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MicroRNA Related Polymorphisms and Breast Cancer Risk

  • Sofia Khan,

    Affiliation Department of Obstetrics and Gynecology, University of Helsinki and Helsinki University Central Hospital, Helsinki, Finland

  • Dario Greco,

    Affiliations Department of Obstetrics and Gynecology, University of Helsinki and Helsinki University Central Hospital, Helsinki, Finland, Finnish Institute of Occupational Health, Helsinki, Finland

  • Kyriaki Michailidou,

    Affiliation Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, United Kingdom

  • Roger L. Milne,

    Affiliations Cancer Epidemiology Centre, Cancer Council Victoria, Melbourne, Australia, Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, Australia

  • Taru A. Muranen,

    Affiliation Department of Obstetrics and Gynecology, University of Helsinki and Helsinki University Central Hospital, Helsinki, Finland

  • Tuomas Heikkinen,

    Affiliation Department of Obstetrics and Gynecology, University of Helsinki and Helsinki University Central Hospital, Helsinki, Finland

  • Kirsimari Aaltonen,

    Affiliations Department of Obstetrics and Gynecology, University of Helsinki and Helsinki University Central Hospital, Helsinki, Finland, Department of Clinical Genetics, University of Helsinki and Helsinki University Central Hospital, Helsinki, Finland, Department of Oncology, University of Helsinki and Helsinki University Central Hospital, Helsinki, Finland

  • Joe Dennis,

    Affiliation Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, United Kingdom

  • Manjeet K. Bolla,

    Affiliation Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, United Kingdom

  • Jianjun Liu,

    Affiliation Human Genetics Division, Genome Institute of Singapore, Singapore, Singapore

  • Per Hall,

    Affiliation Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden

  • Astrid Irwanto,

    Affiliation Human Genetics Division, Genome Institute of Singapore, Singapore, Singapore

  • Keith Humphreys,

    Affiliation Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden

  • Jingmei Li,

    Affiliation Human Genetics Division, Genome Institute of Singapore, Singapore, Singapore

  • Kamila Czene,

    Affiliation Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden

  • Jenny Chang-Claude,

    Affiliation Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany

  • Rebecca Hein,

    Affiliations Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany, PMV Research Group at the Department of Child and Adolescent Psychiatry and Psychotherapy, University of Cologne, Cologne, Germany

  • Anja Rudolph,

    Affiliation Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany

  • Petra Seibold,

    Affiliation Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany

  • Dieter Flesch-Janys,

    Affiliation Department of Cancer Epidemiology/Clinical Cancer Registry and Institute for Medical Biometrics and Epidemiology, University Clinic Hamburg-Eppendorf, Hamburg, Germany

  • Olivia Fletcher,

    Affiliation Breakthrough Breast Cancer Research Centre, The Institute of Cancer Research, London, United Kingdom

  • Julian Peto,

    Affiliation Department of Non-Communicable Disease Epidemiology Department, London School of Hygiene and Tropical Medicine, London, United Kingdom

  • Isabel dos Santos Silva,

    Affiliation Department of Non-Communicable Disease Epidemiology Department, London School of Hygiene and Tropical Medicine, London, United Kingdom

  • Nichola Johnson,

    Affiliation Breakthrough Breast Cancer Research Centre, The Institute of Cancer Research, London, United Kingdom

  • Lorna Gibson,

    Affiliation Department of Non-Communicable Disease Epidemiology Department, London School of Hygiene and Tropical Medicine, London, United Kingdom

  • Zoe Aitken,

    Affiliation Department of Non-Communicable Disease Epidemiology Department, London School of Hygiene and Tropical Medicine, London, United Kingdom

  • John L. Hopper,

    Affiliation Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, Australia

  • Helen Tsimiklis,

    Affiliation Department of Pathology, The University of Melbourne, Melbourne, Australia

  • Minh Bui,

    Affiliation Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, Australia

  • Enes Makalic,

    Affiliation Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, Australia

  • Daniel F. Schmidt,

    Affiliation Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, Australia

  • Melissa C. Southey,

    Affiliation Department of Pathology, The University of Melbourne, Melbourne, Australia

  • Carmel Apicella,

    Affiliation Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, Australia

  • Jennifer Stone,

    Affiliation Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, Australia

  • Quinten Waisfisz,

    Affiliation Department of Clinical Genetics, VU University Medical Center, Amsterdam, The Netherlands

  • Hanne Meijers-Heijboer,

    Affiliation Department of Clinical Genetics, VU University Medical Center, Amsterdam, The Netherlands

  • Muriel A. Adank,

    Affiliation Department of Clinical Genetics, VU University Medical Center, Amsterdam, The Netherlands

  • Rob B. van der Luijt,

    Affiliation Department of Medical Genetics, University Medical Center Utrecht, Utrecht, The Netherlands

  • Alfons Meindl,

    Affiliation Division of Gynaecology and Obstetrics, Technische Universität München, Munich, Germany

  • Rita K. Schmutzler,

    Affiliations Division of Molecular Gyneco-Oncology, Department of Gynaecology and Obstetrics, University Hospital of Cologne, Cologne, Germany, Center of Familial Breast and Ovarian Cancer, University Hospital of Cologne, Cologne, Germany, Center for Integrated Oncology (CIO), University Hospital of Cologne, Cologne, Germany, Center for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany

  • Bertram Müller-Myhsok,

    Affiliation Max Planck Institute of Psychiatry, Munich, Germany

  • Peter Lichtner,

    Affiliation Institute of Human Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany

  • Clare Turnbull,

    Affiliation Section of Cancer Genetics, Institute of Cancer Research, Sutton, United Kingdom

  • Nazneen Rahman,

    Affiliation Section of Cancer Genetics, Institute of Cancer Research, Sutton, United Kingdom

  • Stephen J. Chanock,

    Affiliation Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, Maryland, United States of America

  • David J. Hunter,

    Affiliations Program in Molecular and Genetic Epidemiology, Harvard School of Public Health, Boston, Massachusetts, United States of America, Department of Epidemiology, Harvard School of Public Health, Boston, Massachusetts, United States of America

  • Angela Cox,

    Affiliation CRUK/YCR Sheffield Cancer Research Centre, Department of Oncology, University of Sheffield, Sheffield, United Kingdom

  • Simon S. Cross,

    Affiliation Academic Unit of Pathology, Department of Neuroscience, University of Sheffield, Sheffield, United Kingdom

  • Malcolm W. R. Reed,

    Affiliation CRUK/YCR Sheffield Cancer Research Centre, Department of Oncology, University of Sheffield, Sheffield, United Kingdom

  • Marjanka K. Schmidt,

    Affiliation Netherlands Cancer Institute, Antoni van Leeuwenhoek hospital, Amsterdam, The Netherlands

  • Annegien Broeks,

    Affiliation Netherlands Cancer Institute, Antoni van Leeuwenhoek hospital, Amsterdam, The Netherlands

  • Laura J. V. a. n't. Veer,

    Affiliation Netherlands Cancer Institute, Antoni van Leeuwenhoek hospital, Amsterdam, The Netherlands

  • Frans B. Hogervorst,

    Affiliation Netherlands Cancer Institute, Antoni van Leeuwenhoek hospital, Amsterdam, The Netherlands

