subang Jaya, Selangor, Malaysia.
59
Breast Cancer Research Unit, University Malaya Cancer Research Institute, University Malaya Medical Centre (UMMC), 59100 Kuala Lumpur, Malaysia.
60
Singapore Eye Research Institute, National University of Singapore, Singapore 168751.
61
Department of Genetics, Institute for Cancer Research, Oslo University Hospital, Radiumhospitalet, N-0310 Oslo, Norway.
62
Institute of Clinical Medicine, University of Oslo (UiO), 0450 Oslo, Norway.
63
Department of Clinical Molecular Biology (EpiGen), University of Oslo (UiO), 0450 Oslo, Norway.
64
Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, TN 37203, USA.
65
Laboratory of Cancer Genetics and Tumor Biology, Department of Clinical Chemistry and Biocenter Oulu, University of Oulu, NordLab Oulu/Oulu University Hospital, FI-90220 Oulu, Finland.
66
Lunenfeld-Tanenbaum Research Institute of Mount Sinai Hospital, Toronto, ON, M5G 1X5, Canada.
67
Department of Molecular Genetics, University of Toronto, Toronto, ON, M5S 1A8, Canada.
68
Prosserman Centre for Health Research, Lunenfeld-Tanenbaum Research Institute of Mount Sinai Hospital, Toronto, ON, M5G 1X5, Canada.
69
Division of Epidemiology, Dalla Lana School of Public Health, University of Toronto, Toronto, ON, M5S 1A8, Canada.
70
Department of Human Genetics & Department of Pathology, Leiden University Medical Center, 2333 ZC Leiden, The Netherlands.
71
Family Cancer Clinic, Department of Medical Oncology, Erasmus MC-Daniel den Hoed Cancer Center, 3075 EA Rotterdam, The Netherlands.
72
Division of Genetics and Epidemiology, Institute of Cancer Research, Sutton, SM2 5NG, UK.
73
Breakthrough Breast Cancer Research Centre, Division of Breast Cancer Research, The Institute of Cancer Research, London, SW3 6JB, UK.
74
Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD 20850, USA.
75
Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm SE-17177, Sweden.
76
Department of Medical Oncology, Erasmus University Medical Center, 3075 EA Rotterdam, The Netherlands.
77
Department of Clinical Genetics, Erasmus University Medical Center, 3075 EA Rotterdam, The Netherlands.
78
Department of Epidemiology, Shanghai Cancer Institute, Xuhui, Shanghai, China.
79
CRUK/YCR Sheffield Cancer Research Centre, Department of Oncology, University of Sheffield, Sheffield, S10 2RX, UK.
80
International Epidemiology Institute, Rockville, MD 20850, USA.
81
Division of Cancer Prevention, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
82
Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, CB1 8RN, UK.
83
Department of Preventive Medicine, Seoul National University College of Medicine, Seoul 110-799, Korea.
84
Department of Biomedical Sciences, Seoul National University Graduate School, Seoul 151-742, Korea.
85
Cancer Research Institute, Seoul National University College of Medicine, Seoul 110-799, Korea.
86
Saw Swee Hock School of Public Health, National University of Singapore and National University Health System, Singapore 117597.
87
Department of Surgery, Yong Loo Lin School of Medicine, National University of Singapore and National University Health System, Singapore 117597.
88
Molecular Genetics of Breast Cancer, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany.
89
Department of Genetics and Pathology, Pomeranian Medical University, 70-115 Szczecin, Poland.
90
National Cancer Institute, Bangkok 10400, Thailand.
91
International Agency for Research on Cancer, 69372 Lyon, CEDEX 08, France.
92
Department of Molecular Virology, Immunology and Medical Genetics, Comprehensive Cancer Center, The Ohio State University, Columbus, OH 43210, USA.
93
Molecular Diagnostics Laboratory, IRRP, National Centre for Scientific Research "Demokritos", Aghia Paraskevi Attikis, 153 10 Athens, Greece.
94
Taiwan Biobank, Institute of Biomedical Sciences, Academia Sinica, Taipei 115, Taiwan.
95
Institute of Biomedical Sciences, Academia Sinica, Taipei 115, Taiwan.
96
School of Public Health, China Medical University, Taichung 404, Taiwan.
97
Division of Breast Cancer Research, Institute of Cancer Research, Sutton, SM2 5NG, UK.
98
Breakthrough Breast Cancer Research Centre, The Institute of Cancer Research, London, SW3 6JB, UK.
99
Department of Genetics, QIMR Berghofer Medical Research Institute, Brisbane, QLD 4006, Australia.
100
Rutgers Cancer Institute of New Jersey, New Brunswick, NJ 08901 USA.
101
Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.
102
Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Cambridge, UK.
103
Department of Molecular and Systems Biology, Geisel School of Medicine at Dartmouth, Hanover, NH 03755, USA Michael.D.Cole@dartmouth.edu.

Abstract

Breast cancer is the most diagnosed malignancy and the second leading cause of cancer mortality in females. Previous association studies have identified variants on 2q35 associated with the risk of breast cancer. To identify functional susceptibility loci for breast cancer, we interrogated the 2q35 gene desert for chromatin architecture and functional variation correlated with gene expression. We report a novel intergenic breast cancer risk locus containing an enhancer copy number variation (enCNV; deletion) located approximately 400Kb upstream to IGFBP5, which overlaps an intergenic ERα-bound enhancer that loops to the IGFBP5 promoter. The enCNV is correlated with modified ERα binding and monoallelic-repression of IGFBP5 following oestrogen treatment. We investigated the association of enCNV genotype with breast cancer in 1,182 cases and 1,362 controls, and replicate our findings in an independent set of 62,533 cases and 60,966 controls from 41 case control studies and 11 GWAS. We report a dose-dependent inverse association of 2q35 enCNV genotype (percopy OR = 0.68 95%CI 0.55-0.83, P = 0.0002; replication OR = 0.77 95% CI 0.73-0.82, P = 2.1 × 10-19) and identify 13 additional linked variants (r2 >0.8) in the 20Kb linkage block containing the enCNV (P = 3.2 × 10-15 - 5.6 × 10-17). These associations were independent of previously reported 2q35 variants, rs13387042/rs4442975 and rs16857609, and were stronger for ER-positive than ER-negative disease. Together, these results suggest that 2q35 breast cancer risk loci may be mediating their effect through IGFBP5.

PMID:
27402876
PMCID:
PMC5216618
DOI:
10.1093/hmg/ddw223
[Indexed for MEDLINE]
Free PMC Article

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