Physical activity, sedentary time and breast cancer risk: a Mendelian randomisation study

Suzanne C Dixon-Suen¹, Sarah J Lewis^{2

3}, Richard M Martin^{2

3

4}, Dallas R English^{1

5}, Terry Boyle^{6

7}, Graham G Giles^{1

5

8}, Kyriaki Michailidou^{9

10}, Manjeet K Bolla¹¹, Qin Wang¹¹, Joe Dennis¹¹, Michael Lush¹¹, Abctb Investigators¹², Thomas U Ahearn¹³, Christine B Ambrosone¹⁴, Irene L Andrulis^{15

16}, Hoda Anton-Culver¹⁷, Volker Arndt¹⁸, Kristan J Aronson¹⁹, Annelie Augustinsson²⁰, Päivi Auvinen^{21

22}, Laura E Beane Freeman¹³, Heiko Becher²³, Matthias W Beckmann²⁴, Sabine Behrens²⁵, Marina Bermisheva²⁶, Carl Blomqvist^{27

28}, Natalia V Bogdanova^{29

30}, Stig E Bojesen^{31

32}, Bernardo Bonanni³³, Hermann Brenner^{18

34}, Thomas Brüning³⁵, Saundra S Buys³⁶, Nicola J Camp³⁶, Daniele Campa^{25

37}, Federico Canzian³⁸, Jose E Castelao³⁹, Melissa H Cessna^{40

41}, Jenny Chang-Claude^{25

42}, Stephen J Chanock¹³, Christine L Clarke⁴³, Don M Conroy⁴⁴, Fergus J Couch⁴⁵, Angela Cox⁴⁶, Simon S Cross⁴⁷, Kamila Czene⁴⁸, Mary B Daly⁴⁹, Peter Devilee^{50

51}, Thilo Dörk³⁰, Miriam Dwek⁵², Diana M Eccles⁵³, A Heather Eliassen^{54

55}, Christoph Engel^{56

57}, Mikael Eriksson⁴⁸, D Gareth Evans^{58

59}, Peter A Fasching^{24

60}, Olivia Fletcher⁶¹, Henrik Flyger⁶², Lin Fritschi⁶³, Marike Gabrielson⁴⁸, Manuela Gago-Dominguez^{64

65}, Montserrat García-Closas¹³, José A García-Sáenz⁶⁶, Mark S Goldberg^{67

68}, Pascal Guénel⁶⁹, Melanie Gündert^{70

71}, Eric Hahnen^{72

73}, Christopher A Haiman⁷⁴, Lothar Häberle²⁴, Niclas Håkansson⁷⁵, Per Hall^{48

76}, Ute Hamann⁷⁷, Steven N Hart⁷⁸, Michelle Harvie⁷⁹, Peter Hillemanns³⁰, Antoinette Hollestelle⁸⁰, Maartje J Hooning⁸⁰, Reiner Hoppe^{81

82}, John Hopper⁵, Anthony Howell⁸³, David J Hunter^{55

84}, Anna Jakubowska^{85

86}, Wolfgang Janni⁸⁷, Esther M John^{88

89}, Audrey Jung²⁵, Rudolf Kaaks²⁵, Renske Keeman⁹⁰, Cari M Kitahara⁹¹, Stella Koutros¹³, Peter Kraft^{55

92}, Vessela N Kristensen^{93

94}, Katerina Kubelka-Sabit⁹⁵, Allison W Kurian^{88

89}, James V Lacey^{96

97}, Diether Lambrechts^{98

99}, Loic Le Marchand¹⁰⁰, Annika Lindblom^{101

102}, Sibylle Loibl¹⁰³, Jan Lubiński⁸⁵, Arto Mannermaa^{104

105}, Mehdi Manoochehri⁷⁷, Sara Margolin^{76

106}, Maria Elena Martinez^{65

107}, Dimitrios Mavroudis¹⁰⁸, Usha Menon¹⁰⁹, Anna Marie Mulligan^{110

111}, Rachel A Murphy^{112

113}, Nbcs Collaborators^{93

94}, Heli Nevanlinna¹¹⁴, Ines Nevelsteen¹¹⁵, William G Newman^{58

59}, Kenneth Offit^{116

117}, Andrew F Olshan¹¹⁸, Håkan Olsson²⁰, Nick Orr¹¹⁹, Alpa Patel¹²⁰, Julian Peto¹²¹, Dijana Plaseska-Karanfilska¹²², Nadege Presneau⁵², Brigitte Rack⁸⁷, Paolo Radice¹²³, Erika Rees-Punia¹²⁰, Gad Rennert¹²⁴, Hedy S Rennert¹²⁴, Atocha Romero¹²⁵, Emmanouil Saloustros¹²⁶, Dale P Sandler¹²⁷, Marjanka K Schmidt^{90

