Body mass index and breast cancer survival: a Mendelian randomization analysis

doi:10.1093/ije/dyx131

. 2017 Dec 1;46(6):1814-1822.

doi: 10.1093/ije/dyx131.

Body mass index and breast cancer survival: a Mendelian randomization analysis

Qi Guo¹, Stephen Burgess^{1

2}, Constance Turman³, Manjeet K Bolla⁴, Qin Wang⁴, Michael Lush⁴, Jean Abraham^{5

6}, Kristiina Aittomäki⁷, Irene L Andrulis^{8

9}, Carmel Apicella¹⁰, Volker Arndt¹¹, Myrto Barrdahl¹², Javier Benitez^{13

14}, Christine D Berg¹⁵, Carl Blomqvist¹⁶, Stig E Bojesen^{17

18}, Bernardo Bonanni¹⁹, Judith S Brand²⁰, Hermann Brenner^{11

21

22}, Annegien Broeks²³, Barbara Burwinkel^{24

25}, Carlos Caldas^{6

26

27}, Daniele Campa²⁸, Federico Canzian²⁹, Jenny Chang-Claude^{12

30}, Stephen J Chanock¹⁵, Suet-Feung Chin²⁷, Fergus J Couch³¹, Angela Cox³², Simon S Cross³³, Cezary Cybulski³⁴, Kamila Czene²⁰, Hatef Darabi²⁰, Peter Devilee^{35

36}, W Ryan Diver³⁷, Alison M Dunning⁵, Helena M Earl^{6

26}, Diana M Eccles³⁸, Arif B Ekici³⁹, Mikael Eriksson²⁰, D Gareth Evans⁴⁰, Peter A Fasching^{41

42}, Jonine Figueroa^{15

43}, Dieter Flesch-Janys^{44

45}, Henrik Flyger⁴⁶, Susan M Gapstur³⁷, Mia M Gaudet³⁷, Graham G Giles^{10

47}, Gord Glendon⁸, Mervi Grip⁴⁸, Jacek Gronwald³⁴, Lothar Haeberle⁴¹, Christopher A Haiman⁴⁹, Per Hall²⁰, Ute Hamann⁵⁰, Susan Hankinson⁵¹, Jaana M Hartikainen^{52

53}, Alexander Hein⁴¹, Louise Hiller⁵⁴, Frans B Hogervorst⁵⁵, Bernd Holleczek⁵⁶, Maartje J Hooning⁵⁷, Robert N Hoover¹⁵, Keith Humphreys²⁰, David J Hunter^{3

58}, Anika Hüsing¹², Anna Jakubowska³⁴, Arja Jukkola-Vuorinen⁵⁹, Rudolf Kaaks¹², Maria Kabisch⁵⁰, Vesa Kataja^{52

60}; kConFab/AOCS Investigators; Julia A Knight^{61

62}, Linetta B Koppert⁶³, Veli-Matti Kosma¹, Vessela N Kristensen^{64

65

66}, Diether Lambrechts^{67

68}, Loic Le Marchand⁶⁹, Jingmei Li²⁰, Annika Lindblom⁷⁰, Sara Lindström^{3

71}, Jolanta Lissowska⁷², Jan Lubinski³⁴, Mitchell J Machiela¹⁵, Arto Mannermaa^{52

73

53}, Siranoush Manoukian⁷⁴, Sara Margolin⁷⁵, Federik Marme^{24

76}, John W M Martens⁵⁷, Catriona McLean⁷⁷, Primitiva Menéndez⁷⁸, Roger L Milne^{10

47}, Anna Marie Mulligan^{79

80}, Taru A Muranen⁸¹, Heli Nevanlinna⁸¹, Patrick Neven⁸², Sune F Nielsen^{17

83}, Børge G Nordestgaard^{17

83

18}, Janet E Olson⁸⁴, Jose I A Perez⁸⁵, Paolo Peterlongo⁸⁶, Kelly-Anne Phillips^{10

