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.
| Original language | English |
|---|---|
| Article number | 4999 |
| Journal | Nature Communications |
| Volume | 4 |
| DOIs | |
| State | Published - 2014 |
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In: Nature Communications, Vol. 4, 4999, 2014.
Research output: Contribution to journal › Article › peer-review
TY - JOUR
T1 - Evidence that breast cancer risk at the 2q35 locus is mediated through IGFBP5 regulation
AU - Ghoussaini, Maya
AU - Edwards, Stacey L.
AU - Michailidou, Kyriaki
AU - Nord, Silje
AU - Cowper-Sal-lari, Richard
AU - Desai, Kinjal
AU - Kar, Siddhartha
AU - Hillman, Kristine M.
AU - Kaufmann, Susanne
AU - Glubb, Dylan M.
AU - Beesley, Jonathan
AU - Dennis, Joe
AU - Bolla, Manjeet K.
AU - Wang, Qin
AU - Dicks, Ed
AU - Guo, Qi
AU - Schmidt, Marjanka K.
AU - Shah, Mitul
AU - Luben, Robert
AU - Brown, Judith
AU - Czene, Kamila
AU - Darabi, Hatef
AU - Eriksson, Mikael
AU - Klevebring, Daniel
AU - Bojesen, Stig E.
AU - Nordestgaard, Børge G.
AU - Nielsen, Sune F.
AU - Flyger, Henrik
AU - Lambrechts, Diether
AU - Thienpont, Bernard
AU - Neven, Patrick
AU - Wildiers, Hans
AU - Broeks, Annegien
AU - Vant Veer, Laura J.
AU - Rutgers, Emiel J.Th
AU - Couch, Fergus J.
AU - Olson, Janet E.
AU - Hallberg, Emily
AU - Vachon, Celine
AU - Chang-Claude, Jenny
AU - Rudolph, Anja
AU - Seibold, Petra
AU - Flesch-Janys, Dieter
AU - Peto, Julian
AU - Dos-Santos-Silva, Isabel
AU - Gibson, Lorna
AU - Nevanlinna, Heli
AU - Muranen, Taru A.
AU - Aittomäki, Kristiina
AU - Blomqvist, Carl
AU - Hall, Per
AU - Li, Jingmei
AU - Liu, Jianjun
AU - Humphreys, Keith
AU - Kang, Daehee
AU - Choi, Ji Yeob
AU - Park, Sue K.
AU - Noh, Dong Young
AU - Matsuo, Keitaro
AU - Ito, Hidemi
AU - Iwata, Hiroji
AU - Yatabe, Yasushi
AU - Guénel, Pascal
AU - Truong, Thérèse
AU - Menegaux, Florence
AU - Sanchez, Marie
AU - Burwinkel, Barbara
AU - Marme, Frederik
AU - Schneeweiss, Andreas
AU - Sohn, Christof
AU - Wu, Anna H.
AU - Tseng, Chiu Chen
AU - Van Den Berg, David
AU - Stram, Daniel O.
AU - Benitez, Javier
AU - Zamora, M. Pilar
AU - Perez, Jose Ignacio Arias
AU - Menéndez, Primitiva
AU - Shu, Xiao Ou
AU - Lu, Wei
AU - Gao, Yu Tang
AU - Cai, Qiuyin
AU - Cox, Angela
AU - Cross, Simon S.
AU - Reed, Malcolm W.R.
AU - Andrulis, Irene L.
AU - Knight, Julia A.
AU - Glendon, Gord
AU - Tchatchou, Sandrine
AU - Sawyer, Elinor J.
AU - Tomlinson, Ian
AU - Kerin, Michael J.
AU - Miller, Nicola
AU - Haiman, Christopher A.
AU - Henderson, Brian E.
AU - Schumacher, Fredrick
AU - Marchand, Loic Le
AU - Lindblom, Annika
AU - Margolin, Sara
AU - Teo, Soo Hwang
AU - Yip, Cheng Har
AU - Lee, Daphne S.C.
AU - Wong, Tien Y.
AU - Hooning, Maartje J.
AU - Martens, John W.M.
AU - Collée, J. Margriet
AU - Van Deurzen, Carolien H.M.
AU - Hopper, John L.
AU - Southey, Melissa C.
AU - Tsimiklis, Helen
AU - Kapuscinski, Miroslav K.
AU - Shen, Chen Yang
AU - Wu, Pei Ei
AU - Yu, Jyh Cherng
AU - Chen, Shou Tung
AU - Alnæs, Grethe Grenaker
AU - Borresen-Dale, Anne Lise
AU - Giles, Graham G.
AU - Milne, Roger L.
