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Nat Commun. 2014 Sep 23;4:4999. doi: 10.1038/ncomms5999.

Evidence that breast cancer risk at the 2q35 locus is mediated through IGFBP5 regulation.

Ghoussaini M1, Edwards SL2, Michailidou K3, Nord S4, Cowper-Sal Lari R5, Desai K6, Kar S3, Hillman KM2, Kaufmann S2, Glubb DM7, Beesley J7, Dennis J3, Bolla MK3, Wang Q3, Dicks E1, Guo Q1, Schmidt MK8, Shah M1, Luben R3, Brown J3, Czene K9, Darabi H9, Eriksson M9, Klevebring D9, Bojesen SE10, Nordestgaard BG10, Nielsen SF11, Flyger H12, Lambrechts D13, Thienpont B14, Neven P15, Wildiers H15, Broeks A8, Van't Veer LJ8, Th Rutgers EJ8, Couch FJ16, Olson JE17, Hallberg E17, Vachon C17, Chang-Claude J18, Rudolph A18, Seibold P18, Flesch-Janys D19, Peto J20, Dos-Santos-Silva I20, Gibson L20, Nevanlinna H21, Muranen TA21, Aittomäki K22, Blomqvist C23, Hall P9, Li J24, Liu J24, Humphreys K9, Kang D25, Choi JY26, Park SK25, Noh DY27, Matsuo K28, Ito H29, Iwata H30, Yatabe Y31, Guénel P32, Truong T32, Menegaux F32, Sanchez M32, Burwinkel B33, Marme F34, Schneeweiss A34, Sohn C35, Wu AH36, Tseng CC36, Van Den Berg D36, Stram DO36, Benitez J37, Zamora MP38, Perez JI39, Menéndez P40, Shu XO41, Lu W42, Gao YT43, Cai Q41, Cox A44, Cross SS45, Reed MW44, Andrulis IL46, Knight JA47, Glendon G48, Tchatchou S49, Sawyer EJ50, Tomlinson I51, Kerin MJ52, Miller N52, Haiman CA53, Henderson BE53, Schumacher F53, Le Marchand L54, Lindblom A55, Margolin S56, Teo SH57, Yip CH58, Lee DS59, Wong TY60, Hooning MJ61, Martens JW61, Collée JM62, van Deurzen CH63, Hopper JL64, Southey MC65, Tsimiklis H65, Kapuscinski MK64, Shen CY66, Wu PE67, Yu JC68, Chen ST69, Alnæs GG4, Borresen-Dale AL70, Giles GG71, Milne RL72, McLean C73, Muir K74, Lophatananon A75, Stewart-Brown S75, Siriwanarangsan P76, Hartman M77, Miao H78, Buhari SA79, Teo YY80, Fasching PA81, Haeberle L82, Ekici AB83, Beckmann MW82, Brenner H84, Dieffenbach AK84, Arndt V85, Stegmaier C86, Swerdlow A87, Ashworth A88, Orr N88, Schoemaker MJ89, García-Closas M90, Figueroa J91, Chanock SJ91, Lissowska J92, Simard J93, Goldberg MS94, Labrèche F95, Dumont M93, Winqvist R96, Pylkäs K96, Jukkola-Vuorinen A97, Brauch H98, Brüning T99, Koto YD100, Radice P101, Peterlongo P102, Bonanni B103, Volorio S104, Dörk T105, Bogdanova NV106, Helbig S105, Mannermaa A107, Kataja V108, Kosma VM107, Hartikainen JM107, Devilee P109, Tollenaar RA110, Seynaeve C111, Van Asperen CJ62, Jakubowska A112, Lubinski J112, Jaworska-Bieniek K112, Durda K112, Slager S17, Toland AE113, Ambrosone CB114, Yannoukakos D115, Sangrajrang S116, Gaborieau V117, Brennan P117, McKay J117, Hamann U118, Torres D119, Zheng W41, Long J41, Anton-Culver H120, Neuhausen SL121, Luccarini C1, Baynes C1, Ahmed S1, Maranian M1, Healey CS1, González-Neira A122, Pita G122, Alonso MR122, Alvarez N122, Herrero D122, Tessier DC123, Vincent D124, Bacot F124, de Santiago I125, Carroll J125, Caldas C125, Brown MA126, Lupien M127, Kristensen VN128, Pharoah PD129, Chenevix-Trench G7, French JD2, Easton DF129, Dunning AM1; Australian Ovarian Cancer Management Group; Australian Ovarian Cancer Management Group.