87

88

89}, Christopher J Poole⁵⁴, Katri Pylkäs^{90

91}, Paolo Radice⁹², Nazneen Rahman⁹³, Thomas Rüdiger⁹⁴, Anja Rudolph¹², Elinor J Sawyer⁹⁵, Fredrick Schumacher⁹⁶, Petra Seibold¹², Caroline Seynaeve⁵⁷, Mitul Shah⁵, Ann Smeets⁸², Melissa C Southey⁹⁷, Rob A E M Tollenaar⁹⁸, Ian Tomlinson⁹⁹, Helen Tsimiklis⁹⁷, Hans-Ulrich Ulmer¹⁰⁰, Celine Vachon⁸⁴, Ans M W van den Ouweland¹⁰¹, Laura J Van't Veer²³, Hans Wildiers⁸², Walter Willett¹⁰², Robert Winqvist^{90

91}, M Pilar Zamora¹⁰³, Georgia Chenevix-Trench¹⁰⁴, Thilo Dörk¹⁰⁵, Douglas F Easton^{4

5}, Montserrat García-Closas¹⁵, Peter Kraft^{3

58}, John L Hopper¹⁰, Wei Zheng¹⁰⁶, Marjanka K Schmidt^{23

107}, Paul D P Pharoah^{4

5}

Affiliations

¹ Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.
² MRC Biostatistics Unit, University of Cambridge, Cambridge, UK.
³ Program in Genetic Epidemiology and Statistical Genetics, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
⁴ Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.
⁵ Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Cambridge, UK.
⁶ Cambridge Experimental Cancer Medicine Centre, Cambridge, UK.
⁷ Department of Clinical Genetics, Helsinki University Hospital, University of Helsinki, Helsinki, Finland.
⁸ Fred A. Litwin Center for Cancer Genetics, Lunenfeld-Tanenbaum Research Institute of Mount Sinai Hospital, Toronto, Canada.
⁹ Department of Molecular Genetics, University of Toronto, Toronto, Canada.
¹⁰ Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, Australia.
¹¹ Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany.
¹² Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
¹³ Human Cancer Genetics Program, Spanish National Cancer Research Centre, Madrid, Spain.
¹⁴ Centro de Investigación en Red de Enfermedades Raras (CIBERER), Valencia, Spain.
¹⁵ Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD, USA.
¹⁶ Department of Oncology, Helsinki University Hospital, University of Helsinki, Helsinki, Finland.
¹⁷ Copenhagen General Population Study, Herlev and Gentofte Hospital, Copenhagen University Hospital, Herlev, Denmark.
¹⁸ Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
¹⁹ Division of Cancer Prevention and Genetics, Istituto Europeo di Oncologia, Milan, Italy.
²⁰ Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
²¹ Division of Preventive Oncology, German Cancer Research Center (DKFZ) and National Center for Tumor Diseases (NCT), Heidelberg, Germany.
²² German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany.
²³ Division of Molecular Pathology, The Netherlands Cancer Institute - Antoni van Leeuwenhoek Hospital, Amsterdam, The Netherlands.
²⁴ Department of Obstetrics and Gynecology, University of Heidelberg, Heidelberg, Germany.
²⁵ Molecular Epidemiology Group, C080, German Cancer Research Center (DKFZ), Heidelberg, Germany.
²⁶ Cambridge Breast Unit and NIHR Cambridge Biomedical Research Centre, University of Cambridge NHS Foundation Hospitals, Cambridge, UK.
²⁷ Breast Cancer Functional Genomics Laboratory, Cancer Research UK Cambridge Institute, University of Cambridge, Li Ka Shing Centre, UK.
²⁸ Department of Biology, University of Pisa, Pisa, Italy.
²⁹ Genomic Epidemiology Group, German Cancer Research Center (DKFZ), Heidelberg, Germany.
³⁰ University Cancer Center Hamburg (UCCH), University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
³¹ Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA.
³² Academic Unit of Molecular Oncology, Department of Oncology and Metabolism, University of Sheffield, Sheffield, UK.
³³ Academic Unit of Pathology, Department of Neuroscience, University of Sheffield, Sheffield, UK.
³⁴ Department of Genetics and Pathology, Pomeranian Medical University, Szczecin, Poland.