AU - McLean, Catriona
AU - Muir, Kenneth
AU - Lophatananon, Artitaya
AU - Stewart-Brown, Sarah
AU - Siriwanarangsan, Pornthep
AU - Hartman, Mikael
AU - Miao, Hui
AU - Buhari, Shaik Ahmad Bin Syed
AU - Teo, Yik Ying
AU - Fasching, Peter A.
AU - Haeberle, Lothar
AU - Ekici, Arif B.
AU - Beckmann, Matthias W.
AU - Brenner, Hermann
AU - Dieffenbach, Aida Karina
AU - Arndt, Volker
AU - Stegmaier, Christa
AU - Swerdlow, Anthony
AU - Ashworth, Alan
AU - Orr, Nick
AU - Schoemaker, Minouk J.
AU - García-Closas, Montserrat
AU - Figueroa, Jonine
AU - Chanock, Stephen J.
AU - Lissowska, Jolanta
AU - Simard, Jacques
AU - Goldberg, Mark S.
AU - Labrèche, France
AU - Dumont, Martine
AU - Winqvist, Robert
AU - Pylkäs, Katri
AU - Jukkola-Vuorinen, Arja
AU - Brauch, Hiltrud
AU - Brüning, Thomas
AU - Koto, Yon Dschun
AU - Radice, Paolo
AU - Peterlongo, Paolo
AU - Bonanni, Bernardo
AU - Volorio, Sara
AU - Dörk, Thilo
AU - Bogdanova, Natalia V.
AU - Helbig, Sonja
AU - Mannermaa, Arto
AU - Kataja, Vesa
AU - Kosma, Veli Matti
AU - Hartikainen, Jaana M.
AU - Devilee, Peter
AU - Tollenaar, Robert A.E.M.
AU - Seynaeve, Caroline
AU - Van Asperen, Christi J.
AU - Jakubowska, Anna
AU - Lubinski, Jan
AU - Jaworska-Bieniek, Katarzyna
AU - Durda, Katarzyna
AU - Slager, Susan
AU - Toland, Amanda E.
AU - Ambrosone, Christine B.
AU - Yannoukakos, Drakoulis
AU - Sangrajrang, Suleeporn
AU - Gaborieau, Valerie
AU - Brennan, Paul
AU - McKay, James
AU - Hamann, Ute
AU - Torres, Diana
AU - Zheng, Wei
AU - Long, Jirong
AU - Anton-Culver, Hoda
AU - Neuhausen, Susan L.
AU - Luccarini, Craig
AU - Baynes, Caroline
AU - Ahmed, Shahana
AU - Maranian, Mel
AU - Healey, Catherine S.
AU - González-Neira, Anna
AU - Pita, Guillermo
AU - Alonso, M. Rosario
AU - Álvarez, Nuria
AU - Herrero, Daniel
AU - Tessier, Daniel C.
AU - Vincent, Daniel
AU - Bacot, Francois
AU - De Santiago, Ines
AU - Carroll, Jason
AU - Caldas, Carlos
AU - Brown, Melissa A.
AU - Lupien, Mathieu
AU - Kristensen, Vessela N.
AU - Pharoah, Paul D.P.
AU - Chenevix-Trench, Georgia
AU - French, Juliet D.
AU - Easton, Douglas F.
AU - Dunning, Alison M.