Author information

1
Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Cambridge CB1 8RN, UK.
2
1] Department of Genetics, QIMR Berghofer Medical Research Institute, Brisbane, Queensland 4029, Australia [2] School of Chemistry and Molecular Biosciences, The University of Queensland, Brisbane, Queensland 4072, 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, N-0310 Oslo, Norway.
5
The Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada M5T 2M9.
6
1] The Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada M5T 2M9 [2] Geisel School of Medicine, Dartmouth College, Hanover, New Hampshire 03755, USA.
7
Department of Genetics, QIMR Berghofer Medical Research Institute, Brisbane, Queensland 4029, Australia.
8
Netherlands Cancer Institute, Antoni van Leeuwenhoek hospital, 1066 CX Amsterdam, The Netherlands.
9
Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm SE-17177, Sweden.
10
1] Copenhagen General Population Study, Herlev Hospital, 2730 Herlev, Copenhagen, Denmark [2] Department of Clinical Biochemistry, Herlev Hospital, Copenhagen University Hospital, 2730 Herlev, Copenhagen, Denmark [3] Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark.
11
1] Copenhagen General Population Study, Herlev Hospital, 2730 Herlev, Copenhagen, Denmark [2] Department of Clinical Biochemistry, Herlev Hospital, Copenhagen University Hospital, 2730 Herlev, Copenhagen, Denmark.
12
Department of Breast Surgery, Herlev Hospital, Copenhagen University Hospital, 2730 Herlev, Copenhagen, Denmark.
13
1] Laboratory for Translational Genetics, Department of Oncology, University of Leuven, 3000 Leuven, Belgium [2] Vesalius Research Center (VRC), VIB, 3000 Leuven, Belgium.
14
1] Vesalius Research Center (VRC), VIB, 3000 Leuven, Belgium [2] Vesalius Research Center, University of Leuven, 3000 Leuven, Belgium.
15
1] Department of Oncology, University of Leuven, 3000 Leuven, Belgium [2] Multidisciplinary Breast Center, Department of General Medical Oncology, University Hospitals Leuven, 3000 Leuven, Belgium.
16
Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota 55905, USA.
17
Department of Health Sciences Research, Mayo Clinic, Rochester, Minnesota 55905, USA.
18
Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany.
19
Department of Cancer Epidemiology/Clinical Cancer Registry and Institute for Medical Biometrics and Epidemiology, University Clinic Hamburg-Eppendorf, 20246 Hamburg, Germany.
20
Department of Non-Communicable Disease Epidemiology, London School of Hygiene and Tropical Medicine, London WC1E 7HT, UK.
21
Department of Obstetrics and Gynecology, Helsinki University Central Hospital, Helsinki, FI-00029 HUS, Finland.
22
Department of Clinical Genetics, University of Helsinki, Helsinki University Central Hospital, Helsinki, FI-00029 HUS, Finland.
23
Department of Oncology, University of Helsinki, Helsinki University Central Hospital, Helsinki, FI-00029 HUS, Finland.
24
Human Genetics Division, Genome Institute of Singapore, Singapore 138672, Singapore.
25
1] Cancer Research Institute, Seoul National University College of Medicine, Seoul 110-799, Korea [2] Department of Biomedical Sciences, Seoul National University Graduate School, Seoul 151-742, Korea [3] Department of Preventive Medicine, Seoul National University College of Medicine, Seoul 110-799, Korea.
