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

Maya Ghoussaini, Stacey L. Edwards, Kyriaki Michailidou, Silje Nord, Richard Cowper-Sal·lari, Kinjal Desai, Siddhartha Kar, Kristine M. Hillman, Susanne Kaufmann, Dylan M. Glubb, Jonathan Beesley, Joe Dennis, Manjeet K. Bolla, Qin Wang, Ed Dicks, Qi Guo, Marjanka K. Schmidt, Mitul Shah, Robert Luben, Judith Brown, Kamila Czene, Hatef Darabi, Mikael Eriksson, Daniel Klevebring, Stig E. Bojesen, Børge G. Nordestgaard, Sune F. Nielsen, Henrik Flyger, Diether Lambrechts, Bernard Thienpont, Patrick Neven, Hans Wildiers, Annegien Broeks, Laura J. Van’t Veer, Emiel J. Th Rutgers, Fergus J. Couch, Janet E. Olson, Emily Hallberg, Celine Vachon, Jenny Chang-Claude, Anja Rudolph, Petra Seibold, Dieter Flesch-Janys, Julian Peto, Isabel dos-Santos-Silva, Lorna Gibson, Heli Nevanlinna, Taru A. Muranen, Kristiina Aittomäki, Carl Blomqvist, Per Hall, Jingmei Li, Jianjun Liu, Keith Humphreys, Daehee Kang, Ji-Yeob Choi, Sue K. Park, Dong-Young Noh, Keitaro Matsuo, Hidemi Ito, Hiroji Iwata, Yasushi Yatabe, Pascal Guénel, Thérèse Truong, Florence Menegaux, Marie Sanchez, Barbara Burwinkel, Frederik Marme, Andreas Schneeweiss, Christof Sohn, Anna H. Wu, Chiu-chen Tseng, David Van Den Berg, Daniel O. Stram, Javier Benitez, M. Pilar Zamora, Jose Ignacio Arias Perez, Primitiva Menéndez, Xiao-Ou Shu, Wei Lu, Yu-Tang Gao, Qiuyin Cai, Angela Cox, Simon S. Cross, Malcolm W. R. Reed, Irene L. Andrulis, Julia A. Knight, Gord Glendon, Sandrine Tchatchou, Elinor J. Sawyer, Ian Tomlinson, Michael J. Kerin, Nicola Miller, Christopher A. Haiman, Brian E. Henderson, Fredrick Schumacher, Loic Le Marchand, Annika Lindblom, Sara Margolin, Soo Hwang Teo, Cheng Har Yip, Daphne S. C. Lee, Tien Y. Wong, Maartje J. Hooning, John W. M. Martens, J. Margriet Collée, Carolien H. M. van Deurzen, John L. Hopper, Melissa C. Southey, Helen Tsimiklis, Miroslav K. Kapuscinski, Chen-Yang Shen, Pei-Ei Wu, Jyh-Cherng Yu, Shou-Tung Chen, Grethe Grenaker Alnæs, Anne-Lise Borresen-Dale, Graham G. Giles, Roger L. Milne, Catriona McLean, Kenneth Muir, Artitaya Lophatananon, Sarah Stewart-Brown, Pornthep Siriwanarangsan, Mikael Hartman, Hui Miao, Shaik Ahmad Bin Syed Buhari, Yik Ying Teo, Peter A. Fasching, Lothar Haeberle, Arif B. Ekici, Matthias W. Beckmann, Hermann Brenner, Aida Karina Dieffenbach, Volker Arndt, Christa Stegmaier, Anthony Swerdlow, Alan Ashworth, Nick Orr, Minouk J. Schoemaker, Montserrat García-Closas, Jonine Figueroa, Stephen J. Chanock, Jolanta Lissowska, Jacques Simard, Mark S. Goldberg, France Labrèche, Martine Dumont, Robert Winqvist, Katri Pylkäs, Arja Jukkola-Vuorinen, Hiltrud Brauch, Thomas Brüning, Yon-Dschun Koto, Paolo Radice, Paolo Peterlongo, Bernardo Bonanni, Sara Volorio, Thilo Dörk, Natalia V. Bogdanova, Sonja Helbig, Arto Mannermaa, Vesa Kataja, Veli-Matti Kosma, Jaana M. Hartikainen, Peter Devilee, Robert A. E. M. Tollenaar, Caroline Seynaeve, Christi J. Van Asperen, Anna Jakubowska, Jan Lubinski, Katarzyna Jaworska-Bieniek, Katarzyna Durda, Susan Slager, Amanda E. Toland, Christine B. Ambrosone, Drakoulis Yannoukakos, Suleeporn Sangrajrang, Valerie Gaborieau, Paul Brennan, James McKay, Ute Hamann, Diana Torres, Wei Zheng, Jirong Long, Hoda Anton-Culver, Susan L. Neuhausen, Craig Luccarini, Caroline Baynes, Shahana Ahmed, Mel Maranian, Catherine S. Healey, Anna González-Neira, Guillermo Pita, M. Rosario Alonso, Nuria Álvarez, Daniel Herrero, Daniel C. Tessier, Daniel Vincent, Francois Bacot, Ines de Santiago, Jason Carroll, Carlos Caldas, Melissa A. Brown, Mathieu Lupien, Vessela N. Kristensen, Paul D P Pharoah, Georgia Chenevix-Trench, Juliet D French, Douglas F. Easton and Alison M. Dunning ()