³⁵ Department of Pathology, Leiden University Medical Center, Leiden, The Netherlands.
³⁶ Department of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands.
³⁷ Epidemiology Research Program, American Cancer Society, Atlanta, GA, USA.
³⁸ Cancer Sciences Academic Unit, Faculty of Medicine, University of Southampton, Southampton, UK.
³⁹ Institute of Human Genetics, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nuremberg, Comprehensive Cancer Center Erlangen-EMN, Erlangen, Germany.
⁴⁰ Genomic Medicine, Manchester Academic Health Science Centre, University of Manchester, Central Manchester Foundation Trust, St. Mary's Hospital, Manchester, UK.
⁴¹ Department of Gynaecology and Obstetrics, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nuremberg, Comprehensive Cancer Center Erlangen-EMN, Erlangen, Germany.
⁴² David Geffen School of Medicine, Department of Medicine Division of Hematology and Oncology, University of California at Los Angeles, Los Angeles, CA, USA.
⁴³ Usher Institute of Population Health Sciences and Informatics, The University of Edinburgh Medical School, Edinburgh, UK.
⁴⁴ Institute for Medical Biometrics and Epidemiology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
⁴⁵ Department of Cancer Epidemiology, Clinical Cancer Registry, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
⁴⁶ Department of Breast Surgery, Herlev and Gentofte Hospital, Copenhagen University Hospital, Herlev, Denmark.
⁴⁷ Cancer Epidemiology & Intelligence Division, Cancer Council Victoria, Melbourne, Australia.
⁴⁸ Department of Surgery, Oulu University Hospital, University of Oulu, Oulu, Finland.
⁴⁹ Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
⁵⁰ Molecular Genetics of Breast Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany.
⁵¹ Department of Biostatistics & Epidemiology, University of Massachusetts, Amherst, Amherst, MA, USA.
⁵² Translational Cancer Research Area, University of Eastern Finland, Kuopio, Finland.
⁵³ Imaging Center, Department of Clinical Pathology, Kuopio University Hospital, Kuopio, Finland.
⁵⁴ Warwick Clinical Trials Unit, University of Warwick, Coventry, UK.
⁵⁵ Family Cancer Clinic, The Netherlands Cancer Institute - Antoni van Leeuwenhoek Hospital, Amsterdam, The Netherlands.
⁵⁶ Saarland Cancer Registry, Saarbrücken, Germany.
⁵⁷ Department of Medical Oncology, Family Cancer Clinic, Erasmus MC Cancer Institute, Rotterdam, The Netherlands.
⁵⁸ Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
⁵⁹ Department of Oncology, Oulu University Hospital, University of Oulu, Oulu, Finland.
⁶⁰ Central Finland Health Care District, Jyväskylä Central Hospital, Jyväskylä, Finland.
⁶¹ Prosserman Centre for Health Research, Lunenfeld-Tanenbaum Research Institute of Mount Sinai Hospital, Toronto, Canada.
⁶² Division of Epidemiology, Dalla Lana School of Public Health, University of Toronto, Toronto, Canada.
⁶³ Department of Surgical Oncology, Family Cancer Clinic, Erasmus MC Cancer Institute, Rotterdam, The Netherlands.
⁶⁴ Department of Cancer Genetics, Institute for Cancer Research, Oslo University Hospital Radiumhospitalet, Oslo, Norway.
⁶⁵ Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway.
⁶⁶ Department of Clinical Molecular Biology, Oslo University Hospital, University of Oslo, Oslo, Norway.
⁶⁷ VIB Center for Cancer Biology, VIB, Leuven, Belgium.
⁶⁸ Laboratory for Translational Genetics, Department of Human Genetics, University of Leuven, Leuven, Belgium.
⁶⁹ University of Hawaii Cancer Center, Honolulu, HI, USA.
⁷⁰ Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.
⁷¹ Department of Epidemiology, University of Washington School of Public Health, Seattle, WA, USA.