26
1] Cancer Research Institute, Seoul National University College of Medicine, Seoul 110-799, Korea [2] Department of Biomedical Sciences, Seoul National University Graduate School, Seoul 151-742, Korea.
27
Department of Surgery, Seoul National University College of Medicine, Seoul 110-799, Korea.
28
Department of Preventive Medicine, Kyushu University Faculty of Medical Sciences, Fukuoka 812-8582, Japan.
29
Division of Epidemiology and Prevention, Aichi Cancer Center Research Institute, Nagoya, Aichi 464-8681, Japan.
30
Department of Breast Oncology, Aichi Cancer Center Hospital, Nagoya 484-8681, Japan.
31
Department of Pathology and Molecular Diagnostics, Aichi Cancer Center Hospital, Nagoya 484-8681, Japan.
32
1] 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 [2] University Paris-Sud, UMRS 1018, 94807 Villejuif, France.
33
1] Department of Obstetrics and Gynecology, University of Heidelberg, 69120 Heidelberg, Germany [2] Molecular Epidemiology Group, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany.
34
1] Department of Obstetrics and Gynecology, University of Heidelberg, 69120 Heidelberg, Germany [2] National Center for Tumor Diseases, University of Heidelberg, 69120 Heidelberg, Germany.
35
Department of Obstetrics and Gynecology, University of Heidelberg, 69120 Heidelberg, Germany.
36
Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California 90033, USA.
37
1] Centro de Investigación en Red de Enfermedades Raras (CIBERER), 46010 Valencia, Spain [2] Human Genetics Group, Human Cancer Genetics Program, Spanish National Cancer Research Centre (CNIO), 28029 Madrid, Spain.
38
Servicio de Oncología Médica, Hospital Universitario La Paz, 28046 Madrid, Spain.
39
Servicio de Cirugía General y Especialidades, Hospital Monte Naranco, 33012 Oviedo, Spain.
40
Servicio de Anatomía Patológica, Hospital Monte Naranco, 33013 Oviedo, Spain.
41
Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, Tennessee 37203, USA.
42
Shanghai Center for Disease Control and Prevention, Shanghai 200336, China.
43
Department of Epidemiology, Shanghai Cancer Institute, Shanghai 200032, China.
44
CRUK/YCR Sheffield Cancer Research Centre, Department of Oncology, University of Sheffield, Sheffield S10 2RX, UK.
45
Academic Unit of Pathology, Department of Neuroscience, University of Sheffield, Sheffield S10 2HQ, UK.
46
1] Lunenfeld-Tanenbaum Research Institute of Mount Sinai Hospital, Toronto, Ontario, Canada M5G 1X5 [2] Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada M5S 1A8.
47
1] Division of Epidemiology, Dalla Lana School of Public Health, University of Toronto, Toronto, Ontario, Canada M5T 3M7 [2] Prosserman Centre for Health Research, Lunenfeld-Tanenbaum Research Institute of Mount Sinai Hospital, Toronto, Ontario, Canada M5G 1X5.
48
Ontario Cancer Genetics Network, Lunenfeld-Tanenbaum Research Institute of Mount Sinai Hospital, Toronto, Ontario, Canada M5G 1X5.
49
Lunenfeld-Tanenbaum Research Institute of Mount Sinai Hospital, Toronto, Ontario, Canada M5G 1X5.
50
Division of Cancer Studies, NIHR Comprehensive Biomedical Research Centre, Guy's &St Thomas' NHS Foundation Trust in partnership with King's College London, London SE1 9RT, UK.
51
Wellcome Trust Centre for Human Genetics, Oxford Biomedical Research Centre, University of Oxford, Oxford OX3 7BN, UK.
52
Clinical Science Institute, University Hospital Galway, Galway, Ireland.
53
Department of Preventive Medicine, Keck School of Medicine, University of Southern California Norris Comprehensive Cancer Center, Los Angeles, California 90033, USA.
54
Epidemiology Program, Cancer Research Center, University of Hawaii, Honolulu, Hawaii 96813, USA.
55
Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm SE-17177, Sweden.