AU - Webb, Penny
AU - De Fazio, Anna
N1 - Funding Information: BCAC thanks all the individuals who took part in these studies and all the researchers, clinicians, technicians and administrative staff who have enabled this work to be carried out. BCAC is funded by Cancer Research UK (C1287/A10118, C1287/A12014) and by the European Community’s Seventh Framework Programme under grant agreement number 223175 (grant number HEALTH-F2-2009-223175; COGS). Meetings of the BCAC have been funded by the European Union COST programme (BM0606). The COGS study would not have been possible without the contributions of the following: Andrew Berchuck (OCAC), Rosalind A. Eeles, Ali Amin Al Olama, Zsofia Kote-Jarai, Sara Benlloch (PRACTICAL), Antonis Antoniou, Lesley McGuffog, Ken Offit (CIMBA), Andrew Lee, the staff of the Centre for Genetic Epidemiology Laboratory in Cambridge, the staff of the CNIO genotyping unit, Sylvie LaBoissière and Frederic Robidoux and the staff of the McGill University and Génome Québec Innovation Centre, the staff of the Copenhagen DNA laboratory, and Julie M. Cunningham, Sharon A. Windebank, Christopher A. Hilker, Jeffrey Meyer and the staff of Mayo Clinic Geno-typing Core Facility. Genotyping of the iCOGS array was funded by the European Union (HEALTH-F2-2009-223175), Cancer Research UK (C1287/A10710), the Canadian Institutes of Health Research for the ‘CIHR Team in Familial Risks of Breast Cancer’ program—grant #CRN-87521 and the Ministry of Economic Development, Innovation and Export Trade of Quebec—grant #PSR-SIIRI-701. The QIMR Berghofer group was supported by a National Health and Medical Research Council of Australia project grant (1021731). The Princess Margaret Cancer Centre-University Health Network group was supported by the US National Institutes of Health (NIH; R01CA155004 to M.L.) and OICR Young Investigator Award (M.L.). D.F.E. is a Principal Research Fellow of CR-UK. G.C.-T. is an NHMRC Senior Principal Research Fellow. S.L.E. and J.D.F. are supported by Fellowships from the National Breast Cancer Foundation (NBCF) Australia. The funders have no role in study design, data collection and analysis, decision to publish or preparation of the manuscript. The Australian Breast Cancer Family Study (ABCFS) would like to thank Maggie Angelakos, Judi Maskiell and Gillian Dite. ABCFS was supported by grant UM1 CA164920 from the National Cancer Institute (USA). The content of this manuscript does not necessarily reflect the views or policies of the National Cancer Institute or any of the collaborating centres in the Breast Cancer Family Registry (BCFR), nor does it mention trade names, commercial products or organizations that imply endorsement by the USA Government or the BCFR. The ABCFS was also supported by the National Health and Medical Research Council of Australia, the New South Wales Cancer Council, the Victorian Health Promotion Foundation (Australia) and the Victorian Breast Cancer Research Consortium. J.L.H. is a National Health and Medical Research Council (NHMRC) Australia Fellow and a Victorian Breast Cancer Research Consortium Group Leader. M.C.S. is a NHMRC Senior Research Fellow and a Victorian Breast Cancer Research Consortium Group Leader. The ABCS study was supported by the Dutch Cancer Society (grants NKI 2007-3839; 2009 4363); BBMRI-NL, which is a Research Infrastructure financed by the Dutch government (NWO 184.021.007); and the Dutch National Genomics Initiative. The ACP study wishes to thank the participants in the Thai Breast Cancer study. Special thanks also go to the Thai Ministry of Public Health (MOPH), doctors and nurses who helped with the data collection process. Finally, the study would like to thank Dr Prat Boonyawongviroj, the former Permanent Secretary of MOPH and Dr Pornthep Siriwanarungsan, the Department Director-General of Disease Control who have supported the study throughout. The ACP study is funded by the Breast Cancer Research Trust, UK. The BBCC study would like to thank Matthias Rübner, Alexander Hein and Michael Schneider. The work of the BBCC was partly funded by ELAN-Fond of the University Hospital of Erlangen. The BBCS would like to thank Eileen Williams, Elaine Ryder-Mills and Kara Sargus. The BBCS is funded by Cancer Research, UK, and Breakthrough Breast Cancer and acknowledges NHS funding to the NIHR Biomedical Research Centre, and the National Cancer Research Network (NCRN). The BIGGS would like to thank Niall McInerney, Gabrielle Colleran, Andrew Rowan and Angela Jones. E.J.S. is supported by NIHR Comprehensive Biomedical Research Centre, Guy’s & St Thomas’ NHS Foundation Trust in partnership with King’s College London, UK. I.T. is supported by the Oxford Biomedical Research Centre. The BSUCH would like to thank Peter Bugert, Medical Faculty Mannheim. The BSUCH study was supported by the Dietmar-Hopp Foundation, the Helmholtz Society and the German Cancer Research Center (DKFZ). The CECILE study was funded by Fondation de France, Institut National du Cancer (INCa), Ligue Nationale contre le Cancer, Ligue contre le Cancer Grand Ouest, Agence Nationale de