Additional contact information
Maya Ghoussaini: Centre for Cancer Genetic Epidemiology
Stacey L. Edwards: QIMR Berghofer Medical Research Institute
Kyriaki Michailidou: Centre for Cancer Genetic Epidemiology, University of Cambridge
Silje Nord: Institute for Cancer Research, Oslo University Hospital, Radiumhospitalet
Richard Cowper-Sal·lari: The Princess Margaret Cancer Centre, University Health Network
Kinjal Desai: The Princess Margaret Cancer Centre, University Health Network
Siddhartha Kar: Centre for Cancer Genetic Epidemiology, University of Cambridge
Kristine M. Hillman: QIMR Berghofer Medical Research Institute
Susanne Kaufmann: QIMR Berghofer Medical Research Institute
Dylan M. Glubb: QIMR Berghofer Medical Research Institute
Jonathan Beesley: QIMR Berghofer Medical Research Institute
Joe Dennis: Centre for Cancer Genetic Epidemiology, University of Cambridge
Manjeet K. Bolla: Centre for Cancer Genetic Epidemiology, University of Cambridge
Qin Wang: Centre for Cancer Genetic Epidemiology, University of Cambridge
Ed Dicks: Centre for Cancer Genetic Epidemiology
Qi Guo: Centre for Cancer Genetic Epidemiology
Marjanka K. Schmidt: Netherlands Cancer Institute, Antoni van Leeuwenhoek hospital
Mitul Shah: Centre for Cancer Genetic Epidemiology
Robert Luben: Centre for Cancer Genetic Epidemiology, University of Cambridge
Judith Brown: Centre for Cancer Genetic Epidemiology, University of Cambridge
Kamila Czene: Karolinska Institutet
Hatef Darabi: Karolinska Institutet
Mikael Eriksson: Karolinska Institutet
Daniel Klevebring: Karolinska Institutet
Stig E. Bojesen: Copenhagen General Population Study, Herlev Hospital
Børge G. Nordestgaard: Copenhagen General Population Study, Herlev Hospital
Sune F. Nielsen: Copenhagen General Population Study, Herlev Hospital
Henrik Flyger: Herlev Hospital, Copenhagen University Hospital
Diether Lambrechts: Laboratory for Translational Genetics
Bernard Thienpont: Vesalius Research Center (VRC), VIB
Patrick Neven: University of Leuven
Hans Wildiers: University of Leuven
Annegien Broeks: Netherlands Cancer Institute, Antoni van Leeuwenhoek hospital
Laura J. Van’t Veer: Netherlands Cancer Institute, Antoni van Leeuwenhoek hospital
Emiel J. Th Rutgers: Netherlands Cancer Institute, Antoni van Leeuwenhoek hospital
Fergus J. Couch: Mayo Clinic
Janet E. Olson: Mayo Clinic
Emily Hallberg: Mayo Clinic
Celine Vachon: Mayo Clinic
Jenny Chang-Claude: German Cancer Research Center (DKFZ)
Anja Rudolph: German Cancer Research Center (DKFZ)
Petra Seibold: German Cancer Research Center (DKFZ)
Dieter Flesch-Janys: University Clinic Hamburg-Eppendorf
Julian Peto: London School of Hygiene and Tropical Medicine
Isabel dos-Santos-Silva: London School of Hygiene and Tropical Medicine
Lorna Gibson: London School of Hygiene and Tropical Medicine
Heli Nevanlinna: Helsinki University Central Hospital
Taru A. Muranen: Helsinki University Central Hospital
Kristiina Aittomäki: University of Helsinki Helsinki University Central Hospital