56
Department of Oncology-Pathology, Karolinska Institutet, Stockholm SE-17177, Sweden.
57
1] Breast Cancer Research Unit, University Malaya Cancer Research Institute, University Malaya Medical Centre, 59100 Kuala Lumpur, Malaysia [2] Cancer Research Initiatives Foundation, Sime Darby Medical Centre, Subang Jaya 47500 Selangor, Malaysia.
58
Breast Cancer Research Unit, University Malaya Cancer Research Institute, University Malaya Medical Centre, 59100 Kuala Lumpur, Malaysia.
59
Cancer Research Initiatives Foundation, Sime Darby Medical Centre, Subang Jaya 47500 Selangor, Malaysia.
60
Singapore Eye Research Institute, National University of Singapore, Singapore 168751, Singapore.
61
Department of Medical Oncology, Erasmus MC Cancer Institute, 3008 AE Rotterdam, The Netherlands.
62
Department of Clinical Genetics, Erasmus University Medical Center, 3000 CA Rotterdam, The Netherlands.
63
Department of Pathology, Erasmus University Medical Center, 3075 EA Rotterdam, The Netherlands.
64
Centre for Molecular, Environmental, Genetic and Analytical Epidemiology, Melbourne School of Population Health, University of Melbourne, Melbourne, Victoria 3010, Australia.
65
Department of Pathology, The University of Melbourne, Melbourne, Victoria 3010, Australia.
66
1] College of Public Health, China Medical University, Taichung 40402, Taiwan, China [2] Institute of Biomedical Sciences, Academia Sinica, Taipei 115, Taiwan, China.
67
Taiwan Biobank, Institute of Biomedical Sciences, Academia Sinica, Taipei 115, Taiwan, China.
68
Department of Surgery, Tri-Service General Hospital, Taipei 114, Taiwan, China.
69
Department of Surgery, Changhua Christian Hospital, Changhua City 500, Taiwan, China.
70
1] Department of Genetics, Institute for Cancer Research, Oslo University Hospital, Radiumhospitalet, N-0310 Oslo, Norway [2] Institute of Clinical Medicine, University of Oslo (UiO), 0318 Oslo, Norway.
71
1] Cancer Epidemiology Centre, Cancer Council Victoria, Melbourne, Victoria 3004, Australia [2] Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, Victoria 3010, Australia.
72
1] Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, Victoria 3010, Australia [2] Cancer Epidemiology Centre, The Cancer Council Victoria, Melbourne, Victoria 3053, Australia.
73
Anatomical Pathology, The Alfred Hospital, Melbourne, Victoria 3004, Australia.
74
1] Division of Health Sciences, Warwick Medical School, Warwick University, Coventry CV4 7AL, UK [2] Institute of Population Health, University of Manchester, Manchester M13 9PL, UK.
75
Division of Health Sciences, Warwick Medical School, Warwick University, Coventry CV4 7AL, UK.
76
Ministry of Public Health, Bangkok 10400, Thailand.
77
1] Department of Surgery, Yong Loo Lin School of Medicine, National University of Singapore and National University Health System, Singapore 119228, Singapore [2] Saw Swee Hock School of Public Health, National University of Singapore and National University Health System, Singapore 117597, Singapore.
78
Saw Swee Hock School of Public Health, National University of Singapore and National University Health System, Singapore 117597, Singapore.
79
Division of General Surgery, National University Health System, Singapore 117597, Singapore.
80
1] Saw Swee Hock School of Public Health, National University of Singapore and National University Health System, Singapore 117597, Singapore [2] Department of Statistics and Applied Probability, National University of Singapore, Singapore 117546, Singapore.
81
1] Division of Hematology and Oncology, Department of Medicine, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, California 90095, USA [2] Department of Gynecology and Obstetrics, University Breast Center Franconia, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nuremberg, Comprehensive Cancer Center Erlangen-EMN, 91054 Erlangen, Germany.
82
Department of Gynecology and Obstetrics, University Breast Center Franconia, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nuremberg, Comprehensive Cancer Center Erlangen-EMN, 91054 Erlangen, Germany.