  • Peter A. Fasching,

    Affiliations University Breast Center Franconia, Department of Gynecology and Obstetrics, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nuremberg, Comprehensive Cancer Cancer Erlangen-EMN, Erlangen, Germany, David Geffen School of Medicine, Department of Medicine Division of Hematology and Oncology, University of California Los Angeles, California, United States of America

  • Michael G. Schrauder,

    Affiliation University Breast Center Franconia, Department of Gynecology and Obstetrics, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nuremberg, Comprehensive Cancer Cancer Erlangen-EMN, Erlangen, Germany

  • Arif B. Ekici,

    Affiliation Institute of Human Genetics, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nuremberg, Comprehensive Cancer Center Erlangen-EMN, Erlangen, Germany

  • Matthias W. Beckmann,

    Affiliation University Breast Center Franconia, Department of Gynecology and Obstetrics, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nuremberg, Comprehensive Cancer Cancer Erlangen-EMN, Erlangen, Germany

  • Stig E. Bojesen,

    Affiliations Copenhagen General Population Study, Herlev Hospital, Copenhagen University Hospital, Copenhagen, Denmark, Department of Clinical Biochemistry, Herlev Hospital, Copenhagen University Hospital, Copenhagen, Denmark

  • Børge G. Nordestgaard,

    Affiliations Copenhagen General Population Study, Herlev Hospital, Copenhagen University Hospital, Copenhagen, Denmark, Department of Clinical Biochemistry, Herlev Hospital, Copenhagen University Hospital, Copenhagen, Denmark

  • Sune F. Nielsen,

    Affiliations Copenhagen General Population Study, Herlev Hospital, Copenhagen University Hospital, Copenhagen, Denmark, Department of Clinical Biochemistry, Herlev Hospital, Copenhagen University Hospital, Copenhagen, Denmark

  • Henrik Flyger,

    Affiliation Department of Breast Surgery, Herlev Hospital, Copenhagen University Hospital, Copenhagen, Denmark

  • Javier Benitez,

    Affiliations Human Genetics Group, Human Cancer Genetics Program, Spanish National Cancer Research Centre (CNIO), Madrid, Spain, Centro de Investigación en Red de Enfermedades Raras (CIBERER), Valencia, Spain

  • Pilar M. Zamora,

    Affiliation Servicio de Oncología Médica, Hospital Universitario La Paz, Madrid, Spain

  • Jose I. A. Perez,

    Affiliation Servicio de Cirugía General y Especialidades, Hospital Monte Naranco, Oviedo, Spain

  • Christopher A. Haiman,

    Affiliation Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California, United States of America

  • Brian E. Henderson,

    Affiliation Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California, United States of America

  • Fredrick Schumacher,

    Affiliation Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California, United States of America

  • Loic Le Marchand,

    Affiliation Epidemiology Program, Cancer Research Center, University of Hawaii, Honolulu, Hawaii, United States of America

  • Paul D. P. Pharoah,

    Affiliations Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, United Kingdom, Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Cambridge, United Kingdom

  • Alison M. Dunning,

    Affiliation Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Cambridge, United Kingdom

  • Mitul Shah,

    Affiliation Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Cambridge, United Kingdom

  • Robert Luben,

    Affiliation Clinical Gerontology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, United Kingdom

  • Judith Brown,

    Affiliation Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, United Kingdom

  • Fergus J. Couch,

    Affiliation Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota, United States of America

  • Xianshu Wang,

    Affiliation Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota, United States of America

  • Celine Vachon,

    Affiliation Department of Health Sciences Research, Mayo Clinic, Rochester, Minnesota, United States of America

  • Janet E. Olson,

    Affiliation Department of Health Sciences Research, Mayo Clinic, Rochester, Minnesota, United States of America

  • Diether Lambrechts,

    Affiliations Vesalius Research Center (VRC), VIB, Leuven, Belgium, Laboratory for Translational Genetics, Department of Oncology, University of Leuven, Leuven, Belgium

  • Matthieu Moisse,

    Affiliations Vesalius Research Center (VRC), VIB, Leuven, Belgium, Laboratory for Translational Genetics, Department of Oncology, University of Leuven, Leuven, Belgium

  • Robert Paridaens,

    Affiliation Oncology Department, University Hospital Gasthuisberg, Leuven, Belgium

  • Marie-Rose Christiaens,

    Affiliation Oncology Department, University Hospital Gasthuisberg, Leuven, Belgium

  • Pascal Guénel,

    Affiliations Inserm (National Institute of Health and Medical Research), CESP (Center for Research in Epidemiology and Population Health), U1018, Environmental Epidemiology of Cancer, Villejuif, France, University Paris-Sud, UMRS 1018, Villejuif, France

  • Thérèse Truong,

    Affiliations Inserm (National Institute of Health and Medical Research), CESP (Center for Research in Epidemiology and Population Health), U1018, Environmental Epidemiology of Cancer, Villejuif, France, University Paris-Sud, UMRS 1018, Villejuif, France

  • Pierre Laurent-Puig,

    Affiliation Université Paris Sorbonne Cité, UMR-S775 Inserm, Paris, France

  • Claire Mulot,

    Affiliation Université Paris Sorbonne Cité, UMR-S775 Inserm, Paris, France

  • Frederick Marme,

    Affiliations Department of Obstetrics and Gynecology, University of Heidelberg, Heidelberg, Germany, National Center for Tumor Diseases, University of Heidelberg, Heidelberg, Germany

  • Barbara Burwinkel,

    Affiliations Department of Obstetrics and Gynecology, University of Heidelberg, Heidelberg, Germany, Molecular Epidemiology Group, German Cancer Research Center (DKFZ), Heidelberg, Germany

  • Andreas Schneeweiss,

    Affiliations Department of Obstetrics and Gynecology, University of Heidelberg, Heidelberg, Germany, National Center for Tumor Diseases, University of Heidelberg, Heidelberg, Germany

  • Christof Sohn,

    Affiliation Department of Obstetrics and Gynecology, University of Heidelberg, Heidelberg, Germany

  • Elinor J. Sawyer,

    Affiliation Research Oncology, Division of Cancer Studies, King's College London, Guy's Hospital, London, United Kingdom

  • Ian Tomlinson,

    Affiliation Wellcome Trust Centre for Human Genetics and Oxford Biomedical Research Centre, University of Oxford, Oxford, United Kingdom

  • Michael J. Kerin,

    Affiliation Clinical Science Institute, University Hospital Galway, Galway, Ireland

  • Nicola Miller,

    Affiliation Clinical Science Institute, University Hospital Galway, Galway, Ireland

  • Irene L. Andrulis,

    Affiliations Lunenfeld-Tanenbaum Research Institute of Mount Sinai Hospital, Toronto, Ontario, Canada, Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada

  • Julia A. Knight,

    Affiliations Prosserman Centre for Health Research, Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada, Division of Epidemiology, Dalla Lana School of Public Health, University of Toronto, Toronto, Ontario, Canada

  • Sandrine Tchatchou,

    Affiliation Lunenfeld-Tanenbaum Research Institute of Mount Sinai Hospital, Toronto, Ontario, Canada