Sécurité Sanitaire (ANSES) and Agence Nationale de la Recherche (ANR). The CGPS study would like to thank staff and participants of the Copenhagen General Population Study. It would also like to thank Dorthe Uldall Andersen, Maria Birna Arnadottir, Anne Bank and Dorthe Kjeldgård Hansen for the excellent technical assistance. The Danish Breast Cancer Group (DBCG) is acknowledged for the tumour information. The CGPS was supported by the Chief Physician Johan Boserup and Lise Boserup Fund, the Danish Medical Research Council and Herlev Hospital. The CNIO-BCS would like to thank Guillermo Pita, Charo Alonso, Daniel Herrero, Nuria Álvarez, Pilar Zamora, Primitiva Menendez and the Human Genotyping-CEGEN Unit (CNIO). The CNIO-BCS was supported by the Genome Spain Foundation, the Red Temática de Investigación Cooperativa en Cáncer and grants from the Asociación Española Contra el Cáncer and the Fondo de Investigación Sanitario (PI11/00923 and PI081120). The Human Genotyping-CEGEN Unit (CNIO) is supported by the Instituto de Salud Carlos III. The CTS study would like to thank the CTS steering committee: Leslie Bernstein, Susan Neuhausen, James Lacey, Sophia Wang, Huiyan Ma, Yani Lu and Jessica Clague DeHart at the Beckman Research Institute of the City of Hope; Dennis Deapen, Rich Pinder, Eunjung Lee and Fred Schumacher at the University of Southern California; Pam Horn-Ross, Peggy Reynolds, Christina Clarke and David Nelson at the Cancer Prevention Institute of California; and Hoda Anton-Culver, Hannah Park and Al Ziogas at the University of California, Irvine. The CTS was initially supported by the California Breast Cancer Act of 1993 and the California Breast Cancer Research Fund (contract 97-10500) and is currently funded through the National Institutes of Health (R01 CA77398). Collection of cancer incidence data was supported by the California Department of Public Health as part of the statewide cancer reporting program mandated by California Health and Safety Code Section 103885. H.A.-C. receives support from the Lon V Smith Foundation (LVS39420). The ESTHER study would like to thank Hartwig Ziegler, Sonja Wolf and Volker Hermann. The ESTHER study was supported by a grant from the Baden Württemberg Ministry of Science, Research and Arts. Additional cases were recruited in the context of the VERDI study, which was supported by a grant from the German Cancer Aid (Deutsche Krebshilfe). The GENICA Network would like to thank Dr Margarete Fischer-Bosch-Institute of Clinical Pharmacology, Stuttgart; and University of Tübingen, Germany (H.B., Wing-Yee Lo, Christina Justenhoven); Department of Internal Medicine, Evangelische Kliniken Bonn gGmbH, Johanniter Krankenhaus, Bonn, Germany (Yon-Dschun Ko, Christian Baisch); Institute of Pathology, University of Bonn, Germany (Hans-Peter Fischer); Molecular Genetics of Breast Cancer, Deutsches Krebsforschungszentrum (DKFZ), Heidelberg, Germany (Ute Hamann); Institute for Prevention and Occupational Medicine of the German Social Accident Insurance, Institute of the Ruhr University Bochum (IPA), Bochum, Germany (T.B., Beate Pesch, Sylvia Rabstein, Anne Lotz); and Institute of Occupational Medicine and Maritime Medicine, University Medical Center Hamburg-Eppendorf, Germany (Volker Harth). The GENICA was funded by the Federal Ministry of Education and Research (BMBF) Germany grants 01KW9975/5, 01KW9976/8, 01KW9977/0 and 01KW0114; the Robert Bosch Foundation, Stuttgart; Deutsches Krebsforschungszentrum (DKFZ), Heidelberg; the Institute for Prevention and Occupational Medicine of the German Social Accident Insurance, Institute of the Ruhr University Bochum (IPA), Bochum; as well as the Department of Internal Medicine, Evangelische Kliniken Bonn gGmbH, Johanniter Krankenhaus, Bonn, Germany. The HEBCS would like to thank Kirsimari Aaltonen, Karl von Smitten, Sofia Khan, Tuomas Heikkinen and Irja Erkkilä. The HEBCS was financially supported by the Helsinki University Central Hospital Research Fund, Academy of Finland (266528), the Finnish Cancer Society, The Nordic Cancer Union and the Sigrid Juselius Foundation. The HERPACC was supported by a Grant-in-Aid for Scientific Research on Priority Areas from the Ministry of Education, Science, Sports, Culture and Technology of Japan, by a Grant-in-Aid for the Third Term Comprehensive 10-Year Strategy for Cancer Control from Ministry Health, Labour and Welfare of Japan, by Health and Labour Sciences Research Grants for Research on Applying Health Technology from Ministry Health, Labour and Welfare of Japan and by National Cancer Center Research and Development Fund. The HMBCS would like to thank Natalia Antonenkova, Peter Hillemanns, Hans Christiansen and Johann H. Karstens.
PY - 2014
Y1 - 2014
N2 - 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.
AB - 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.
UR - https://www.scopus.com/pages/publications/84920763076
U2 - 10.1038/ncomms5999
DO - 10.1038/ncomms5999
M3 - Article
C2 - 25248036
AN - SCOPUS:84920763076
SN - 2041-1723
VL - 4
JO - Nature Communications
JF - Nature Communications
M1 - 4999
ER -