Carl Blomqvist: University of Helsinki, Helsinki University Central Hospital
Per Hall: Karolinska Institutet
Jingmei Li: Genome Institute of Singapore
Jianjun Liu: Genome Institute of Singapore
Keith Humphreys: Karolinska Institutet
Daehee Kang: Cancer Research Institute, Seoul National University College of Medicine
Ji-Yeob Choi: Cancer Research Institute, Seoul National University College of Medicine
Sue K. Park: Cancer Research Institute, Seoul National University College of Medicine
Dong-Young Noh: Seoul National University College of Medicine
Keitaro Matsuo: Kyushu University Faculty of Medical Sciences
Hidemi Ito: Aichi Cancer Center Research Institute
Hiroji Iwata: Aichi Cancer Center Hospital
Yasushi Yatabe: Aichi Cancer Center Hospital
Pascal Guénel: Inserm (National Institute of Health and Medical Research), CESP (Center for Research in Epidemiology and Population Health), U1018, Environmental Epidemiology of Cancer
Thérèse Truong: Inserm (National Institute of Health and Medical Research), CESP (Center for Research in Epidemiology and Population Health), U1018, Environmental Epidemiology of Cancer
Florence Menegaux: Inserm (National Institute of Health and Medical Research), CESP (Center for Research in Epidemiology and Population Health), U1018, Environmental Epidemiology of Cancer
Marie Sanchez: Inserm (National Institute of Health and Medical Research), CESP (Center for Research in Epidemiology and Population Health), U1018, Environmental Epidemiology of Cancer
Barbara Burwinkel: University of Heidelberg
Frederik Marme: University of Heidelberg
Andreas Schneeweiss: University of Heidelberg
Christof Sohn: University of Heidelberg
Anna H. Wu: Keck School of Medicine University of Southern California
Chiu-chen Tseng: Keck School of Medicine University of Southern California
David Van Den Berg: Keck School of Medicine University of Southern California
Daniel O. Stram: Keck School of Medicine University of Southern California
Javier Benitez: Centro de Investigación en Red de Enfermedades Raras (CIBERER)
M. Pilar Zamora: Servicio de Oncología Médica, Hospital Universitario La Paz
Jose Ignacio Arias Perez: Servicio de Cirugía General y Especialidades, Hospital Monte Naranco
Primitiva Menéndez: Servicio de Anatomía Patológica, Hospital Monte Naranco
Xiao-Ou Shu: Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine
Wei Lu: Shanghai Center for Disease Control and Prevention
Yu-Tang Gao: Shanghai Cancer Institute
Qiuyin Cai: Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine
Angela Cox: CRUK/YCR Sheffield Cancer Research Centre, University of Sheffield
Simon S. Cross: Academic Unit of Pathology
Malcolm W. R. Reed: CRUK/YCR Sheffield Cancer Research Centre, University of Sheffield
Irene L. Andrulis: Lunenfeld-Tanenbaum Research Institute of Mount Sinai Hospital
Julia A. Knight: Dalla Lana School of Public Health University of Toronto
Gord Glendon: Ontario Cancer Genetics Network, Lunenfeld-Tanenbaum Research Institute of Mount Sinai Hospital
Sandrine Tchatchou: Lunenfeld-Tanenbaum Research Institute of Mount Sinai Hospital
Elinor J. Sawyer: NIHR Comprehensive Biomedical Research Centre, Guy’s & St Thomas’ NHS Foundation Trust in partnership with King's College London