⁷² Department of Cancer Epidemiology and Prevention, M. Sklodowska-Curie Memorial Cancer Center - Oncology Institute, Warsaw, Poland.
⁷³ Institute of Clinical Medicine, Pathology and Forensic Medicine, University of Eastern Finland, Kuopio, Finland.
⁷⁴ Unit of Medical Genetics, Department of Medical Oncology and Hematology, Fondazione IRCCS (Istituto di Ricovero e Cura a Carattere Scientifico) Istituto Nazionale dei Tumori (INT), Milan, Italy.
⁷⁵ Department of Oncology - Pathology, Karolinska Institutet, Stockholm, Sweden.
⁷⁶ National Center for Tumor Diseases, University of Heidelberg, Heidelberg, Germany.
⁷⁷ Anatomical Pathology, The Alfred Hospital, Melbourne, Australia.
⁷⁸ Servicio de Anatomía Patológica, Hospital Monte Naranco, Oviedo, Spain.
⁷⁹ Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Canada.
⁸⁰ Laboratory Medicine Program, University Health Network, Toronto, Canada.
⁸¹ Department of Obstetrics and Gynecology, Helsinki University Hospital, University of Helsinki, Helsinki, Finland.
⁸² Leuven Multidisciplinary Breast Center, Department of Oncology, Leuven Cancer Institute, University Hospitals Leuven, Leuven, Belgium.
⁸³ Department of Clinical Biochemistry, Herlev and Gentofte Hospital, Copenhagen University Hospital, Herlev, Denmark.
⁸⁴ Department of Health Sciences Research, Mayo Clinic, Rochester, MN, USA.
⁸⁵ Servicio de Cirugía General y Especialidades, Hospital Monte Naranco, Oviedo, Spain.
⁸⁶ IFOM, The FIRC (Italian Foundation for Cancer Research) Institute of Molecular Oncology, Milan, Italy.
⁸⁷ Division of Cancer Medicine, Peter MacCallum Cancer Center, Melbourne, Australia.
⁸⁸ Sir Peter MacCallum Department of Oncology, The University of Melbourne, Melbourne, Australia.
⁸⁹ Department of Medicine, St Vincent's Hospital, The University of Melbourne, Fitzroy, Australia.
⁹⁰ Laboratory of Cancer Genetics and Tumor Biology, Cancer and Translational Medicine Research Unit, Biocenter Oulu, University of Oulu, Oulu, Finland.
⁹¹ Laboratory of Cancer Genetics and Tumor Biology, Northern Finland Laboratory Centre Oulu, Oulu, Finland.
⁹² Unit of Molecular Bases of Genetic Risk and Genetic Testing, Department of Research, Fondazione IRCCS (Istituto Di Ricovero e Cura a Carattere Scientifico) Istituto Nazionale dei Tumori (INT), Milan, Italy.
⁹³ Division of Genetics and Epidemiology, The Institute of Cancer Research, London, UK.
⁹⁴ Institute of Pathology, Staedtisches Klinikum Karlsruhe, Karlsruhe, Germany.
⁹⁵ Research Oncology, Guy's Hospital, King's College London, London, UK.
⁹⁶ Department of Epidemiology and Biostatistics, Case Western Reserve University, Cleveland, OH, USA.
⁹⁷ Department of Pathology, The University of Melbourne, Melbourne, Australia.
⁹⁸ Department of Surgery, Leiden University Medical Center, Leiden, The Netherlands.
⁹⁹ Wellcome Trust Centre for Human Genetics and Oxford NIHR Biomedical Research Centre, University of Oxford, Oxford, UK.
¹⁰⁰ Frauenklinik der Stadtklinik Baden-Baden, Baden-Baden, Germany.
¹⁰¹ Department of Clinical Genetics, Erasmus University Medical Center, Rotterdam, The Netherlands.
¹⁰² Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
¹⁰³ Servicio de Oncología Médica, Hospital Universitario La Paz, Madrid, Spain.
¹⁰⁴ Department of Genetics and Computational Biology, QIMR Berghofer Medical Research Institute, Brisbane, Australia.
¹⁰⁵ Gynaecology Research Unit, Hannover Medical School, Hannover, Germany.
¹⁰⁶ Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, TN, USA.
¹⁰⁷ Division of Psychosocial Research and Epidemiology, The Netherlands Cancer Institute - Antoni van Leeuwenhoek Hospital, Amsterdam, The Netherlands.