128}, Rita K Schmutzler^{72

73}, Lukas Schwentner⁸⁷, Christopher Scott⁷⁸, Mitul Shah⁴⁴, Xiao-Ou Shu¹²⁹, Jacques Simard¹³⁰, Melissa C Southey^{1

8}, Jennifer Stone^{5

131}, Harald Surowy^{70

71}, Anthony J Swerdlow^{132

133}, Rulla M Tamimi^{55

134}, William J Tapper⁵³, Jack A Taylor^{127

135}, Mary Beth Terry¹³⁶, Rob A E M Tollenaar¹³⁷, Melissa A Troester¹¹⁸, Thérèse Truong⁶⁹, Michael Untch¹³⁸, Celine M Vachon¹³⁹, Vijai Joseph¹¹⁶, Barbara Wappenschmidt^{72

73}, Clarice R Weinberg¹⁴⁰, Alicja Wolk^{75

141}, Drakoulis Yannoukakos¹⁴², Wei Zheng¹²⁹, Argyrios Ziogas¹⁷, Alison M Dunning⁴⁴, Paul D P Pharoah^{11

44}, Douglas F Easton^{11

44}, Roger L Milne^#^{1

5

8}, Brigid M Lynch^#^{143

5

144}; Breast Cancer Association Consortium

Affiliations

¹ Cancer Epidemiology Division, Cancer Council Victoria, Melbourne, Victoria, Australia.
² Bristol Medical School, Department of Population Health Sciences, University of Bristol, Bristol, UK.
³ MRC Integrative Epidemiology Unit, University of Bristol, Bristol, UK.
⁴ NIHR Biomedical Research Centre, University Hospitals Bristol and Weston NHS Foundation Trust and the University of Bristol, Bristol, UK.
⁵ Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, Victoria, Australia.
⁶ Allied Health and Human Performance, University of South Australia, Adelaide, South Australia, Australia.
⁷ Australian Centre for Precision Health, University of South Australia Cancer Research Institute, Adelaide, South Australia, Australia.
⁸ Precision Medicine, School of Clinical Sciences at Monash Health, Monash University, Clayton, Victoria, Australia.
⁹ Biostatistics Unit, The Cyprus Institute of Neurology and Genetics, Nicosia, Cyprus.
¹⁰ Cyprus School of Molecular Medicine, The Cyprus Institute of Neurology and Genetics, Nicosia, Cyprus.
¹¹ Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.
¹² Australian Breast Cancer Tissue Bank, Westmead Institute for Medical Research, The University of Sydney, Sydney, New South Wales, Australia.
¹³ Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA.
¹⁴ Roswell Park Comprehensive Cancer Center, Buffalo, New York, USA.
¹⁵ Fred A. Litwin Center for Cancer Genetics, Lunenfeld-Tanenbaum Research Institute of Mount Sinai Hospital, Toronto, Ontario, Canada.
¹⁶ Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada.
¹⁷ Department of Medicine, Genetic Epidemiology Research Institute, University of California Irvine, Irvine, California, USA.
¹⁸ Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany.
¹⁹ Department of Public Health Sciences, and Cancer Research Institute, Queen's University, Kingston, Ontario, Canada.
²⁰ Department of Cancer Epidemiology, Clinical Sciences, Lund University, Lund, Sweden.
²¹ Department of Oncology, Cancer Center, Kuopio University Hospital, Kuopio, Finland.
²² Institute of Clinical Medicine, Oncology, University of Eastern Finland, Kuopio, Finland.
²³ Institute of Medical Biometry and Epidemiology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
²⁴ Department of Gynecology and Obstetrics, Comprehensive Cancer Center ER-EMN, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nuremberg, Erlangen, Germany.
²⁵ Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
²⁶ Institute of Biochemistry and Genetics, FSBSI Ufa Federal Research Centre of the Russian Academy of Sciences, Ufa, Russian Federation.
²⁷ Department of Oncology, Helsinki University Hospital, University of Helsinki, Helsinki, Finland.
²⁸ Department of Oncology, Örebro University Hospital, Örebro, Sweden.
²⁹ Department of Radiation Oncology, Hannover Medical School, Hannover, Germany.
³⁰ Gynaecology Research Unit, Hannover Medical School, Hannover, Germany.
³¹ Copenhagen General Population Study, Herlev and Gentofte Hospital, Copenhagen University Hospital, Herlev, Denmark.
³² Department of Clinical Biochemistry, Herlev and Gentofte Hospital, Copenhagen University Hospital, Herlev, Denmark.