Ian Tomlinson: Wellcome Trust Centre for Human Genetics, Oxford Biomedical Research Centre, University of Oxford
Michael J. Kerin: Clinical Science Institute, University Hospital Galway
Nicola Miller: Clinical Science Institute, University Hospital Galway
Christopher A. Haiman: Keck School of Medicine University of Southern California Norris Comprehensive Cancer Center
Brian E. Henderson: Keck School of Medicine University of Southern California Norris Comprehensive Cancer Center
Fredrick Schumacher: Keck School of Medicine University of Southern California Norris Comprehensive Cancer Center
Loic Le Marchand: Epidemiology Program, Cancer Research Center, University of Hawaii
Annika Lindblom: Karolinska Institutet
Sara Margolin: Karolinska Institutet
Soo Hwang Teo: Breast Cancer Research Unit, University Malaya Cancer Research Institute, University Malaya Medical Centre
Cheng Har Yip: Breast Cancer Research Unit, University Malaya Cancer Research Institute, University Malaya Medical Centre
Daphne S. C. Lee: Cancer Research Initiatives Foundation, Sime Darby Medical Centre
Tien Y. Wong: Singapore Eye Research Institute, National University of Singapore
Maartje J. Hooning: Erasmus MC Cancer Institute
John W. M. Martens: Erasmus MC Cancer Institute
J. Margriet Collée: Erasmus University Medical Center
Carolien H. M. van Deurzen: Erasmus University Medical Center
John L. Hopper: Centre for Molecular, Environmental, Genetic and Analytical Epidemiology, Melbourne School of Population Health, University of Melbourne
Melissa C. Southey: The University of Melbourne
Helen Tsimiklis: The University of Melbourne
Miroslav K. Kapuscinski: Centre for Molecular, Environmental, Genetic and Analytical Epidemiology, Melbourne School of Population Health, University of Melbourne
Chen-Yang Shen: College of Public Health, China Medical University
Pei-Ei Wu: Taiwan Biobank, Institute of Biomedical Sciences, Academia Sinica
Jyh-Cherng Yu: Tri-Service General Hospital
Shou-Tung Chen: Changhua Christian Hospital
Grethe Grenaker Alnæs: Institute for Cancer Research, Oslo University Hospital, Radiumhospitalet
Anne-Lise Borresen-Dale: Institute for Cancer Research, Oslo University Hospital, Radiumhospitalet
Graham G. Giles: Cancer Epidemiology Centre, Cancer Council Victoria
Roger L. Milne: Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne
Catriona McLean: Anatomical Pathology, The Alfred Hospital
Kenneth Muir: Warwick Medical School, Warwick University
Artitaya Lophatananon: Warwick Medical School, Warwick University
Sarah Stewart-Brown: Warwick Medical School, Warwick University
Pornthep Siriwanarangsan: Ministry of Public Health
Mikael Hartman: Yong Loo Lin School of Medicine National University of Singapore and National University Health System
Hui Miao: Saw Swee Hock School of Public Health, National University of Singapore and National University Health System
Shaik Ahmad Bin Syed Buhari: National University Health System
Yik Ying Teo: Saw Swee Hock School of Public Health, National University of Singapore and National University Health System
Peter A. Fasching: University of California at Los Angeles
Lothar Haeberle: University Breast Center Franconia, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nuremberg, Comprehensive Cancer Center Erlangen-EMN
Arif B. Ekici: Institute of Human Genetics, University Hospital Erlangen, Friedrich Alexander University Erlangen-Nuremberg
