Journal article

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 Show all

Nature Communications | NATURE PUBLISHING GROUP | Published : 2014

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Awarded by National Health and Medical Research Council of Australia


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Awarded by National Cancer Institute (USA)


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Awarded by Fondo de Investigacion Sanitario


Awarded by California Breast Cancer Research Fund


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Awarded by End Results Program


Awarded by Stichting tegen Kanker


Awarded by Deutsche Krebshilfe e.V.


Awarded by NIH


Awarded by Australian NHMRC


Awarded by Canadian Institutes of Health Research for the 'CIHR Team in Familial Risks of Breast Cancer' program-grant


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Awarded by Malaysian Ministry of Higher Education


Awarded by Biomedical Research Council


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Awarded by Norwegian Research council


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Awarded by Biobanking and Biomolecular Resources Research Infrastructure


Awarded by Genetic Associations and Mechanisms in Oncology (GAME-ON) Network


Awarded by Yorkshire Cancer Research


Awarded by BRL (Basic Research Laboratory) program through the National Research Foundation of Korea - Ministry of Education, Science and Technology


Awarded by National Medical Research Council


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Awarded by Hellenic Cooperative Oncology Group research grant



Awarded by National Institute for Health Research


Funding Acknowledgements

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 LaBoissiere and Frederic Robidoux and the staff of the McGill University and Genome Quebec 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 Genotyping 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 Rubner, 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 Securite 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 Kjeldgard 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 Alvarez, Pilar Zamora, Primitiva Menendez and the Human Genotyping-CEGEN Unit (CNIO). The CNIO-BCS was supported by the Genome Spain Foundation, the Red Tematica de Investigacion Cooperativa en Cancer and grants from the Asociacion Espanola Contra el Cancer and the Fondo de Investigacion 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 Wurttemberg 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 Tubingen, 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 Erkkila. 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. The HMBCS was supported by a grant from the Friends of Hannover Medical School and by the Rudolf Bartling Foundation. Financial support for KARBAC was provided through the regional agreement on medical training and clinical research (ALF) between Stockholm County Council and Karolinska Institutet, the Swedish Cancer Society, The Gustav V Jubilee foundation and Bert von Kantzows foundation. The KBCP would like to thank Eija Myohanen and Helena Kemilainen. The KBCP was financially supported by the special Government Funding (EVO) of Kuopio University Hospital grants, Cancer Fund of North Savo, the Finnish Cancer Organizations, the Academy of Finland and by the strategic funding of the University of Eastern Finland.The kConFab/AOCS study would like to thank Heather Thorne, Eveline Niedermayr, all the kConFab research nurses and staff, the heads and staff of the Family Cancer Clinics and the Clinical Follow Up Study (which has received funding from the NHMRC, the National Breast Cancer Foundation, Cancer Australia and the National Institute of Health (USA)) for their contributions to this resource, and the many families who contributed to kConFab. kConFab is supported by a grant from the National Breast Cancer Foundation and previously by the National Health and Medical Research Council (NHMRC), the Queensland Cancer Fund, the Cancer Councils of New South Wales, Victoria, Tasmania and South Australia, and the Cancer Foundation of Western Australia. The LAABC study would like to thank all the study participants and the entire data collection team, especially Annie Fung and June Yashiki. LAABC is supported by grants (1RB-0287, 3PB-0102, 5PB-0018, 10PB-0098) from the California Breast Cancer Research Program. Incident breast cancer cases were collected by the USC Cancer Surveillance Program (CSP), which is supported under subcontract by the California Department of Health. The