³³ Division of Cancer Prevention and Genetics, European Institute of Oncology IRCCS, Milan, Italy.
³⁴ Division of Preventive Oncology, German Cancer Research Center (DKFZ) and National Center for Tumor Diseases (NCT), Heidelberg, Germany.
³⁵ Institute for Prevention and Occupational Medicine of the German Social Accident Insurance (IPA), Institute of the Ruhr University Bochum, Bochum, Germany.
³⁶ Department of Internal Medicine and Huntsman Cancer Institute, The University of Utah, Salt Lake City, Utah, USA.
³⁷ Department of Biology, University of Pisa, Pisa, Italy.
³⁸ Genomic Epidemiology Group, German Cancer Research Center (DKFZ), Heidelberg, Germany.
³⁹ Oncology and Genetics Unit, Instituto de Investigación Sanitaria Galicia Sur (IISGS), Xerencia de Xestion Integrada de Vigo-SERGAS, Vigo, Spain.
⁴⁰ Department of Pathology, Intermountain Medical Center, Intermountain Healthcare, Salt Lake City, Utah, USA.
⁴¹ Intermountain Biorepository, Intermountain Healthcare, Salt Lake City, Utah, USA.
⁴² Cancer Epidemiology Group, University Cancer Center Hamburg (UCCH), University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
⁴³ Westmead Institute for Medical Research, The University of Sydney, Sydney, New South Wales, Australia.
⁴⁴ Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Cambridge, UK.
⁴⁵ Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota, USA.
⁴⁶ Sheffield Institute for Nucleic Acids (SInFoNiA), Department of Oncology and Metabolism, The University of Sheffield, Sheffield, UK.
⁴⁷ Academic Unit of Pathology, Department of Neuroscience, The University of Sheffield, Sheffield, UK.
⁴⁸ Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
⁴⁹ Department of Clinical Genetics, Fox Chase Cancer Center, Philadelphia, Pennsylvania, USA.
⁵⁰ Department of Pathology, Leiden University Medical Center, Leiden, The Netherlands.
⁵¹ Department of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands.
⁵² School of Life Sciences, University of Westminster, London, UK.
⁵³ Faculty of Medicine, University of Southampton, Southampton, UK.
⁵⁴ Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA.
⁵⁵ Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA.
⁵⁶ Institute for Medical Informatics, Statistics and Epidemiology, University of Leipzig, Leipzig, Germany.
⁵⁷ LIFE - Leipzig Research Centre for Civilization Diseases, University of Leipzig, Leipzig, Germany.
⁵⁸ Division of Evolution and Genomic Sciences, School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester Academic Health Science Centre, Manchester, UK.
⁵⁹ North West Genomics Laboratory Hub, Manchester Centre for Genomic Medicine, St Mary's Hospital, Manchester University NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester, UK.
⁶⁰ David Geffen School of Medicine, Department of Medicine Division of Hematology and Oncology, University of California Los Angeles, Los Angeles, California, USA.
⁶¹ The Breast Cancer Now Toby Robins Research Centre, The Institute of Cancer Research, London, UK.
⁶² Department of Breast Surgery, Herlev and Gentofte Hospital, Copenhagen University Hospital, Herlev, Denmark.
⁶³ School of Population Health, Curtin University, Perth, Western Australia, Australia.
⁶⁴ Genomic Medicine Group, International Cancer Genetics and Epidemiology Group, Fundación Pública Galega de Medicina Xenómica, Instituto de Investigación Sanitaria de Santiago de Compostela (IDIS), Complejo Hospitalario Universitario de Santiago, SERGAS, Santiago de Compostela, Spain.
⁶⁵ Moores Cancer Center, University of California San Diego, La Jolla, California, USA.
⁶⁶ Medical Oncology Department, Hospital Clínico San Carlos, Instituto de Investigación Sanitaria San Carlos (IdISSC), Centro de Investigación Biomédica en Red de Cáncer, Madrid, Spain.
⁶⁷ Department of Medicine, McGill University, Montréal, Québec, Canada.