  • Anna Marie Mulligan,

    Affiliations Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada, Department of Laboratory Medicine, and the Keenan Research Centre of the Li Ka Shing Knowledge Institute, St Michael's Hospital, Toronto, Ontario, Canada

  • Thilo Dörk,

    Affiliation Department of Obstetrics and Gynaecology, Hannover Medical School, Hannover, Germany

  • Natalia V. Bogdanova,

    Affiliation Department of Radiation Oncology, Hannover Medical School, Hannover, Germany

  • Natalia N. Antonenkova,

    Affiliation N.N. Alexandrov Research Institute of Oncology and Medical Radiology, Minsk, Belarus

  • Hoda Anton-Culver,

    Affiliation Department of Epidemiology, University of California Irvine, Irvine, California, United States of America

  • Hatef Darabi,

    Affiliation Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden

  • Mikael Eriksson,

    Affiliation Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden

  • Montserrat Garcia-Closas,

    Affiliations Division of Genetics and Epidemiology, Institute of Cancer Research, Sutton, United Kingdom, Breakthrough Breast Cancer Research Centre, Division of Breast Cancer Research, The Institute of Cancer Research, London, United Kingdom

  • Jonine Figueroa,

    Affiliation Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, Maryland, United States of America

  • Jolanta Lissowska,

    Affiliation Department of Cancer Epidemiology and Prevention, M. Sklodowska-Curie Memorial Cancer Center and Institute of Oncology, Warsaw, Poland

  • Louise Brinton,

    Affiliation Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, Maryland, United States of America

  • Peter Devilee,

    Affiliation Department of Human Genetics & Department of Pathology, Leiden University Medical Center, Leiden, Netherlands

  • Robert A. E. M. Tollenaar,

    Affiliation Department of Surgical Oncology, Leiden University Medical Center, Leiden, Netherlands

  • Caroline Seynaeve,

    Affiliation Family Cancer Clinic, Department of Medical Oncology, Erasmus MC-Daniel den Hoed Cancer Center, Rotterdam, Netherlands

  • Christi J. van Asperen,

    Affiliation Department of Clinical Genetics, Leiden University Medical Center, Leiden, Netherlands

  • Vessela N. Kristensen,

    Affiliations Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway, Department of Clinical Molecular Biology (EpiGen), University of Oslo, Oslo, Norway, Department of Genetics, Institute for Cancer Research, Oslo University Hospital, Radiumhospitalet, Oslo, Norway

  • kConFab Investigators ,

    Membership of the GENICA Network, kConFab Investigators, and AOCS is provided in the Acknowledgments.

    Affiliation Peter MacCallum Cancer Center, Melbourne, Australia

  • Australian Ovarian Cancer Study Group ,

    Membership of the GENICA Network, kConFab Investigators, and AOCS is provided in the Acknowledgments.

    Affiliations Peter MacCallum Cancer Center, Melbourne, Australia, QIMR Berghofer Medical Research Institute, Brisbane, Australia

  • Susan Slager,

    Affiliation Department of Health Sciences Research, Mayo Clinic, Rochester, Minnesota, United States of America

  • Amanda E. Toland,

    Affiliation Department of Molecular Virology, Immunology and Medical Genetics, Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio, United States of America

  • Christine B. Ambrosone,

    Affiliation Roswell Park Cancer Institute, Buffalo, New York, United States of America

  • Drakoulis Yannoukakos,

    Affiliation Molecular Diagnostics Laboratory, IRRP, National Centre for Scientific Research "Demokritos", Aghia Paraskevi Attikis, Athens, Greece

  • Annika Lindblom,

    Affiliation Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden

  • Sara Margolin,

    Affiliation Department of Oncology - Pathology, Karolinska Institutet, Stockholm, Sweden

  • Paolo Radice,

    Affiliation Unit of Molecular Bases of Genetic Risk and Genetic Testing, Department of Preventive and Predictive Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori (INT), Milan, Italy

  • Paolo Peterlongo,

    Affiliation IFOM, Fondazione Istituto FIRC di Oncologia Molecolare, Milan, Italy

  • Monica Barile,

    Affiliation Division of Cancer Prevention and Genetics, Istituto Europeo di Oncologia (IEO), Milan, Italy

  • Paolo Mariani,

    Affiliations IFOM, Fondazione Istituto FIRC di Oncologia Molecolare, Milan, Italy, Cogentech Cancer Genetic Test Laboratory, Milan, Italy

  • Maartje J. Hooning,

    Affiliation Department of Medical Oncology, Erasmus University Medical Center, Rotterdam, The Netherlands

  • John W. M. Martens,

    Affiliation Department of Medical Oncology, Erasmus University Medical Center, Rotterdam, The Netherlands

  • J. Margriet Collée,

    Affiliation Department of Clinical Genetics, Erasmus University Medical Center, Rotterdam, The Netherlands

  • Agnes Jager,

    Affiliation Department of Medical Oncology, Erasmus University Medical Center, Rotterdam, The Netherlands

  • Anna Jakubowska,

    Affiliation Department of Genetics and Pathology, Pomeranian Medical University, Szczecin, Poland

  • Jan Lubinski,

    Affiliation Department of Genetics and Pathology, Pomeranian Medical University, Szczecin, Poland

  • Katarzyna Jaworska-Bieniek,

    Affiliations Department of Genetics and Pathology, Pomeranian Medical University, Szczecin, Poland, Postgraduate School of Molecular Medicine, Warsaw Medical University, Warsaw, Poland

  • Katarzyna Durda,

    Affiliation Department of Genetics and Pathology, Pomeranian Medical University, Szczecin, Poland

  • Graham G. Giles,

    Affiliations Cancer Epidemiology Centre, Cancer Council Victoria, Melbourne, Australia, Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, Australia

  • Catriona McLean,

    Affiliation Anatomical Pathology, The Alfred Hospital, Melbourne, Australia

  • Hiltrud Brauch,

    Affiliations Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology, Stuttgart, Germany, University of Tübingen, Tübingen, Germany

  • Thomas Brüning,

    Affiliation Institute for Prevention and Occupational Medicine of the German Social Accident Insurance, Institute of the Ruhr-University Bochum (IPA), Bochum, Germany

  • Yon-Dschun Ko,

    Affiliation Department of Internal Medicine, Evangelische Kliniken Bonn gGmbH, Johanniter Krankenhaus, Bonn, Germany

  • The GENICA Network ,

    Membership of the GENICA Network, kConFab Investigators, and AOCS is provided in the Acknowledgments.