CSP is also part of the National Cancer Institute's Division of Cancer Prevention and Control Surveillance, Epidemiology, and End Results Program, under contract number N01CN25403. The LMBC would like to thank Gilian Peuteman, Dominiek Smeets, Thomas Van Brussel and Kathleen Corthouts. LMBC is supported by the 'Stichting tegen Kanker' (232-2008 and 196-2010). Diether Lambrechts is supported by the FWO and the KULPFV/10/016-SymBioSysII. The MARIE study would like to Judith Heinz, Nadia Obi, Alina Vrieling, Sabine Behrens, Ursula Eilber, Muhabbet Celik, Til Olchers and Stefan Nickels. The MARIE study was supported by the Deutsche Krebshilfe e.V. (70-2892-BR I), the Hamburg Cancer Society, the German Cancer Research Center and the genotype work in part by the Federal Ministry of Education and Research (BMBF) Germany (01KH0402). The MBCSG would like to thank Siranoush Manoukian, Bernard Peissel and Daniela Zaffaroni of the Fondazione IRCCS Istituto Nazionale dei Tumori (INT); Monica Barile and Irene Feroce of the Istituto Europeo di Oncologia (IEO); and Loris Bernard and the personnel of the Cogentech Cancer Genetic Test Laboratory. MBCSG is supported by grants from the Italian Association for Cancer Research (AIRC) and by funds from the Italian citizens who allocated the 5/1,000 share of their tax payment in support of the Fondazione IRCCS Istituto Nazionale Tumori, according to Italian laws (INT-Institutional strategic projects '5 x 1000'). The MCBCS was supported by the NIH grants CA128978, CA116167, CA176785, an NIH Specialized Program of Research Excellence (SPORE) in Breast Cancer (CA116201), and the Breast Cancer Research Foundation and a generous gift from the David F. and Margaret T. Grohne Family Foundation and the Ting Tsung and Wei Fong Chao Foundation. MCCS cohort recruitment was funded by VicHealth and Cancer Council Victoria. The MCCS was further supported by Australian NHMRC grants 209057, 251553 and 504711 and by infrastructure provided by Cancer Council Victoria. The MEC was support by NIH grants CA63464, CA54281, CA098758 and CA132839. The MTLGEBCS would like to thank Martine Tranchant (Cancer Genomics Laboratory, CHU de Quebec Research Center), Marie-France Valois, Annie Turgeon and Lea Heguy (McGill University Health Center, Royal Victoria Hospital, McGill University) for DNA extraction, sample management and skilful technical assistance. J.S.is Chairholder of the Canada Research Chair in Oncogenetics. The work of MTLGEBCS was supported by the Quebec Breast Cancer Foundation, 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-grant #PSR-SIIRI-701. The MYBRCA study would like to thank Phuah Sze Yee, Peter Kang, Kang In Nee, Kavitta Sivanandan, Shivaani Mariapun, Yoon Sook-Yee, Teh Yew Ching and Nur Aishah Mohd Taib for DNA Extraction and patient recruitment. MYBRCA is funded by research grants from the Malaysian Ministry of Science, Technology and Innovation (MOSTI), Malaysian Ministry of Higher Education (UM.C/HlR/MOHE/06) and Cancer Research Initiatives Foundation (CARIF). Additional controls were recruited by the Singapore Eye Research Institute, which was supported by a grant from the Biomedical Research Council (BMRC08/1/35/19/550), Singapore and the National medical Research Council, Singapore (NMRC/CG/SERI/2010). The NBCS was supported by grants from the Norwegian Research council, 155218/V40, 175240/S10 to A.-L.B.-D., FUGE-NFR 181600/V11 to V.N.K. and a Swizz Bridge Award to A.-L.B.-D. The NBHS_TN study would like to thank participants and research staff for their contributions and commitment to this study. The NBHS was supported by NIH grant R01CA100374. Biological sample preparation was conducted by the Survey and Biospecimen Shared Resource, which is supported by P30 CA68485. The OBCS study would like to thank Meeri Otsukka, Kari Mononen, Mervi Grip and Saila Kauppila. The OBCS was supported by research grants from the Finnish Cancer Foundation, the Academy of Finland (grant number 250083, 122715 and Center of Excellence grant number 251314), the Finnish Cancer Foundation, the Sigrid Juselius Foundation, the University of Oulu, the University of Oulu Support Foundation and the special Governmental EVO funds for Oulu University Hospital-based research activities. The OFBCR study would like to thank Teresa Selander and Nayana Weerasooriya. The Ontario Familial Breast Cancer Registry (OFBCR) 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 ORIGO study would like to thank E. Krol-Warmerdam, and J. Blom for patient accrual, administering questionnaires and managing clinical information. The LUMC