⁶⁸ Division of Clinical Epidemiology, Royal Victoria Hospital, McGill University, Montréal, Québec, Canada.
⁶⁹ Team 'Exposome and Heredity', Center for Research in Epidemiology and Population Health (CESP), Gustave Roussy, INSERM, University Paris-Saclay, Villejuif, France.
⁷⁰ Molecular Epidemiology Group, C080, German Cancer Research Center (DKFZ), Heidelberg, Germany.
⁷¹ Molecular Biology of Breast Cancer, University Womens Clinic Heidelberg, University of Heidelberg, Heidelberg, Germany.
⁷² Center for Familial Breast and Ovarian Cancer, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany.
⁷³ Center for Integrated Oncology (CIO), Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany.
⁷⁴ Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California, USA.
⁷⁵ Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.
⁷⁶ Department of Oncology, Södersjukhuset, Stockholm, Sweden.
⁷⁷ Molecular Genetics of Breast Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany.
⁷⁸ Department of Health Sciences Research, Mayo Clinic, Rochester, Minnesota, USA.
⁷⁹ Prevent Breast Cancer Research Unit, Manchester University Hospital Foundation NHS Trust, Manchester, UK.
⁸⁰ Department of Medical Oncology, Erasmus MC Cancer Institute, Rotterdam, The Netherlands.
⁸¹ Dr Margarete Fischer Bosch Institute of Clinical Pharmacology, Stuttgart, Germany.
⁸² University of Tübingen, Tübingen, Germany.
⁸³ Division of Cancer Sciences, The University of Manchester, Manchester, UK.
⁸⁴ Nuffield Department of Population Health, University of Oxford, Oxford, UK.
⁸⁵ Department of Genetics and Pathology, Pomeranian Medical University in Szczecin, Szczecin, Poland.
⁸⁶ Independent Laboratory of Molecular Biology and Genetic Diagnostics, Pomeranian Medical University in Szczecin, Szczecin, Poland.
⁸⁷ Department of Gynaecology and Obstetrics, University Hospital Ulm, Ulm, Germany.
⁸⁸ Department of Epidemiology and Population Health, Stanford University School of Medicine, Stanford, California, USA.
⁸⁹ Department of Medicine, Division of Oncology, Stanford Cancer Institute, Stanford University School of Medicine, Stanford, California, USA.
⁹⁰ Division of Molecular Pathology, Netherlands Cancer Institute, Amsterdam, The Netherlands.
⁹¹ Radiation Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland, USA.
⁹² Program in Genetic Epidemiology and Statistical Genetics, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA.
⁹³ Department of Medical Genetics, Oslo University Hospital and University of Oslo, Oslo, Norway.
⁹⁴ Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway.
⁹⁵ Department of Histopathology and Cytology, Clinical Hospital Acibadem Sistina, Skopje, Macedonia (the former Yugoslav Republic of).
⁹⁶ Department of Computational and Quantitative Medicine, City of Hope, Duarte, California, USA.
⁹⁷ City of Hope Comprehensive Cancer Center, City of Hope, Duarte, California, USA.
⁹⁸ VIB Center for Cancer Biology, VIB, Gent, Oost-Vlaanderen, Belgium.
⁹⁹ Laboratory for Translational Genetics, Department of Human Genetics, KU Leuven, Leuven, Belgium.
¹⁰⁰ Epidemiology Program, University of Hawai'i Cancer Center, Honolulu, Hawaii, USA.
¹⁰¹ Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.
¹⁰² Department of Clinical Genetics, Karolinska University Hospital, Stockholm, Sweden.
¹⁰³ German Breast Group, Neu-Isenburg, Germany.
¹⁰⁴ Translational Cancer Research Area, University of Eastern Finland, Kuopio, Finland.
¹⁰⁵ Institute of Clinical Medicine, Pathology and Forensic Medicine, University of Eastern Finland, Kuopio, Finland.
¹⁰⁶ Department of Clinical Science and Education, Södersjukhuset, Karolinska Institutet, Stockholm, Sweden.
¹⁰⁷ Herbert Wertheim School of Public Health and Human Longevity Science, University of California San Diego, La Jolla, California, USA.
¹⁰⁸ Department of Medical Oncology, University Hospital of Heraklion, Heraklion, Greece.
¹⁰⁹ MRC Clinical Trials Unit, Institute of Clinical Trials & Methodology, University College London, London, UK.