83
Institute of Human Genetics, University Hospital Erlangen, Friedrich Alexander University Erlangen-Nuremberg, 91054 Erlangen, Germany.
84
1] Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany [2] German Cancer Consortium (DKTK), 69120 Heidelberg, Germany.
85
Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany.
86
Saarland Cancer Registry, 66119 Saarbrücken, Germany.
87
1] Division of Breast Cancer Research, Institute of Cancer Research, London SM2 5NG, UK [2] Division of Genetics and Epidemiology, Institute of Cancer Research, London SM2 5NG, UK.
88
Breakthrough Breast Cancer Research Centre, Division of Breast Cancer Research, The Institute of Cancer Research, London SW3 6JB, UK.
89
Division of Genetics and Epidemiology, Institute of Cancer Research, London SM2 5NG, UK.
90
1] Breakthrough Breast Cancer Research Centre, Division of Breast Cancer Research, The Institute of Cancer Research, London SW3 6JB, UK [2] Division of Genetics and Epidemiology, Institute of Cancer Research, Sutton, Surrey SM2 5NG, UK.
91
Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, Maryland 20850, USA.
92
Department of Cancer Epidemiology and Prevention, M. Sklodowska-Curie Memorial Cancer Center and Institute of Oncology, 02-781 Warsaw, Poland.
93
Cancer Genomics Laboratory, Centre Hospitalier Universitaire de Québec Research Center, Laval University, Quebec, Canada G1V 4G2.
94
1] Department of Medicine, McGill University, Montreal, Quebec, Canada H3G 2M1 [2] Division of Clinical Epidemiology, McGill University Health Centre, Royal Victoria Hospital, Montreal, Quebec, Canada H3A 1A8.
95
Département de médecine sociale et préventive, Département de santé environnementale et santé au travail, Université de Montréal, Montreal, Quebec, Canada H3T 1A8.
96
Laboratory of Cancer Genetics and Tumor Biology, Department of Clinical Chemistry and Biocenter Oulu, NordLab Oulu/Oulu University Hospital, University of Oulu, FI-90220 Oulu, Finland.
97
Department of Oncology, Oulu University Hospital, University of Oulu, FI-90220 Oulu, Finland.
98
1] Dr Margarete Fischer-Bosch-Institute of Clinical Pharmacology, 70376 Stuttgart, Germany [2] University of Tübingen, 72074 Tübingen, Germany [3] German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany.
99
Institute for Prevention and Occupational Medicine of the German Social Accident Insurance, Institute of the Ruhr University Bochum (IPA), 44789 Bochum, Germany.
100
Department of Internal Medicine, Evangelische Kliniken Bonn gGmbH, Johanniter Krankenhaus, 53113 Bonn, Germany.
101
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.
102
IFOM, Fondazione Istituto FIRC di Oncologia Molecolare, 20139 Milan, Italy.
103
Division of Cancer Prevention and Genetics, Istituto Europeo di Oncologia (IEO), 20141 Milan, Italy.
104
1] IFOM, Fondazione Istituto FIRC di Oncologia Molecolare, 20139 Milan, Italy [2] Cogentech Cancer Genetic Test Laboratory, 20133 Milan, Italy.
105
Department of Obstetrics and Gynaecology, Hannover Medical School, 30625 Hannover, Germany.
106
Department of Radiation Oncology, Hannover Medical School, 30625 Hannover, Germany.
107
1] Cancer Center of Eastern Finland, University of Eastern Finland, FI-70211 Kuopio, Finland [2] Imaging Center, Department of Clinical Pathology, Kuopio University Hospital, FI-70210 Kuopio, Finland [3] School of Medicine, Institute of Clinical Medicine, Oncology, University of Eastern Finland, FI-70211 Kuopio, Finland.
108
1] Cancer Center of Eastern Finland, University of Eastern Finland, FI-70211 Kuopio, Finland [2] School of Medicine, Institute of Clinical Medicine, Oncology, University of Eastern Finland, FI-70211 Kuopio, Finland.