    Affiliations Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology, Stuttgart, Germany, University of Tübingen, Tübingen, Germany, Institute for Prevention and Occupational Medicine of the German Social Accident Insurance, Institute of the Ruhr-University Bochum (IPA), Bochum, Germany, Department of Internal Medicine, Evangelische Kliniken Bonn gGmbH, Johanniter Krankenhaus, Bonn, Germany, Molecular Genetics of Breast Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany, Institute for Occupational Medicine and Maritime Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany, Institute of Pathology, Medical Faculty of the University of Bonn, Bonn, Germany

  • Hermann Brenner,

    Affiliations Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany, German Cancer Consortium (DKTK), Heidelberg, Germany

  • Aida Karina Dieffenbach,

    Affiliations Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany, German Cancer Consortium (DKTK), Heidelberg, Germany

  • Volker Arndt,

    Affiliation Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany

  • Christa Stegmaier,

    Affiliation Saarland Cancer Registry, Saarbrücken, Germany

  • Anthony Swerdlow,

    Affiliation Division of Genetics and Epidemiology and Division of Breast Cancer Research, The Institute of Cancer Research, Sutton, Surrey, United Kingdom

  • Alan Ashworth,

    Affiliation Breakthrough Breast Cancer Research Centre, The Institute of Cancer Research, London, United Kingdom

  • Nick Orr,

    Affiliation Breakthrough Breast Cancer Research Centre, The Institute of Cancer Research, London, United Kingdom

  • Michael Jones,

    Affiliation Division of Genetics and Epidemiology, Institute of Cancer Research, Sutton, United Kingdom

  • Jacques Simard,

    Affiliation Cancer Genomics Laboratory, Centre Hospitalier Universitaire de Québec Research Center and Laval University, Quebec, Canada

  • Mark S. Goldberg,

    Affiliations Department of Medicine, McGill University, Montreal, Canada, Division of Clinical Epidemiology, McGill University Health Centre, Royal Victoria Hospital, Montreal, Quebec, Canada

  • France Labrèche,

    Affiliation Départements de Santé Environnementale et Santé au Travail et de Médecine Sociale et Préventive, Université de Montréal, Montreal, Quebec, Canada

  • Martine Dumont,

    Affiliation Cancer Genomics Laboratory, Centre Hospitalier Universitaire de Québec Research Center and Laval University, Quebec, Canada

  • Robert Winqvist,

    Affiliation Laboratory of Cancer Genetics and Tumor Biology, Department of Clinical Chemistry and Biocenter Oulu, University of Oulu, NordLab Oulu/Oulu University Hospital, Oulu, Finland

  • Katri Pylkäs,

    Affiliation Laboratory of Cancer Genetics and Tumor Biology, Department of Clinical Chemistry and Biocenter Oulu, University of Oulu, NordLab Oulu/Oulu University Hospital, Oulu, Finland

  • Arja Jukkola-Vuorinen,

    Affiliation Department of Oncology, Oulu University Hospital, University of Oulu, Oulu, Finland

  • Mervi Grip,

    Affiliation Department of Surgery, Oulu University Hospital, University of Oulu, Oulu, Finland

  • Vesa Kataja,

    Affiliations School of Medicine, Institute of Clinical Medicine, Oncology, University of Eastern Finland, Kuopio, Finland, Cancer Center, Kuopio University Hospital, Kuopio, Finland

  • Veli-Matti Kosma,

    Affiliations School of Medicine, Institute of Clinical Medicine, Pathology and Forensic Medicine, University of Eastern Finland, Kuopio, Finland, Imaging Center, Department of Clinical Pathology, Kuopio University Hospital, Kuopio, Finland, Cancer Center of Eastern Finland, University of Eastern Finland, Kuopio, Finland

  • Jaana M. Hartikainen,

    Affiliations School of Medicine, Institute of Clinical Medicine, Pathology and Forensic Medicine, University of Eastern Finland, Kuopio, Finland, Imaging Center, Department of Clinical Pathology, Kuopio University Hospital, Kuopio, Finland, Cancer Center of Eastern Finland, University of Eastern Finland, Kuopio, Finland

  • Arto Mannermaa,

    Affiliations School of Medicine, Institute of Clinical Medicine, Pathology and Forensic Medicine, University of Eastern Finland, Kuopio, Finland, Imaging Center, Department of Clinical Pathology, Kuopio University Hospital, Kuopio, Finland, Cancer Center of Eastern Finland, University of Eastern Finland, Kuopio, Finland

  • Ute Hamann,

    Affiliation Molecular Genetics of Breast Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany

  • Georgia Chenevix-Trench,

    Affiliation Department of Genetics, QIMR Berghofer Medical Research Institute, Brisbane, Australia

  • Carl Blomqvist,

    Affiliation Department of Oncology, University of Helsinki and Helsinki University Central Hospital, Helsinki, Finland

  • Kristiina Aittomäki,

    Affiliation Department of Clinical Genetics, University of Helsinki and Helsinki University Central Hospital, Helsinki, Finland

  • Douglas F. Easton,

    Affiliations Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, United Kingdom, Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Cambridge, United Kingdom

  •  [ ... ],
  • Heli Nevanlinna

    heli.nevanlinna@hus.fi

    Affiliation Department of Obstetrics and Gynecology, University of Helsinki and Helsinki University Central Hospital, Helsinki, Finland

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Abstract

Genetic variations, such as single nucleotide polymorphisms (SNPs) in microRNAs (miRNA) or in the miRNA binding sites may affect the miRNA dependent gene expression regulation, which has been implicated in various cancers, including breast cancer, and may alter individual susceptibility to cancer. We investigated associations between miRNA related SNPs and breast cancer risk. First we evaluated 2,196 SNPs in a case-control study combining nine genome wide association studies (GWAS). Second, we further investigated 42 SNPs with suggestive evidence for association using 41,785 cases and 41,880 controls from 41 studies included in the Breast Cancer Association Consortium (BCAC). Combining the GWAS and BCAC data within a meta-analysis, we estimated main effects on breast cancer risk as well as risks for estrogen receptor (ER) and age defined subgroups. Five miRNA binding site SNPs associated significantly with breast cancer risk: rs1045494 (odds ratio (OR) 0.92; 95% confidence interval (CI): 0.88–0.96), rs1052532 (OR 0.97; 95% CI: 0.95–0.99), rs10719 (OR 0.97; 95% CI: 0.94–0.99), rs4687554 (OR 0.97; 95% CI: 0.95–0.99, and rs3134615 (OR 1.03; 95% CI: 1.01–1.05) located in the 3′ UTR of CASP8, HDDC3, DROSHA, MUSTN1, and MYCL1, respectively. DROSHA belongs to miRNA machinery genes and has a central role in initial miRNA processing. The remaining genes are involved in different molecular functions, including apoptosis and gene expression regulation. Further studies are warranted to elucidate whether the miRNA binding site SNPs are the causative variants for the observed risk effects.

Introduction

Breast cancer is the most common women's cancer and is a leading cause of cancer mortality [1]. Inherited genetic variation has been associated with the initiation, development and progression of breast cancer. Studies on twins have suggested that hereditary predisposing factors are involved in up to one third of all breast cancers [2]. Many genetic loci have been associated with breast cancer risk and collectively explain approximately 35% of the familial risk [3], [4]. The largest genetic association study of breast cancer to date identified 41 novel low penetrance susceptibility loci [4] by selecting nearly 30,000 SNPs from a meta-analysis of nine genome-wide association (GWA) studies and genotyping them using 41,785 cases and 41,880 controls of European ancestry from studies in the Breast Cancer Association Consortium (BCAC). These 41 susceptibility loci probably represent the tip of the ice berg, and additional SNPs from the combined GWAS might explain a similar fraction of familial risk to that attributed to the already identified loci [4].