Matthias W. Beckmann: University Breast Center Franconia, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nuremberg, Comprehensive Cancer Center Erlangen-EMN
Hermann Brenner: German Cancer Research Center (DKFZ)
Aida Karina Dieffenbach: German Cancer Research Center (DKFZ)
Volker Arndt: German Cancer Research Center (DKFZ)
Christa Stegmaier: Saarland Cancer Registry
Anthony Swerdlow: Institute of Cancer Research
Alan Ashworth: Breakthrough Breast Cancer Research Centre, The Institute of Cancer Research
Nick Orr: Breakthrough Breast Cancer Research Centre, The Institute of Cancer Research
Minouk J. Schoemaker: Institute of Cancer Research
Montserrat García-Closas: Breakthrough Breast Cancer Research Centre, The Institute of Cancer Research
Jonine Figueroa: National Cancer Institute
Stephen J. Chanock: National Cancer Institute
Jolanta Lissowska: M. Sklodowska-Curie Memorial Cancer Center and Institute of Oncology
Jacques Simard: Cancer Genomics Laboratory, Centre Hospitalier Universitaire de Québec Research Center, Laval University
Mark S. Goldberg: McGill University
France Labrèche: Université de Montréal
Martine Dumont: Cancer Genomics Laboratory, Centre Hospitalier Universitaire de Québec Research Center, Laval University
Robert Winqvist: Laboratory of Cancer Genetics and Tumor Biology, NordLab Oulu/Oulu University Hospital University of Oulu
Katri Pylkäs: Laboratory of Cancer Genetics and Tumor Biology, NordLab Oulu/Oulu University Hospital University of Oulu
Arja Jukkola-Vuorinen: Oulu University Hospital, University of Oulu
Hiltrud Brauch: Dr Margarete Fischer-Bosch-Institute of Clinical Pharmacology
Thomas Brüning: Institute for Prevention and Occupational Medicine of the German Social Accident Insurance, Institute of the Ruhr University Bochum (IPA)
Yon-Dschun Koto: Evangelische Kliniken Bonn gGmbH, Johanniter Krankenhaus
Paolo Radice: Fondazione IRCCS Istituto Nazionale dei Tumori (INT)
Paolo Peterlongo: IFOM, Fondazione Istituto FIRC di Oncologia Molecolare
Bernardo Bonanni: Istituto Europeo di Oncologia (IEO)
Sara Volorio: IFOM, Fondazione Istituto FIRC di Oncologia Molecolare
Thilo Dörk: Hannover Medical School
Natalia V. Bogdanova: Hannover Medical School
Sonja Helbig: Hannover Medical School
Arto Mannermaa: Cancer Center of Eastern Finland, University of Eastern Finland
Vesa Kataja: Cancer Center of Eastern Finland, University of Eastern Finland
Veli-Matti Kosma: Cancer Center of Eastern Finland, University of Eastern Finland
Jaana M. Hartikainen: Cancer Center of Eastern Finland, University of Eastern Finland
Peter Devilee: Leiden University Medical Center
Robert A. E. M. Tollenaar: Leiden University Medical Center
Caroline Seynaeve: Family Cancer Clinic, Erasmus MC-Daniel den Hoed Cancer Centre
Christi J. Van Asperen: Erasmus University Medical Center
Anna Jakubowska: Pomeranian Medical University
Jan Lubinski: Pomeranian Medical University
Katarzyna Jaworska-Bieniek: Pomeranian Medical University
Katarzyna Durda: Pomeranian Medical University
Susan Slager: Mayo Clinic
Amanda E. Toland: Immunology and Medical Genetics, Comprehensive Cancer Center, The Ohio State University
Christine B. Ambrosone: Roswell Park Cancer Institute
Drakoulis Yannoukakos: Molecular Diagnostics Laboratory, IRRP, National Centre for Scientific Research ‘Demokritos’, Aghia Paraskevi Attikis