109
Department of Human Genetics &Department of Pathology, Leiden University Medical Center, 2300 RC Leiden, The Netherlands.
110
Department of Surgical Oncology, Leiden University Medical Center, 2300 RC Leiden, The Netherlands.
111
Family Cancer Clinic, Department of Medical Oncology, Erasmus MC-Daniel den Hoed Cancer Centre, 3075 EA Rotterdam, The Netherlands.
112
Department of Genetics and Pathology, Pomeranian Medical University, 70-115 Szczecin, Poland.
113
Department of Molecular Virology, Immunology and Medical Genetics, Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio 43210, USA.
114
Roswell Park Cancer Institute, Buffalo, New York 14263, USA.
115
Molecular Diagnostics Laboratory, IRRP, National Centre for Scientific Research 'Demokritos', Aghia Paraskevi Attikis, Athens 15310, Greece.
116
National Cancer Institute, Bangkok 10400, Thailand.
117
International Agency for Research on Cancer, Lyon, Cedex 08, France.
118
Molecular Genetics of Breast Cancer, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany.
119
1] Molecular Genetics of Breast Cancer, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany [2] Institute of Human Genetics, Pontificia University Javeriana, Bogota, DC 11001000, Colombia.
120
Department of Epidemiology, University of California Irvine, Irvine, California 92697, USA.
121
Department of Population Sciences, Beckman Research Institute of City of Hope, Duarte, California 92697, USA.
122
Human Genotyping-CEGEN Unit, Human Cancer Genetics Program, Spanish National Cancer Research Centre (CNIO), 28029 Madrid, Spain.
123
Centre d'innovation Génome Québec et Université McGill, Montréal, Quebec, Canada H3A OG1.
124
McGill University, Montreal, Quebec, Canada H3A OG1.
125
Cancer Research UK, Cambridge Institute, University of Cambridge, Robinson Way, Cambridge CB2 0RE, UK.
126
School of Chemistry and Molecular Biosciences, The University of Queensland, Brisbane, Queensland 4072, Australia.
127
1] The Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada M5T 2M9 [2] Ontario Cancer Genetics Network, Lunenfeld-Tanenbaum Research Institute of Mount Sinai Hospital, Toronto, Ontario, Canada M5G 1X5 [3] Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada M5G 1L7.
128
1] Department of Genetics, Institute for Cancer Research, Oslo University Hospital, Radiumhospitalet, N-0310 Oslo, Norway [2] Institute of Clinical Medicine, University of Oslo (UiO), 0318 Oslo, Norway [3] Department of Clinical Molecular Biology (EpiGen), University of Oslo (UiO), 0450 Oslo, Norway.
129
1] Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Cambridge CB1 8RN, UK [2] Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge CB1 8RN, UK.

Abstract

GWAS have identified a breast cancer susceptibility locus on 2q35. Here we report the fine mapping of this locus using data from 101,943 subjects from 50 case-control studies. We genotype 276 SNPs using the 'iCOGS' genotyping array and impute genotypes for a further 1,284 using 1000 Genomes Project data. All but two, strongly correlated SNPs (rs4442975 G/T and rs6721996 G/A) are excluded as candidate causal variants at odds against >100:1. The best functional candidate, rs4442975, is associated with oestrogen receptor positive (ER+) disease with an odds ratio (OR) in Europeans of 0.85 (95% confidence interval=0.84-0.87; P=1.7 × 10(-43)) per t-allele. This SNP flanks a transcriptional enhancer that physically interacts with the promoter of IGFBP5 (encoding insulin-like growth factor-binding protein 5) and displays allele-specific gene expression, FOXA1 binding and chromatin looping. Evidence suggests that the g-allele confers increased breast cancer susceptibility through relative downregulation of IGFBP5, a gene with known roles in breast cell biology.

PMID:
25248036
PMCID:
PMC4321900
DOI:
10.1038/ncomms5999
[Indexed for MEDLINE]
Free PMC Article

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