PMID: 29232439
PMCID: PMC5837506
DOI: 10.1093/ije/dyx131

Body mass index and breast cancer survival: a Mendelian randomization analysis

Qi Guo et al. Int J Epidemiol. 2017.

. 2017 Dec 1;46(6):1814-1822.

doi: 10.1093/ije/dyx131.

Authors

Affiliations

¹ Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.
² MRC Biostatistics Unit, University of Cambridge, Cambridge, UK.
³ Program in Genetic Epidemiology and Statistical Genetics, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
⁴ Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.
⁵ Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Cambridge, UK.
⁶ Cambridge Experimental Cancer Medicine Centre, Cambridge, UK.
⁷ Department of Clinical Genetics, Helsinki University Hospital, University of Helsinki, Helsinki, Finland.
⁸ Fred A. Litwin Center for Cancer Genetics, Lunenfeld-Tanenbaum Research Institute of Mount Sinai Hospital, Toronto, Canada.
⁹ Department of Molecular Genetics, University of Toronto, Toronto, Canada.
¹⁰ Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, Australia.
¹¹ Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany.
¹² Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
¹³ Human Cancer Genetics Program, Spanish National Cancer Research Centre, Madrid, Spain.
¹⁴ Centro de Investigación en Red de Enfermedades Raras (CIBERER), Valencia, Spain.
¹⁵ Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD, USA.
¹⁶ Department of Oncology, Helsinki University Hospital, University of Helsinki, Helsinki, Finland.
¹⁷ Copenhagen General Population Study, Herlev and Gentofte Hospital, Copenhagen University Hospital, Herlev, Denmark.
¹⁸ Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
¹⁹ Division of Cancer Prevention and Genetics, Istituto Europeo di Oncologia, Milan, Italy.
²⁰ Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
²¹ Division of Preventive Oncology, German Cancer Research Center (DKFZ) and National Center for Tumor Diseases (NCT), Heidelberg, Germany.
²² German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany.
²³ Division of Molecular Pathology, The Netherlands Cancer Institute - Antoni van Leeuwenhoek Hospital, Amsterdam, The Netherlands.
²⁴ Department of Obstetrics and Gynecology, University of Heidelberg, Heidelberg, Germany.
²⁵ Molecular Epidemiology Group, C080, German Cancer Research Center (DKFZ), Heidelberg, Germany.
²⁶ Cambridge Breast Unit and NIHR Cambridge Biomedical Research Centre, University of Cambridge NHS Foundation Hospitals, Cambridge, UK.
²⁷ Breast Cancer Functional Genomics Laboratory, Cancer Research UK Cambridge Institute, University of Cambridge, Li Ka Shing Centre, UK.
²⁸ Department of Biology, University of Pisa, Pisa, Italy.
²⁹ Genomic Epidemiology Group, German Cancer Research Center (DKFZ), Heidelberg, Germany.
³⁰ University Cancer Center Hamburg (UCCH), University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
³¹ Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA.
³² Academic Unit of Molecular Oncology, Department of Oncology and Metabolism, University of Sheffield, Sheffield, UK.
³³ Academic Unit of Pathology, Department of Neuroscience, University of Sheffield, Sheffield, UK.
³⁴ Department of Genetics and Pathology, Pomeranian Medical University, Szczecin, Poland.
³⁵ Department of Pathology, Leiden University Medical Center, Leiden, The Netherlands.
³⁶ Department of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands.
³⁷ Epidemiology Research Program, American Cancer Society, Atlanta, GA, USA.