¹¹⁰ Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada.
¹¹¹ Laboratory Medicine Program, University Health Network, Toronto, Ontario, Canada.
¹¹² Cancer Control Research, BC Cancer, Vancouver, British Columbia, Canada.
¹¹³ School of Population and Public Health, The University of British Columbia, Vancouver, British Columbia, Canada.
¹¹⁴ Department of Obstetrics and Gynecology, Helsinki University Hospital, University of Helsinki, Helsinki, Finland.
¹¹⁵ Leuven Multidisciplinary Breast Center, Department of Oncology, Leuven Cancer Institute, University Hospitals Leuven, Leuven, Belgium.
¹¹⁶ Clinical Genetics Research Lab, Department of Cancer Biology and Genetics, Memorial Sloan Kettering Cancer Center, New York City, New York, USA.
¹¹⁷ Clinical Genetics Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York City, New York, USA.
¹¹⁸ Department of Epidemiology, Gillings School of Global Public Health and UNC Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
¹¹⁹ Centre for Cancer Research and Cell Biology, Queen's University Belfast, Belfast, UK.
¹²⁰ Department of Population Science, American Cancer Society, Atlanta, Georgia, USA.
¹²¹ Department of Non-Communicable Disease Epidemiology, London School of Hygiene and Tropical Medicine, London, UK.
¹²² Research Centre for Genetic Engineering and Biotechnology 'Georgi D. Efremov', MASA, Skopje, Macedonia (the former Yugoslav Republic of).
¹²³ Unit of Molecular Bases of Genetic Risk and Genetic Testing, Department of Research, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
¹²⁴ Clalit National Cancer Control Center, Carmel Medical Center and Technion Faculty of Medicine, Haifa, Israel.
¹²⁵ Medical Oncology Department, Hospital Universitario Puerta de Hierro, Madrid, Spain.
¹²⁶ Department of Oncology, University Hospital of Larissa, Larissa, Greece.
¹²⁷ Epidemiology Branch, National Institute of Environmental Health Sciences, NIH, Research Triangle Park, North Carolina, USA.
¹²⁸ Division of Psychosocial Research and Epidemiology, The Netherlands Cancer Institute - Antoni van Leeuwenhoek Hospital, Amsterdam, The Netherlands.
¹²⁹ Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, Tennessee, USA.
¹³⁰ Genomics Center, Centre Hospitalier Universitaire de Québec - Université Laval Research Center, Québec City, Québec, Canada.
¹³¹ Genetic Epidemiology Group, School of Population and Global Health, The University of Western Australia, Perth, Western Australia, Australia.
¹³² Division of Genetics and Epidemiology, The Institute of Cancer Research, London, UK.
¹³³ Division of Breast Cancer Research, The Institute of Cancer Research, London, UK.
¹³⁴ Department of Population Health Sciences, Weill Cornell Medicine, New York City, New York, USA.
¹³⁵ Epigenetic and Stem Cell Biology Laboratory, National Institute of Environmental Health Sciences, NIH, Research Triangle Park, North Carolina, USA.
¹³⁶ Department of Epidemiology, Mailman School of Public Health, Columbia University, New York City, New York, USA.
¹³⁷ Department of Surgery, Leiden University Medical Center, Leiden, The Netherlands.
¹³⁸ Department of Gynecology and Obstetrics, Helios Clinics Berlin-Buch, Berlin, Germany.
¹³⁹ Department of Quantitative Health Sciences, Division of Epidemiology, Mayo Clinic, Rochester, Minnesota, USA.
¹⁴⁰ Biostatistics and Computational Biology Branch, National Institute of Environmental Health Sciences, NIH, Research Triangle Park, North Carolina, USA.
¹⁴¹ Department of Surgical Sciences, Uppsala University, Uppsala, Sweden.
¹⁴² Molecular Diagnostics Laboratory, INRASTES, National Centre for Scientific Research-Demokritos, Athens, Greece.
¹⁴³ Cancer Epidemiology Division, Cancer Council Victoria, Melbourne, Victoria, Australia brigid.lynch@cancervic.org.au.
¹⁴⁴ Physical Activity Laboratory, Baker Heart and Diabetes Institute, Melbourne, Victoria, Australia.