Suleeporn Sangrajrang: National Cancer Institute
Valerie Gaborieau: International Agency for Research on Cancer
Paul Brennan: International Agency for Research on Cancer
James McKay: International Agency for Research on Cancer
Ute Hamann: Molecular Genetics of Breast Cancer, German Cancer Research Center (DKFZ)
Diana Torres: Molecular Genetics of Breast Cancer, German Cancer Research Center (DKFZ)
Wei Zheng: Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine
Jirong Long: Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine
Hoda Anton-Culver: University of California Irvine
Susan L. Neuhausen: Beckman Research Institute of City of Hope
Craig Luccarini: Centre for Cancer Genetic Epidemiology
Caroline Baynes: Centre for Cancer Genetic Epidemiology
Shahana Ahmed: Centre for Cancer Genetic Epidemiology
Mel Maranian: Centre for Cancer Genetic Epidemiology
Catherine S. Healey: Centre for Cancer Genetic Epidemiology
Anna González-Neira: Human Genotyping-CEGEN Unit, Human Cancer Genetics Program, Spanish National Cancer Research Centre (CNIO)
Guillermo Pita: Human Genotyping-CEGEN Unit, Human Cancer Genetics Program, Spanish National Cancer Research Centre (CNIO)
M. Rosario Alonso: Human Genotyping-CEGEN Unit, Human Cancer Genetics Program, Spanish National Cancer Research Centre (CNIO)
Nuria Álvarez: Human Genotyping-CEGEN Unit, Human Cancer Genetics Program, Spanish National Cancer Research Centre (CNIO)
Daniel Herrero: Human Genotyping-CEGEN Unit, Human Cancer Genetics Program, Spanish National Cancer Research Centre (CNIO)
Daniel C. Tessier: Centre d’innovation Génome Québec et Université McGill
Daniel Vincent: McGill University
Francois Bacot: McGill University
Ines de Santiago: Cancer Research UK, Cambridge Institute, University of Cambridge, Robinson Way
Jason Carroll: Cancer Research UK, Cambridge Institute, University of Cambridge, Robinson Way
Carlos Caldas: Cancer Research UK, Cambridge Institute, University of Cambridge, Robinson Way
Melissa A. Brown: School of Chemistry and Molecular Biosciences, The University of Queensland
Mathieu Lupien: The Princess Margaret Cancer Centre, University Health Network
Vessela N. Kristensen: Institute for Cancer Research, Oslo University Hospital, Radiumhospitalet
Paul D P Pharoah: Centre for Cancer Genetic Epidemiology
Georgia Chenevix-Trench: QIMR Berghofer Medical Research Institute
Juliet D French: QIMR Berghofer Medical Research Institute
Douglas F. Easton: Centre for Cancer Genetic Epidemiology
Alison M. Dunning: Centre for Cancer Genetic Epidemiology

Nature Communications, 2014, vol. 5, issue 1, 1-12

Abstract: 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.

Date: 2014
References: Add references at CitEc
Citations:

Downloads: (external link)
https://www.nature.com/articles/ncomms5999 Abstract (text/html)

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:5:y:2014:i:1:d:10.1038_ncomms5999

Ordering information: This journal article can be ordered from
https://www.nature.com/ncomms/

DOI: 10.1038/ncomms5999

Access Statistics for this article

Nature Communications is currently edited by Nathalie Le Bot, Enda Bergin and Fiona Gillespie

More articles in Nature Communications from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().