survival data were retrieved from the Leiden hospital-based cancer registry system (ONCDOC) with the help of Dr J. Molenaar. The ORIGO study was supported by the Dutch Cancer Society (RUL 1997-1505) and the Biobanking and Biomolecular Resources Research Infrastructure (BBMRI-NL CP16). The PBCS study would like to thank Louise Brinton, Mark Sherman, Neonila Szeszenia-Dabrowska, Beata Peplonska, Witold Zatonski, Pei Chao and Michael Stagner. The PBCS was funded by Intramural Research Funds of the National Cancer Institute, Department of Health and Human Services, USA. The pKARMA study would like to thank The Swedish Medical Research Counsel. The pKARMA study was supported by Marit and Hans Rausings Initiative Against Breast Cancer. The RBCS study would like to thank Petra Bos, Jannet Blom, Ellen Crepin, Elisabeth Huijskens, Annette Heemskerk and the Erasmus MC Family Cancer Clinic.The RBCS was funded by the Dutch Cancer Society (DDHK 2004-3124, DDHK 2009-4318). The SASBAC would like to thank The Swedish Medical Research Counsel. The SASBAC study was supported by funding from the Agency for Science, Technology and Research of Singapore (A*STAR), the US National Institute of Health (NIH) and the Susan G. Komen Breast Cancer Foundation. The SBCGS would like to thank participants and research staff for their contributions and commitment to this study. The SBCGS was supported primarily by NIH grants R01CA64277, R01CA148667 and R37CA70867. Biological sample preparation was conducted by the Survey and Biospecimen Shared Resource, which is supported by P30 CA68485. The scientific development and funding of this project were, in part, supported by the Genetic Associations and Mechanisms in Oncology (GAME-ON) Network U19 CA148065. The SBCS would like to thank Sue Higham, Helen Cramp, Sabapathy Balasubramanian, Ian Borck and Dan Connley. The SBCS was supported by Yorkshire Cancer Research S295, S299 and S305PA. The SEARCH study would like to thank The SEARCH and EPIC teams. SEARCH is funded by a programme grant from Cancer Research UK (C490/A10124) and supported by the UK National Institute for Health Research Biomedical Research Centre at the University of Cambridge. SEBCS was supported by the BRL (Basic Research Laboratory) program through the National Research Foundation of Korea funded by the Ministry of Education, Science and Technology (2012-0000347). The SGBCC study would like to thank the participants and research coordinator Kimberley Chua. SGBCC is funded by the National Medical Research Council start-up Grant and Centre Grant (NMRC/CG/NCIS/2010). Additional controls were recruited by the Singapore Consortium of Cohort Studies-Multi-ethnic cohort (SCCS-MEC), which was funded by the Biomedical Research Council, grant number: 05/1/21/19/425. The SKKDKFZS study thanks all study participants, clinicians, family doctors, researchers and technicians for their contributions and commitment to this study. SKKDKFZS is supported by the DKFZ. The SZBCS was supported by Grant PBZ_KBN_122/P05/2004. The TBCS was funded by The National Cancer Institute, Thailand. The TNBCC was supported by: a Specialized Program of Research Excellence (SPORE) in Breast Cancer (CA116201), a grant from the Breast Cancer Research Foundation, a generous gift from the David F. and Margaret T. Grohne Family Foundation and the Ting Tsung and Wei Fong Chao Foundation, the Stefanie Spielman Breast Cancer fund and the OSU Comprehensive Cancer Center, DBBR (a CCSG Share Resource by National Institutes of Health Grant P30 CA016056), the Hellenic Cooperative Oncology Group research grant (HR R_BG/04) and the Greek General Secretary for Research and Technology (GSRT) Program, Research Excellence II, the European Union (European Social Fund-ESF), and Greek national funds through the Operational Program 'Education and Lifelong Learning' of the National Strategic Reference Framework (NSRF)-ARISTEIA. The TWBCS is supported by the Taiwan Biobank project of the Institute of Biomedical Sciences, Academia Sinica, Taiwan. The UKBGS study would like to thank Breakthrough Breast Cancer and the Institute of Cancer Research for support and funding of the Breakthrough Generations Study, and the study participants, study staff, and the doctors, nurses and other health care providers and health information sources who have contributed to the study. We acknowledge NHS funding to the Royal Marsden/ICR NIHR Biomedical Research Centre.The UKBGS is funded by Breakthrough Breast Cancer and the Institute of Cancer Research (ICR), London. ICR acknowledges NHS funding to the NIHR Biomedical Research Centre.