^# Contributed equally.

PMID: 36328784
PMCID: PMC9876601
DOI: 10.1136/bjsports-2021-105132

Physical activity, sedentary time and breast cancer risk: a Mendelian randomisation study

Suzanne C Dixon-Suen et al. Br J Sports Med. 2022 Oct.

. 2022 Oct;56(20):1157-1170.

doi: 10.1136/bjsports-2021-105132. Epub 2022 Sep 6.

Authors

Affiliations

¹ Cancer Epidemiology Division, Cancer Council Victoria, Melbourne, Victoria, Australia.
² Bristol Medical School, Department of Population Health Sciences, University of Bristol, Bristol, UK.
³ MRC Integrative Epidemiology Unit, University of Bristol, Bristol, UK.
⁴ NIHR Biomedical Research Centre, University Hospitals Bristol and Weston NHS Foundation Trust and the University of Bristol, Bristol, UK.
⁵ Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, Victoria, Australia.
⁶ Allied Health and Human Performance, University of South Australia, Adelaide, South Australia, Australia.
⁷ Australian Centre for Precision Health, University of South Australia Cancer Research Institute, Adelaide, South Australia, Australia.
⁸ Precision Medicine, School of Clinical Sciences at Monash Health, Monash University, Clayton, Victoria, Australia.
⁹ Biostatistics Unit, The Cyprus Institute of Neurology and Genetics, Nicosia, Cyprus.
¹⁰ Cyprus School of Molecular Medicine, The Cyprus Institute of Neurology and Genetics, Nicosia, Cyprus.
¹¹ Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.
¹² Australian Breast Cancer Tissue Bank, Westmead Institute for Medical Research, The University of Sydney, Sydney, New South Wales, Australia.
¹³ Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA.
¹⁴ Roswell Park Comprehensive Cancer Center, Buffalo, New York, USA.
¹⁵ Fred A. Litwin Center for Cancer Genetics, Lunenfeld-Tanenbaum Research Institute of Mount Sinai Hospital, Toronto, Ontario, Canada.
¹⁶ Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada.
¹⁷ Department of Medicine, Genetic Epidemiology Research Institute, University of California Irvine, Irvine, California, USA.
¹⁸ Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany.
¹⁹ Department of Public Health Sciences, and Cancer Research Institute, Queen's University, Kingston, Ontario, Canada.
²⁰ Department of Cancer Epidemiology, Clinical Sciences, Lund University, Lund, Sweden.
²¹ Department of Oncology, Cancer Center, Kuopio University Hospital, Kuopio, Finland.
²² Institute of Clinical Medicine, Oncology, University of Eastern Finland, Kuopio, Finland.
²³ Institute of Medical Biometry and Epidemiology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
²⁴ Department of Gynecology and Obstetrics, Comprehensive Cancer Center ER-EMN, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nuremberg, Erlangen, Germany.
²⁵ Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
²⁶ Institute of Biochemistry and Genetics, FSBSI Ufa Federal Research Centre of the Russian Academy of Sciences, Ufa, Russian Federation.
²⁷ Department of Oncology, Helsinki University Hospital, University of Helsinki, Helsinki, Finland.
²⁸ Department of Oncology, Örebro University Hospital, Örebro, Sweden.
²⁹ Department of Radiation Oncology, Hannover Medical School, Hannover, Germany.
³⁰ Gynaecology Research Unit, Hannover Medical School, Hannover, Germany.
³¹ Copenhagen General Population Study, Herlev and Gentofte Hospital, Copenhagen University Hospital, Herlev, Denmark.
³² Department of Clinical Biochemistry, Herlev and Gentofte Hospital, Copenhagen University Hospital, Herlev, Denmark.
³³ Division of Cancer Prevention and Genetics, European Institute of Oncology IRCCS, Milan, Italy.
³⁴ Division of Preventive Oncology, German Cancer Research Center (DKFZ) and National Center for Tumor Diseases (NCT), Heidelberg, Germany.