Mature miRNAs are 20–23 nucleotide, single-stranded RNA molecules that play a crucial role in gene expression regulation for many cellular processes including differentiation potential and development pattern. MiRNAs undergo a stepwise maturation process involving an array of miRNA machinery components. Drosha and DGCR8 mediate the cleavage of long primary miRNA transcripts (pri-miRNAs) into shorter pre-miRNAs in the nucleus [5], [6]. The pre-miRNAs are then transported to the cytoplasm where they are further cleaved by Dicer to produce mature miRNAs [7]. MiRNAs interact by pairing with the 3′ untranslated region (UTR), and also within the coding region and 5′ UTR of the corresponding mRNAs leading to mRNA destabilization, cleavage or translation repression. More effective mRNA destabilization is achieved when miRNA targets the 3'UTR rather than other mRNA regions [8][10]. An individual miRNA may regulate approximately 100 distinct mRNAs, and together more than 1000 human miRNAs are believed to modulate more than half of the mRNA species encoded in the genome [11], [12]. Additionally, most mRNAs possess binding sites for miRNAs [13]. MiRNAs are involved in tumorigenesis in that they can be either oncogenic when tumor suppressor genes are targeted, or genomic guardians (tumour suppressor miRNAs) when oncogenes are targeted [14]. Additionally it has been suggested that they may modulate both metastasis [15] and chemotherapy resistance [16]. MiRNAs have also been shown to have altered expression levels in tumours compared to normal tissue and between tumor subtypes in breast cancer among other carcinoma types [17][19]. SNPs may affect miRNA machinery genes or miRNAs activity; however SNPs can also create, abolish or modify miRNA binding sites in their binding regions. Polymorphisms in miRNA binding sites have been studied in regard to the risk of several cancers [20], including breast cancer [21][23]. These studies have found evidence for association of miRNA related SNPs and cancer risk, but the study sample sizes have been relatively small.

In this study, we investigate associations between miRNA-related polymorphisms and breast cancer risk by using a meta-analysis of nine GWAS and subsequent genotyping of top hits using 41,785 cases and 41,880 controls of European ancestry from the BCAC. To our knowledge, this is thus far the largest investigation of associations between miRNA-related polymorphisms and breast cancer susceptibility.

Materials and Methods

SNP selection and genotyping

SNPs in mature or pre-miRNAs, in genes of the miRNA machinery and in 3'UTR regions of protein coding genes with a potential effect on miRNA binding were systematically searched from Ensembl (hg18/build36) and Patrocles databases [24]. Additionally, tagging SNPs for such with r2≥0.8 were also identified utilizing the public HapMap SNP database. By this in silico approach we identified altogether 147,801 candidate SNPs and 12,550 tagging SNPs. These SNPs were then overlayed with those from the combined GWAS from the BCAC [4] and altogether 2196 SNPs were present (either genotyped or imputed) in the combined GWAS. These SNPs were genotyped with Illumina or Affymetrix arrays, as described previously [25][32]. The combined GWAS data were imputed for all scans using HapMap version 2 CEU as a reference in similar fashion to that presented by Michailidou and colleagues [4] with the exception that the HapMap version 2 release 21 was used at the time the overlay was performed. Analysis using a 1-degree-of-freedom trend test of these 2196 SNPs in the combined GWAS indicated some evidence of association with breast cancer risk for 44 SNPs (p<0.09). Notably, the combined GWAS included imputed data generated using HapMap version 2 release 21 (based on NCBI build 35 (dbSNP b125)), whereas the results presented here for the combined GWAS are based on imputation using HapMap version 2 release 22 (based on NCBI build 36 (dbSNP b126)). In the release 22, a number of SNPs were excluded due to mapping inconsistencies in build 35 relative to build 36. Hence, the estimates from the combined GWAS may slightly differ from the initial association analysis. The 44 SNPs (including 30 candidate and 14 tagging SNP) were genotyped on additional samples in the BCAC using the custom Illumina Infinium array (iCOGS) which included a total of 211,155 SNPs as described previously. The detailed description of quality control process for combined GWAS and iCOGS genotyping data was presented in [4].

Of the 42 SNPs that passed quality control [4], two were located in miRNA genes (one candidate SNP located in pre-miRNA hsa-miR-2110 and one tag SNP tagging a mature hsa-mir-548l variant), and four SNPs were located in miRNA machinery genes (SMAD5, SND1, CNOT4 and DROSHA). The genotyped DROSHA SNP tags the 3′ UTR miRNA binding site variant in the DROSHA gene. The remaining 38 candidate or tag SNPs were located in, or tagged to a predicted miRNA binding site in the 3′ UTR of protein coding genes. All 42 SNPs are described in Table 1. The workflow of the SNP selection in different stages is illustrated in Figure 1.

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Table 1. The 42 studied SNPs in miRNAs, miRNA machinery genes and miRNA target genes.

https://doi.org/10.1371/journal.pone.0109973.t001

Study sample

The combined GWAS included nine breast cancer studies totalling 10,052 cases and 12,575 controls of European ethnic background. Details and study-specific subject numbers are presented in Table S1. Since the GWAS were limited to patients of European ethnic background we further utilized 41,785 cases ascertained for their first primary, invasive breast cancer and 41,880 controls of European ancestry from 41 BCAC studies genotyped using the iCOGS array (Table S2). For a subgroup analysis of ER negative and ER positive cases, as well as cases aged less than 50 years at diagnosis, we included all the cases for which the respective data were available. The ER subgroup analysis was based on 702 ER negative cases and 2,019 ER positive cases from five GWAS studies and 7,200 ER negative cases from 40 BCAC studies and 26,302 ER positive cases from 34 BCAC studies. The analysis of cases aged less than 50 years at diagnosis was based on 3,470 cases from three GWAS studies and 9,483 cases from 35 BCAC studies. All participating studies conform to the Declaration of Helsinki and were approved by the respective ethical review boards and ethics committees (Tables S1 and S2), and all participants in these studies had provided written consent for the research.

Statistical methods

We used logistic regression to estimate per-allele log-odds ratios and standard errors including the study as a covariate. We also included principal components as covariates in order to correct for potential hidden population structure. In the GWAS, for two studies (UK2 and HEBCS) the estimates were adjusted for the first three principal components and in the iCOGS analysis we used the first six principal components and an additional component to reduce inflation for the LMBC study, as described previously [4]. Subgroup analyses were carried out for ER negative and positive subgroups and for the group aged less than 50 years at diagnosis. For meta-analysis, we combined the estimates from the combined GWAS and iCOGS with a fixed effects model using the inverse variance weighted method. In the meta-analysis, the subjects involved in both combined GWAS and iCOGS (1880) were only taken into account once. In order to adust for P-values against multiple testing, we used Benjamini Hochberg correction. The adjusted P-values are shown in Table 2 along with the nominal P-values. In the text we report the nominal P-values. The statistical analyses were conducted using the R 2.14.0 statistical computing environment (http://www.r-project.org/).