³⁸ Cancer Sciences Academic Unit, Faculty of Medicine, University of Southampton, Southampton, UK.
³⁹ Institute of Human Genetics, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nuremberg, Comprehensive Cancer Center Erlangen-EMN, Erlangen, Germany.
⁴⁰ Genomic Medicine, Manchester Academic Health Science Centre, University of Manchester, Central Manchester Foundation Trust, St. Mary's Hospital, Manchester, UK.
⁴¹ Department of Gynaecology and Obstetrics, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nuremberg, Comprehensive Cancer Center Erlangen-EMN, Erlangen, Germany.
⁴² David Geffen School of Medicine, Department of Medicine Division of Hematology and Oncology, University of California at Los Angeles, Los Angeles, CA, USA.
⁴³ Usher Institute of Population Health Sciences and Informatics, The University of Edinburgh Medical School, Edinburgh, UK.
⁴⁴ Institute for Medical Biometrics and Epidemiology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
⁴⁵ Department of Cancer Epidemiology, Clinical Cancer Registry, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
⁴⁶ Department of Breast Surgery, Herlev and Gentofte Hospital, Copenhagen University Hospital, Herlev, Denmark.
⁴⁷ Cancer Epidemiology & Intelligence Division, Cancer Council Victoria, Melbourne, Australia.
⁴⁸ Department of Surgery, Oulu University Hospital, University of Oulu, Oulu, Finland.
⁴⁹ Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
⁵⁰ Molecular Genetics of Breast Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany.
⁵¹ Department of Biostatistics & Epidemiology, University of Massachusetts, Amherst, Amherst, MA, USA.
⁵² Translational Cancer Research Area, University of Eastern Finland, Kuopio, Finland.
⁵³ Imaging Center, Department of Clinical Pathology, Kuopio University Hospital, Kuopio, Finland.
⁵⁴ Warwick Clinical Trials Unit, University of Warwick, Coventry, UK.
⁵⁵ Family Cancer Clinic, The Netherlands Cancer Institute - Antoni van Leeuwenhoek Hospital, Amsterdam, The Netherlands.
⁵⁶ Saarland Cancer Registry, Saarbrücken, Germany.
⁵⁷ Department of Medical Oncology, Family Cancer Clinic, Erasmus MC Cancer Institute, Rotterdam, The Netherlands.
⁵⁸ Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
⁵⁹ Department of Oncology, Oulu University Hospital, University of Oulu, Oulu, Finland.
⁶⁰ Central Finland Health Care District, Jyväskylä Central Hospital, Jyväskylä, Finland.
⁶¹ Prosserman Centre for Health Research, Lunenfeld-Tanenbaum Research Institute of Mount Sinai Hospital, Toronto, Canada.
⁶² Division of Epidemiology, Dalla Lana School of Public Health, University of Toronto, Toronto, Canada.
⁶³ Department of Surgical Oncology, Family Cancer Clinic, Erasmus MC Cancer Institute, Rotterdam, The Netherlands.
⁶⁴ Department of Cancer Genetics, Institute for Cancer Research, Oslo University Hospital Radiumhospitalet, Oslo, Norway.
⁶⁵ Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway.
⁶⁶ Department of Clinical Molecular Biology, Oslo University Hospital, University of Oslo, Oslo, Norway.
⁶⁷ VIB Center for Cancer Biology, VIB, Leuven, Belgium.
⁶⁸ Laboratory for Translational Genetics, Department of Human Genetics, University of Leuven, Leuven, Belgium.
⁶⁹ University of Hawaii Cancer Center, Honolulu, HI, USA.
⁷⁰ Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.
⁷¹ Department of Epidemiology, University of Washington School of Public Health, Seattle, WA, USA.
⁷² Department of Cancer Epidemiology and Prevention, M. Sklodowska-Curie Memorial Cancer Center - Oncology Institute, Warsaw, Poland.