³⁵ Institute for Prevention and Occupational Medicine of the German Social Accident Insurance (IPA), Institute of the Ruhr University Bochum, Bochum, Germany.
³⁶ Department of Internal Medicine and Huntsman Cancer Institute, The University of Utah, Salt Lake City, Utah, USA.
³⁷ Department of Biology, University of Pisa, Pisa, Italy.
³⁸ Genomic Epidemiology Group, German Cancer Research Center (DKFZ), Heidelberg, Germany.
³⁹ Oncology and Genetics Unit, Instituto de Investigación Sanitaria Galicia Sur (IISGS), Xerencia de Xestion Integrada de Vigo-SERGAS, Vigo, Spain.
⁴⁰ Department of Pathology, Intermountain Medical Center, Intermountain Healthcare, Salt Lake City, Utah, USA.
⁴¹ Intermountain Biorepository, Intermountain Healthcare, Salt Lake City, Utah, USA.
⁴² Cancer Epidemiology Group, University Cancer Center Hamburg (UCCH), University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
⁴³ Westmead Institute for Medical Research, The University of Sydney, Sydney, New South Wales, Australia.
⁴⁴ Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Cambridge, UK.
⁴⁵ Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota, USA.
⁴⁶ Sheffield Institute for Nucleic Acids (SInFoNiA), Department of Oncology and Metabolism, The University of Sheffield, Sheffield, UK.
⁴⁷ Academic Unit of Pathology, Department of Neuroscience, The University of Sheffield, Sheffield, UK.
⁴⁸ Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
⁴⁹ Department of Clinical Genetics, Fox Chase Cancer Center, Philadelphia, Pennsylvania, USA.
⁵⁰ Department of Pathology, Leiden University Medical Center, Leiden, The Netherlands.
⁵¹ Department of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands.
⁵² School of Life Sciences, University of Westminster, London, UK.
⁵³ Faculty of Medicine, University of Southampton, Southampton, UK.
⁵⁴ Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA.
⁵⁵ Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA.
⁵⁶ Institute for Medical Informatics, Statistics and Epidemiology, University of Leipzig, Leipzig, Germany.
⁵⁷ LIFE - Leipzig Research Centre for Civilization Diseases, University of Leipzig, Leipzig, Germany.
⁵⁸ Division of Evolution and Genomic Sciences, School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester Academic Health Science Centre, Manchester, UK.
⁵⁹ North West Genomics Laboratory Hub, Manchester Centre for Genomic Medicine, St Mary's Hospital, Manchester University NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester, UK.
⁶⁰ David Geffen School of Medicine, Department of Medicine Division of Hematology and Oncology, University of California Los Angeles, Los Angeles, California, USA.
⁶¹ The Breast Cancer Now Toby Robins Research Centre, The Institute of Cancer Research, London, UK.
⁶² Department of Breast Surgery, Herlev and Gentofte Hospital, Copenhagen University Hospital, Herlev, Denmark.
⁶³ School of Population Health, Curtin University, Perth, Western Australia, Australia.
⁶⁴ Genomic Medicine Group, International Cancer Genetics and Epidemiology Group, Fundación Pública Galega de Medicina Xenómica, Instituto de Investigación Sanitaria de Santiago de Compostela (IDIS), Complejo Hospitalario Universitario de Santiago, SERGAS, Santiago de Compostela, Spain.
⁶⁵ Moores Cancer Center, University of California San Diego, La Jolla, California, USA.
⁶⁶ Medical Oncology Department, Hospital Clínico San Carlos, Instituto de Investigación Sanitaria San Carlos (IdISSC), Centro de Investigación Biomédica en Red de Cáncer, Madrid, Spain.
⁶⁷ Department of Medicine, McGill University, Montréal, Québec, Canada.
⁶⁸ Division of Clinical Epidemiology, Royal Victoria Hospital, McGill University, Montréal, Québec, Canada.