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Table 2. Associations of SNPs in the GWAS and iCOGS separately and combined GWAS + iCOGS and breast cancer risk.

https://doi.org/10.1371/journal.pone.0109973.t002

Results

For the 42 SNPs we successfully genotyped, estimates of association from the combined GWAS and from iCOGS analysis are shown in Table S3. Twenty-one SNPs showed consistent associations with breast cancer risk in the combined GWAS and in iCOGS analysis; results from the meta-analysis are shown in Table 2. The most significantly associated SNP, rs702681 (OR 1.06 [95%CI 1.04–1.08]; P 3.9×10−10), is located in the 3'UTR of MIER3, close to the known breast cancer susceptibility gene MAP3K1. The SNP rs702681 is located at the same 5q11.2 locus as the previously published risk SNP rs889312 [33] (correlation r2 = 0.3). When the two SNPs were analysed in the same logistic regression model, the association with rs889312, but not that with rs702681 remained nominally statistically significant, suggesting that rs702681 is unlikely to be the causal SNP at this locus. The five SNPs with the significant novel associations from the meta-analysis (P≤5.07×10−3and adjusted P≤3.55×10−2 after correction for multiple testing) were rs1045494, (OR 0.92 [95%CI 0.88–0.96]; P =  5.90×10−5), rs1052532, (OR 0.97 [95%CI 0.95–0.99]; P = 7.78×10−4), rs10719, (OR 0.97 [95%CI 0.94–0.99]; P = 1.35×10−3) rs4687554 (OR 0.97 [95%CI 0.95–0.99]; P = 1.71×10−3) and rs3134615 (OR 1.03 [95%CI 1.01–1.05]; P = 5.07×10−3) located in 3′ UTR of Caspase-8 (CASP8), HD Domain Containing 3 (HDDC3), DROSHA, Musculoskeletal, Embryonic Nuclear Protein 1 (MUSTN1) and V-Myc Myelocytomatosis Viral Oncogene Homolog 1 (MYCL1), respectively (Table 2). SNP rs1045494 is tagging the hsa-miR-938 binding site SNP rs1045487 (r2 = 1.0) of CASP8 and the SNP rs1052532 in HDDC3 is predicted to abolish the binding site for hsa-miR-1224-3p. The SNP rs10719 is predicted to abolish the hsa-miR-1298 binding site in the 3′ UTR of DROSHA. SNP rs4687554 tags the hsa-miR-891b binding site SNP rs6445538 (r2 = 1.0) of MUSTN1 and rs3134615 is located at the binding site of hsa-miR-1827 of MYCL1. There was no evidence for heterogeneity in the per-allele OR for any SNP. The per study per allele ORs for these five miRNA binding site SNPs from the combined GWAS along with per-SNP heterogeneity variance P-values are shown in Figure S1 and from the iCOGS in Figure S2. Next we analysed the SNPs by ER status-defined subtype, and for cases aged less than 50 years at diagnosis, for risk associations in the meta-analysis of combined GWAS and iCOGS (Tables S4, S5 and S6). These analyses did not reveal any additional significant results. For rs1045494 in CASP8, rs4687554 in MUSTN1 and rs3134615 in MYCL1 (OR 1.03 [95%CI 1.01–1.05]; P = 7.75×10−4) a more significant association with breast cancer risk was found for the ER positive subgroup than in the main analysis, but the result from the test for heterogeneity by ER status was not significant (data not shown). All associations were estimated using an additive inheritance model. Dominant and recessive models did not improve the estimates (data not shown).

Discussion

We investigated associations between genetic variation in miRNAs, in the genes of the miRNA machinery and in the miRNA binding sites and the risk of breast cancer. We identified several SNPs that are predicted to abolish an miRNA binding site and that are significantly associated with breast cancer risk. Previous studies investigating miRNA related SNPs, especially in miRNA binding sites have included predefined sets of genes. Nicoloso and colleagues investigated 38 previously identified breast cancer risk SNPs and found two to modify miRNA binding sites in TGFB1 and XRCC1 in vitro [23]. Neither of these were included in our data set. Liang and colleagues investigated 134 potential miRNA binding sites in cancer-related genes and found six miRNA binding site SNPs that were associated with ovarian cancer risk [34].

In the meta-analysis of combined GWAS and iCOGS for main effects, for four of the five most significant miRNA binding site SNPs, the minor allele was associated with a decreased breast cancer risk. The minor allele of SNP rs3134615 in 3′ UTR of MYCL1 was associated with an increased breast cancer risk. All the five most significant miRNA binding site SNPs locate in 3′ UTR and have been predicted to abolish the miRNA binding site. The defect in miRNA-mediated regulation would be expected to lead to an increase in the translation of the corresponding encoded protein. The five genes, whose regulation may be affected by the miRNA-associated SNPs, include the pre-apoptotic gene CASP8, HDDC3, miRNA biogenesis master regulator DROSHA, MYC-family member MYCL1 and MUSTN1. CASP8 is involved in apoptosis in breast cancer cells [35], and many studies have reported polymorphisms in this gene to be associated with risks for several cancers [36], [37] including breast cancer [38], [39], indicating the importance of CASP8 in tumor development. SNP rs1045494 studied here is located close to the coding region SNP rs1045485 that has been previously shown to have a stronger protective effect [38], [40], [41]. Interestingly, Michalidou and colleagues reported this SNP as having only weak evidence for an association (P 0.0013 in combined GWAS and iCOGS) [4], but these two SNPs (rs1045485 and rs1045494) are not correlated (r2 = 0.001 in Caucasian population). Neither is rs1045494 correlated with the more strongly associated rs1830298 SNP, identified through fine-mapping of the region (r2 = 0.02) [42]. Rs1045494 tags SNP rs1045487 (r2 = 1.0) which is predicted to abolish the hsa-miR-938 binding site and thus may affect CASP8 expression. There is very little reported evidence on the involvement of HDDC3 or the hsa-miR-1224-3p in cancer, indicating a novel association with risk. HDDC3 has been suggested to be involved in the starvation response [43]. The HDDC3 gene is expressed at higher levels by several different tumor types, including breast tumors, than by normal tissue [44]. DROSHA is a miRNA master regulator. It is a member of the RNase III enzyme family, belongs to the miRNA biogenesis pathway and is the core nuclease that processes pri-miRNAs into pre-miRNAs in the nucleus [5], [6]. The SNP rs10719 in the 3′ UTR of DROSHA is predicted to abolish the hsa-miR-1298 binding site. Hsa-miR-1298 is predicted to target DROSHA by the Patrocles prediction as well as by TargetScan [45] and PITA [46] prediction algorithms. Recently a small Korean study reported another SNP rs644236, tagging the SNP rs10719 (r2 = 0.955 in CEU population and r2 = 0.876 in Asian population (combined CHB and JPT)) to be associated with elevated breast cancer risk [47]. When taking into account the opposite major and minors alleles in the Asian and European populations for SNPs rs644236 and rs10719, this result is in concordance with our results where both the combined GWAS as well as the iCOGS analysis consistently indicated an association of the minor allele of SNP rs10719 with reduced breast cancer risk. We also found the minor allele of SNP rs3134615 in the 3′ UTR of MYCL1 to be associated with an increased risk. MYCL1 (L-MYC) belongs to the same family of transcription factors as the known proto-oncogene MYC (C-MYC) and they share a high degree of structural similarity [48]. The MYCL1 gene has previously been reported to be amplified and overexpressed in ovarian cancer [49]. A case-control study by Xiong and colleagues reported SNP rs3134615 to be significantly associated with increased risk of small cell lung cancer [50]. SNP rs3134615 was predicted by Patrocles to abolish the hsa-miR-1827 binding site. This has also been suggested by functional studies where MYCL1 was found as the target of hsa-miR-1827 and the SNP rs3134615 was also found to increase MYCL1 expression [50]. The evidence from functional studies is consistent with our finding that SNP rs3134615 might increase breast cancer risk. MUSTN1 has been shown to be involved in the development and regeneration of the musculoskeletal system [51]. Thus far no evidence of association between MUSTN1 and breast cancer has been reported, but the MUSTN1 gene is expressed in the mammary glands [52].

