Fulltext

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

Ghoussaini M 1 , Edwards SL 2 , Michailidou K 3 , Nord S 4 , Cowper-Sal Lari R 5 , Desai K 6 Show all authors , Kar S 3 , Hillman KM 2 , Kaufmann S 2 , Glubb DM 7 , Beesley J 7 , Dennis J 3 , Bolla MK 3 , Wang Q 3 , Dicks E 1 , Guo Q 1 , Schmidt MK 8 , Shah M 1 , Luben R 3 , Brown J 3 , Czene K 9 , Darabi H 9 , Eriksson M 9 , Klevebring D 9 , Bojesen SE 10 , Nordestgaard BG 10 , Nielsen SF 11 , Flyger H 12 , Lambrechts D 13 , Thienpont B 14 , Neven P 15 , Wildiers H 15 , Broeks A 8 , Van't Veer LJ 8 , Th Rutgers EJ 8 , Couch FJ 16 , Olson JE 17 , Hallberg E 17 , Vachon C 17 , Chang-Claude J 18 , Rudolph A 18 , Seibold P 18 , Flesch-Janys D 19 , Peto J 20 , Dos-Santos-Silva I 20 , Gibson L 20 , Nevanlinna H 21 , Muranen TA 21 , Aittomäki K 22 , Blomqvist C 23 , Hall P 9 , Li J 24 , Liu J 24 , Humphreys K 9 , Kang D 25 , Choi JY 26 , Park SK 25 , Noh DY 27 , Matsuo K 28 , Ito H 29 , Iwata H 30 , Yatabe Y 31 , Guénel P 32 , Truong T 32 , Menegaux F 32 , Sanchez M 32 , Burwinkel B 33 , Marme F 34 , Schneeweiss A 34 , Sohn C 35 , Wu AH 36 , Tseng CC 36 , Van Den Berg D 36 , Stram DO 36 , Benitez J 37 , Zamora MP 38 , Perez JI 39 , Menéndez P 40 , Shu XO 41 , Lu W 42 , Gao YT 43 , Cai Q 41 , Cox A 44 , Cross SS 45 , Reed MW 44 , Andrulis IL 46 , Knight JA 47 , Glendon G 48 , Tchatchou S 49 , Sawyer EJ 50 , Tomlinson I 51 , Kerin MJ 52 , Miller N 52 , Haiman CA 53 , Henderson BE 53 , Schumacher F 53 , Le Marchand L 54 , Lindblom A 55 , Margolin S 56 , Teo SH 57 , Yip CH 58 , Lee DS 59 , Wong TY 60 , Hooning MJ 61 , Martens JW 61 , Collée JM 62 , van Deurzen CH 63 , Hopper JL 64 , Southey MC 65 , Tsimiklis H 65 , Kapuscinski MK 64 , Shen CY 66 , Wu PE 67 , Yu JC 68 , Chen ST 69 , Alnæs GG 4 , Borresen-Dale AL 70 , Giles GG 71 , Milne RL 72 , McLean C 73 , Muir K 74 , Lophatananon A 75 , Stewart-Brown S 75 , Siriwanarangsan P 76 , Hartman M 77 , Miao H 78 , Buhari SA 79 , Teo YY 80 , Fasching PA 81 , Haeberle L 82 , Ekici AB 83 , Beckmann MW 82 , Brenner H 84 , Dieffenbach AK 84 , Arndt V 85 , Stegmaier C 86 , Swerdlow A 87 , Ashworth A 88 , Orr N 88 , Schoemaker MJ 89 , García-Closas M 90 , Figueroa J 91 , Chanock SJ 91 , Lissowska J 92 , Simard J 93 , Goldberg MS 94 , Labrèche F 95 , Dumont M 93 , Winqvist R 96 , Pylkäs K 96 , Jukkola-Vuorinen A 97 , Brauch H 98 , Brüning T 99 , Koto YD 100 , Radice P 101 , Peterlongo P 102 , Bonanni B 103 , Volorio S 104 , Dörk T 105 , Bogdanova NV 106 , Helbig S 105 , Mannermaa A 107 , Kataja V 108 , Kosma VM 107 , Hartikainen JM 107 , Devilee P 109 , Tollenaar RA 110 , Seynaeve C 111 , Van Asperen CJ 62 , Jakubowska A 112 , Lubinski J 112 , Jaworska-Bieniek K 112 , Durda K 112 , Slager S 17 , Toland AE 113 , Ambrosone CB 114 , Yannoukakos D 115 , Sangrajrang S 116 , Gaborieau V 117 , Brennan P 117 , McKay J 117 , Hamann U 118 , Torres D 119 , Zheng W 41 , Long J 41 , Anton-Culver H 120 , Neuhausen SL 121 , Luccarini C 1 , Baynes C 1 , Ahmed S 1 , Maranian M 1 , Healey CS 1 , González-Neira A 122 , Pita G 122 , Alonso MR 122 , Alvarez N 122 , Herrero D 122 , Tessier DC 123 , Vincent D 124 , Bacot F 124 , de Santiago I 125 , Carroll J 125 , Caldas C 125 , Brown MA 126 , Lupien M 127 , Kristensen VN 128 , Pharoah PD 129 , Chenevix-Trench G 7 , French JD 2 , Easton DF 129 , Dunning AM 1 , Australian Ovarian Cancer Management Group Australian Ovarian Cancer Management Group

Affiliations 

  • 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
Nat Commun, 2014 Sep 23;4:4999.
PMID: 25248036 DOI: 10.1038/ncomms5999

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.

* Title and MeSH Headings from MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

MeSH terms
Similar publications