⁷³ Institute of Clinical Medicine, Pathology and Forensic Medicine, University of Eastern Finland, Kuopio, Finland.
⁷⁴ Unit of Medical Genetics, Department of Medical Oncology and Hematology, Fondazione IRCCS (Istituto di Ricovero e Cura a Carattere Scientifico) Istituto Nazionale dei Tumori (INT), Milan, Italy.
⁷⁵ Department of Oncology - Pathology, Karolinska Institutet, Stockholm, Sweden.
⁷⁶ National Center for Tumor Diseases, University of Heidelberg, Heidelberg, Germany.
⁷⁷ Anatomical Pathology, The Alfred Hospital, Melbourne, Australia.
⁷⁸ Servicio de Anatomía Patológica, Hospital Monte Naranco, Oviedo, Spain.
⁷⁹ Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Canada.
⁸⁰ Laboratory Medicine Program, University Health Network, Toronto, Canada.
⁸¹ Department of Obstetrics and Gynecology, Helsinki University Hospital, University of Helsinki, Helsinki, Finland.
⁸² Leuven Multidisciplinary Breast Center, Department of Oncology, Leuven Cancer Institute, University Hospitals Leuven, Leuven, Belgium.
⁸³ Department of Clinical Biochemistry, Herlev and Gentofte Hospital, Copenhagen University Hospital, Herlev, Denmark.
⁸⁴ Department of Health Sciences Research, Mayo Clinic, Rochester, MN, USA.
⁸⁵ Servicio de Cirugía General y Especialidades, Hospital Monte Naranco, Oviedo, Spain.
⁸⁶ IFOM, The FIRC (Italian Foundation for Cancer Research) Institute of Molecular Oncology, Milan, Italy.
⁸⁷ Division of Cancer Medicine, Peter MacCallum Cancer Center, Melbourne, Australia.
⁸⁸ Sir Peter MacCallum Department of Oncology, The University of Melbourne, Melbourne, Australia.
⁸⁹ Department of Medicine, St Vincent's Hospital, The University of Melbourne, Fitzroy, Australia.
⁹⁰ Laboratory of Cancer Genetics and Tumor Biology, Cancer and Translational Medicine Research Unit, Biocenter Oulu, University of Oulu, Oulu, Finland.
⁹¹ Laboratory of Cancer Genetics and Tumor Biology, Northern Finland Laboratory Centre Oulu, Oulu, Finland.
⁹² Unit of Molecular Bases of Genetic Risk and Genetic Testing, Department of Research, Fondazione IRCCS (Istituto Di Ricovero e Cura a Carattere Scientifico) Istituto Nazionale dei Tumori (INT), Milan, Italy.
⁹³ Division of Genetics and Epidemiology, The Institute of Cancer Research, London, UK.
⁹⁴ Institute of Pathology, Staedtisches Klinikum Karlsruhe, Karlsruhe, Germany.
⁹⁵ Research Oncology, Guy's Hospital, King's College London, London, UK.
⁹⁶ Department of Epidemiology and Biostatistics, Case Western Reserve University, Cleveland, OH, USA.
⁹⁷ Department of Pathology, The University of Melbourne, Melbourne, Australia.
⁹⁸ Department of Surgery, Leiden University Medical Center, Leiden, The Netherlands.
⁹⁹ Wellcome Trust Centre for Human Genetics and Oxford NIHR Biomedical Research Centre, University of Oxford, Oxford, UK.
¹⁰⁰ Frauenklinik der Stadtklinik Baden-Baden, Baden-Baden, Germany.
¹⁰¹ Department of Clinical Genetics, Erasmus University Medical Center, Rotterdam, The Netherlands.
¹⁰² Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
¹⁰³ Servicio de Oncología Médica, Hospital Universitario La Paz, Madrid, Spain.
¹⁰⁴ Department of Genetics and Computational Biology, QIMR Berghofer Medical Research Institute, Brisbane, Australia.
¹⁰⁵ Gynaecology Research Unit, Hannover Medical School, Hannover, Germany.
¹⁰⁶ Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, TN, USA.
¹⁰⁷ Division of Psychosocial Research and Epidemiology, The Netherlands Cancer Institute - Antoni van Leeuwenhoek Hospital, Amsterdam, The Netherlands.