Since only a small fraction of miRNA binding sites has been experimentally validated, we selected SNPs that had been computationally predicted to affect miRNA binding sites. For our original SNP selection we used the Patrocles database that contains predicted miRNA binding sites and also compiles perturbation prediction of SNP effects. There are a multitude of prediction programs and their performance has been evaluated [53]. Witkos and colleagues find target prediction algorithms that utilize orthologous sequence alignment, like Patrocles, to be the most reliable.

The followup of the 42 miRNA related SNPs identified five significant associations with breast cancer risk. Although the individual risk effects were subtle, considering that we could only investigate a small proportion of our initial in silico data set of miRNA related SNPs (over 140,000 SNPs) this may suggest that genetic polymorphisms affecting the miRNA regulation could have a considerable combined effect on breast cancer risk.

It should be noted that, until fine mapping studies are carried out for these loci, it is not clear whether these miRNA-related SNPs are the variants responsible for the observed associations.

This comprehensive analysis of miRNA related polymorphisms using a large two stage study of women with European ancestry provides evidence for miRNA related SNPs being potential modulators of breast cancer risk.

Supporting Information

Figure S1.

Forest plots for the five most significant miRNA binding site SNPs from the combined GWAS. Squares indicate the estimated per-allele OR for the minor allele in Europeans. The horizontal lines indicate 95% confidence limits. The vertical blue dashed lines indicate clipping of the confidence intervals for presentation purpose. The area of the square is inversely proportional to the variance of the estimate. The diamond indicates the estimated per-allele OR from the combined analysis.

https://doi.org/10.1371/journal.pone.0109973.s001

(PDF)

Figure S2.

Forest plots for the five most significant miRNA binding site SNPs from the iCOGS. Squares indicate the estimated per-allele OR for the minor allele in Europeans. The horizontal lines indicate 95% confidence limits. The vertical blue dashed lines indicate clipping of the confidence intervals for presentation purpose. The area of the square is inversely proportional to the variance of the estimate. The diamond indicates the estimated per-allele OR from the combined analysis.

https://doi.org/10.1371/journal.pone.0109973.s002

(PDF)

Table S1.

A description of each GWAS study, number of subjects and genotyping platform used in combined GWAS.

https://doi.org/10.1371/journal.pone.0109973.s003

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Table S2.

A description of each BCAC study with subjects of European origin in iCOGS.

https://doi.org/10.1371/journal.pone.0109973.s004

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Table S3.

Frequencies and effect sizes of the 42 SNPs in the main analysis; combined GWAS and iCOGS.

https://doi.org/10.1371/journal.pone.0109973.s005

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Table S4.

Results for SNPs in the GWAS and iCOGS separately and combined GWAS+iCOGS analysis for ER negative subgroup.

https://doi.org/10.1371/journal.pone.0109973.s006

(DOC)

Table S5.

Results for SNPs in the GWAS and iCOGS separately and combined GWAS+iCOGS analysis for ER positive subgroup.

https://doi.org/10.1371/journal.pone.0109973.s007

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Table S6.

Results for SNPs in the GWAS and iCOGS separately and combined GWAS+iCOGS analysis for cases less than 50 years at diagnosis.

https://doi.org/10.1371/journal.pone.0109973.s008

(DOC)

Acknowledgments

We thank all the individuals who took part in these studies and all the researchers, study staff, clinicians and other health care providers, technicians and administrative staff who have enabled this work to be carried out. The HEBCS thanks Dr. Karl von Smitten and RN Irja Erkkilä for their help with the HEBCS data and samples. The ABCFS thanks Maggie Angelakos, Judi Maskiell and Gillian Dite. The OFBCR thanks Teresa Selander, Nayana Weerasooriya and Gord Glendon. The ABCS would like to acknowledge Ellen van der Schoot for DNA of controls. The BBCC thanks Silke Landrith, Sonja Oeser, Matthias Rübner. The BBCS thanks Eileen Williams, Elaine Ryder-Mills and Kara Sargus. The BIGGS thanks Niall McInerney, Gabrielle Colleran, Andrew Rowan and Angela Jones. The BSUCH thanks Peter Bugert and the Medical Faculty, Mannheim. The CGPS thanks the staff and participants of the Copenhagen General Population Study, and Dorthe Uldall Andersen, Maria Birna Arnadottir, Anne Bank, Dorthe Kjeldgård Hansen for excellent technical assistance. The CNIO-BCS acknowledge the support of Nuria Álvarez, Daniel Herrero, Primitiva Menendez and the Human Genotyping-CEGEN Unit (CNIO). The DFBBCS thanks Margreet Ausems, Christi van Asperen, Senno Verhoef, and Rogier van Oldenburg for providing samples from their Clinical Genetic centers. We also thank Pascal Arp, Mila Jhamai, Marijn Verkerk, Lizbeth Herrera and Marjolein Peters for their help in creating the GWAS database, and Karol Estrada and Maksim V. Struchalin for their support in creation and analysis of imputed data. The authors are grateful to the study participants, the staff from the Rotterdam Study and the participating general practitioners and pharmacists. The ESTHER thanks Hartwig Ziegler, Sonja Wolf and Volker Hermann, Katja Butterbach. The GC-HBOC would like to thank the following persons for providing additional information and samples: Prof. Dr. Norbert Arnold, Dr. Sabine Preissler-Adams, Dr. Monika Mareeva-Varon, Dr. Dieter Niederacher, Prof. Dr. Brigitte Schlegelberger, Dr. Clemens Mül, Heide Hellebrand, and Stefanie Engert. The HMBCS thanks Peter Hillemanns, Hans Christiansen and Johann H. Karstens. The KBCP thanks Eija Myöhänen and Helena Kemiläinen. kConFab/AOCS wish 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 for their contributions to this resource, and the many families who contribute to kConFab. The LMBC thanks Gilian Peuteman, Dominiek Smeets, Thomas Van Brussel and Kathleen Corthouts. The MARIE would like to thank Alina Vrieling, Katharina Buck, Ursula Eilber, Muhabbet Celik, and Sabine Behrens. The MBCSG thanks Siranoush Manoukian, Bernard Peissel and Daniela Zaffaroni of the Fondazione IRCCS Istituto Nazionale dei Tumori (INT); Bernardo Bonanni, Irene Feroce and Angela Maniscalco of the Istituto Europeo di Oncologia (IEO) and the personnel of the Cogentech Cancer Genetic Test Laboratory. The MTLGEBCS gratefully acknowledge the assistance of Lesley Richardson and Marie-Claire Goulet in conducting the study. We would like to thank Martine Tranchant (Cancer Genomics Laboratory, CHU de Québec 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 skillful technical assistance. J.S. is Chairholder of the Canada Research Chair in Oncogenetics. The OBCS thanks Meeri Otsukka and Kari Mononen. The ORIGO thanks 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 OSU thanks Robert Pilarksi and Charles Shapiro, who were instrumental in the formation of the OSU Breast Cancer Tissue Bank. We thank the Human Genetics Sample Bank for processing of samples. OSU Columbus area control specimens were provided by the Ohio State University's Human Genetics Sample Bank. The PBCS thanks Mark Sherman, Neonila Szeszenia-Dabrowska, Beata Peplonska, Witold Zatonski, Pei Chao and Michael Stagner. The RBCS thanks Petra Bos, Jannet Blom, Ellen Crepin, Anja Nieuwlaat, Annette Heemskerk and the Erasmus MC Family Cancer Clinic. The SBCS thanks Sue Higham, Ian Brock, Sabapathy Balasubramanian, Helen Cramp and Dan Connley. The SEARCH thanks the SEARCH and EPIC-Norfolk teams. The iCOGS study would not have been possible without the contributions of the following: Qin Wang (BCAC), Andrew Berchuck (OCAC), Rosalind A. Eeles, Ali Amin Al Olama, Zsofia Kote-Jarai, Sara Benlloch (PRACTICAL), Antonis Antoniou, Lesley McGuffog and Ken Offit (CIMBA), Andrew Lee, and Ed Dicks, Craig Luccarini and the staff of the Centre for Genetic Epidemiology Laboratory, Anna Gonzalez-Neira and the staff of the CNIO genotyping unit, Daniel C. Tessier, Francois Bacot, Daniel Vincent, Sylvie LaBoissière and Frederic Robidoux and the staff of the McGill University and Génome Québec Innovation Centre, and 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.