PMID: 29232439
PMCID: PMC5837506
DOI: 10.1093/ije/dyx131

Abstract

Background: There is increasing evidence that elevated body mass index (BMI) is associated with reduced survival for women with breast cancer. However, the underlying reasons remain unclear. We conducted a Mendelian randomization analysis to investigate a possible causal role of BMI in survival from breast cancer.

Methods: We used individual-level data from six large breast cancer case-cohorts including a total of 36 210 individuals (2475 events) of European ancestry. We created a BMI genetic risk score (GRS) based on genotypes at 94 known BMI-associated genetic variants. Association between the BMI genetic score and breast cancer survival was analysed by Cox regression for each study separately. Study-specific hazard ratios were pooled using fixed-effect meta-analysis.

Results: BMI genetic score was found to be associated with reduced breast cancer-specific survival for estrogen receptor (ER)-positive cases [hazard ratio (HR) = 1.11, per one-unit increment of GRS, 95% confidence interval (CI) 1.01-1.22, P = 0.03). We observed no association for ER-negative cases (HR = 1.00, per one-unit increment of GRS, 95% CI 0.89-1.13, P = 0.95).

Conclusions: Our findings suggest a causal effect of increased BMI on reduced breast cancer survival for ER-positive breast cancer. There is no evidence of a causal effect of higher BMI on survival for ER-negative breast cancer cases.

Keywords: Body mass index; Mendelian randomization; breast cancer survival; epidemiology; genetics.

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Figures

**Figure 1**
Genetic associations of BMI GRS and breast cancer survival for ER-positive cases. (A) Scatter plot of log hazard ratio of genetic associations with breast cancer survival for ER-positive cases against log odds ratio of association with BMI. Slope of the regression lines: inverse variance-weighted (dotted) and MR-Egger (dashed) provide an estimate of the predicted log hazard ratio per unit increase in BMI. (B) Funnel plot of minor allele frequency (MAF)-corrected log odds ratio of genetic associations with BMI against log hazard ratio per predicted unit increase in BMI on breast cancer survival for each genetic variant individually.

See this image and copyright information in PMC

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References

1. World Cancer Research Fund International, Breast cancer statistics. http://www.wcrf.org/int/cancer-facts-figures/data-specific-cancers/breas... (25 May 2016, date last accessed).
1. Guo Q, Schmidt M, Kraft P. et al. Identification of novel genetic markers of breast cancer survival. J Natl Cancer Inst 2015;107 doi: 10.1093/jnci/djv081. - PMC - PubMed
1. Protani M, Coory M, Martin JH. Effect of obesity on survival of women with breast cancer: systematic review and meta-analysis. Breast Cancer Res Treat 2010;123:627–35. - PubMed
1. Chan DSM, Vieira AR, Aune D. et al. Body mass index and survival in women with breast cancer—systematic literature review and meta-analysis of 82 follow-up studies. Ann Oncol 2014;25:1901–14. - PMC - PubMed
1. Kroenke CH, Chen WY, Rosner B, Holmes MD. Weight, weight gain, and survival after breast cancer diagnosis. J Clin Oncol 2005;23:1370–78. - PubMed

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[1] World Cancer Research Fund International, Breast cancer statistics. http://www.wcrf.org/int/cancer-facts-figures/data-specific-cancers/breas... (25 May 2016, date last accessed).

[2] World Cancer Research Fund International, Breast cancer statistics. http://www.wcrf.org/int/cancer-facts-figures/data-specific-cancers/breas... (25 May 2016, date last accessed).

[3] Guo Q, Schmidt M, Kraft P. et al. Identification of novel genetic markers of breast cancer survival. J Natl Cancer Inst 2015;107 doi: 10.1093/jnci/djv081. - PMC - PubMed

[4] Guo Q, Schmidt M, Kraft P. et al. Identification of novel genetic markers of breast cancer survival. J Natl Cancer Inst 2015;107 doi: 10.1093/jnci/djv081. - PMC - PubMed

[5] Protani M, Coory M, Martin JH. Effect of obesity on survival of women with breast cancer: systematic review and meta-analysis. Breast Cancer Res Treat 2010;123:627–35. - PubMed

[6] Protani M, Coory M, Martin JH. Effect of obesity on survival of women with breast cancer: systematic review and meta-analysis. Breast Cancer Res Treat 2010;123:627–35. - PubMed

[7] Chan DSM, Vieira AR, Aune D. et al. Body mass index and survival in women with breast cancer—systematic literature review and meta-analysis of 82 follow-up studies. Ann Oncol 2014;25:1901–14. - PMC - PubMed

[8] Chan DSM, Vieira AR, Aune D. et al. Body mass index and survival in women with breast cancer—systematic literature review and meta-analysis of 82 follow-up studies. Ann Oncol 2014;25:1901–14. - PMC - PubMed

[9] Kroenke CH, Chen WY, Rosner B, Holmes MD. Weight, weight gain, and survival after breast cancer diagnosis. J Clin Oncol 2005;23:1370–78. - PubMed

[10] Kroenke CH, Chen WY, Rosner B, Holmes MD. Weight, weight gain, and survival after breast cancer diagnosis. J Clin Oncol 2005;23:1370–78. - PubMed

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Body mass index and breast cancer survival: a Mendelian randomization analysis

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