Consortia members

GENICA Network. Hiltrud Brauch, Wing-Yee Lo, Christina Justenhoven: Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology, Stuttgart, and University of Tübingen, Germany. Yon-Dschun Ko, Christian Baisch: Department of Internal Medicine, Evangelische Kliniken Bonn gGmbH, Johanniter Krankenhaus, Bonn, Germany. Hans-Peter Fischer: Institute of Pathology, University of Bonn, Bonn, Germany. Ute Hamann: Molecular Genetics of Breast Cancer, Deutsches Krebsforschungszentrum (DKFZ), Heidelberg, Germany. Thomas Brüning, Beate Pesch, Sylvia Rabstein, Anne Lotz: Institute of the Ruhr University Bochum (IPA), Bochum, Germany. Volker Harth: Institute for Occupational Medicine and Maritime Medicine, University Medical Center Hamburg-Eppendorf, Germany.

kConFab Investigators. See http://www.kconfab.org/Organisation/Members.aspx

AOCS. See http://www.aocstudy.org/org_coll.asp

Author Contributions

Conceived and designed the experiments: HN DG GCT AC RLM DFE SK KM JCC AD MS MGC PH. Performed the experiments: SK DG KM RLM DFE. Analyzed the data: SK DG KM RLM HN DFE. Contributed reagents/materials/analysis tools: SK HN DG KM GCT AC RLM PDPP UH MKS A. Meindl RW TH CB K. Aaltonen GGG DFE PAF MJH ILA H. Brauch QW EJS H. Brenner AKD MSG FL TAM K. Aittomäki J. Liu PH AI KH J. Li KC JCC RH AR PS DFJ OF JP IdSS NJ LG ZA JLH HT M. Bui EM DFS MCS CA J. Stone HMH MAA RBvdL A. Mannermaa RKS BMM PL CT NR SJC DJH SSC MWRR AB LJVV FBH MGS ABE MWB SEB BGN SFN HF PMZ JIAP J. Benitez CAH BEH FS LLM AMD MS RL J. Brown FJC XW CV JEO DL MM RP MRC PG TT PLP C. Mulot FM A. Schneeweiss C. Sohn BB IT MJK NM JAK ST AMM NVB NNA TD HAC HD ME MGC JF J. Lissowska LB PD RAEMT C. Seynaeve CJvA VNK SS AET CBA DY AL SM PR PP M. Barile PM JWMM JMC A. Jager A. Jakubowska J. Lubinski KJB KD C. McLean TB YDK VA C. Stegmaier A. Swerdlow AA NO MJ J. Simard MD KP AJV MG VK MKB JD VMK JMH kConFab Investigators Australian Ovarian Cancer Study Group The GENICA Network. Wrote the paper: SK HN RLM AC. Provided critical review of the manuscript: SK HN DG KM GCT AC RLM PDPP UH MKS A. Meindl RW TH CB K. Aaltonen GGG DFE PAF MJH ILA H. Brauch QW EJS H. Brenner AKD MSG FL TAM K. Aittomäki J. Liu PH AI KH J. Li KC JCC RH AR PS DFJ OF JP IdSS NJ LG ZA JLH HT M. Bui EM DFS MCS CA J. Stone HMH MAA RBvdL A. Mannermaa RKS BMM PL CT NR SJC DJH SSC MWRR AB LJVV FBH MGS ABE MWB SEB BGN SFN HF PMZ JIAP J. Benitez CAH BEH FS LLM AMD MS RL J. Brown FJC XW CV JEO DL MM RP MRC PG TT PLP C. Mulot FM A. Schneeweiss C. Sohn BB IT MJK NM JAK ST AMM NVB NNA TD HAC HD ME MGC JF J. Lissowska LB PD RAEMT C. Seynaeve CJvA VNK SS AET CBA DY AL SM PR PP M. Barile PM JWMM JMC A. Jager A. Jakubowska J. Lubinski KJB KD C. McLean TB YDK VA C. Stegmaier A. Swerdlow AA NO MJ J. Simard MD KP AJV MG VK MKB JD VMK JMH kConFab Investigators Australian Ovarian Cancer Study Group The GENICA Network. Approved the final version of the manuscript: SK HN DG KM GCT AC RLM PDPP UH MKS A. Meindl RW TH CB K. Aaltonen GGG DFE PAF MJH ILA H. Brauch QW EJS H. Brenner AKD MSG FL TAM K. Aittomäki J. Liu PH AI KH J. Li KC JCC RH AR PS DFJ OF JP IdSS NJ LG ZA JLH HT M. Bui EM DFS MCS CA J. Stone HMH MAA RBvdL A. Mannermaa RKS BMM PL CT NR SJC DJH SSC MWRR AB LJVV FBH MGS ABE MWB SEB BGN SFN HF PMZ JIAP J. Benitez CAH BEH FS LLM AMD MS RL J. Brown FJC XW CV JEO DL MM RP MRC PG TT PLP C. Mulot FM A. Schneeweiss C. Sohn BB IT MJK NM JAK ST AMM NVB NNA TD HAC HD ME MGC JF J. Lissowska LB PD RAEMT C. Seynaeve CJvA VNK SS AET CBA DY AL SM PR PP M. Barile PM JWMM JMC A. Jager A. Jakubowska J. Lubinski KJB KD C. McLean TB YDK VA C. Stegmaier A. Swerdlow AA NO MJ J. Simard MD KP AJV MG VK MKB JD VMK JMH kConFab Investigators Australian Ovarian Cancer Study Group The GENICA Network. Administrative technical or material support: MKB JD MS RL.

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