⁶⁹ Team 'Exposome and Heredity', Center for Research in Epidemiology and Population Health (CESP), Gustave Roussy, INSERM, University Paris-Saclay, Villejuif, France.
⁷⁰ Molecular Epidemiology Group, C080, German Cancer Research Center (DKFZ), Heidelberg, Germany.
⁷¹ Molecular Biology of Breast Cancer, University Womens Clinic Heidelberg, University of Heidelberg, Heidelberg, Germany.
⁷² Center for Familial Breast and Ovarian Cancer, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany.
⁷³ Center for Integrated Oncology (CIO), Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany.
⁷⁴ Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California, USA.
⁷⁵ Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.
⁷⁶ Department of Oncology, Södersjukhuset, Stockholm, Sweden.
⁷⁷ Molecular Genetics of Breast Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany.
⁷⁸ Department of Health Sciences Research, Mayo Clinic, Rochester, Minnesota, USA.
⁷⁹ Prevent Breast Cancer Research Unit, Manchester University Hospital Foundation NHS Trust, Manchester, UK.
⁸⁰ Department of Medical Oncology, Erasmus MC Cancer Institute, Rotterdam, The Netherlands.
⁸¹ Dr Margarete Fischer Bosch Institute of Clinical Pharmacology, Stuttgart, Germany.
⁸² University of Tübingen, Tübingen, Germany.
⁸³ Division of Cancer Sciences, The University of Manchester, Manchester, UK.
⁸⁴ Nuffield Department of Population Health, University of Oxford, Oxford, UK.
⁸⁵ Department of Genetics and Pathology, Pomeranian Medical University in Szczecin, Szczecin, Poland.
⁸⁶ Independent Laboratory of Molecular Biology and Genetic Diagnostics, Pomeranian Medical University in Szczecin, Szczecin, Poland.
⁸⁷ Department of Gynaecology and Obstetrics, University Hospital Ulm, Ulm, Germany.
⁸⁸ Department of Epidemiology and Population Health, Stanford University School of Medicine, Stanford, California, USA.
⁸⁹ Department of Medicine, Division of Oncology, Stanford Cancer Institute, Stanford University School of Medicine, Stanford, California, USA.
⁹⁰ Division of Molecular Pathology, Netherlands Cancer Institute, Amsterdam, The Netherlands.
⁹¹ Radiation Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland, USA.
⁹² Program in Genetic Epidemiology and Statistical Genetics, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA.
⁹³ Department of Medical Genetics, Oslo University Hospital and University of Oslo, Oslo, Norway.
⁹⁴ Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway.
⁹⁵ Department of Histopathology and Cytology, Clinical Hospital Acibadem Sistina, Skopje, Macedonia (the former Yugoslav Republic of).
⁹⁶ Department of Computational and Quantitative Medicine, City of Hope, Duarte, California, USA.
⁹⁷ City of Hope Comprehensive Cancer Center, City of Hope, Duarte, California, USA.
⁹⁸ VIB Center for Cancer Biology, VIB, Gent, Oost-Vlaanderen, Belgium.
⁹⁹ Laboratory for Translational Genetics, Department of Human Genetics, KU Leuven, Leuven, Belgium.
¹⁰⁰ Epidemiology Program, University of Hawai'i Cancer Center, Honolulu, Hawaii, USA.
¹⁰¹ Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.
¹⁰² Department of Clinical Genetics, Karolinska University Hospital, Stockholm, Sweden.
¹⁰³ German Breast Group, Neu-Isenburg, Germany.
¹⁰⁴ Translational Cancer Research Area, University of Eastern Finland, Kuopio, Finland.
¹⁰⁵ Institute of Clinical Medicine, Pathology and Forensic Medicine, University of Eastern Finland, Kuopio, Finland.
¹⁰⁶ Department of Clinical Science and Education, Södersjukhuset, Karolinska Institutet, Stockholm, Sweden.
¹⁰⁷ Herbert Wertheim School of Public Health and Human Longevity Science, University of California San Diego, La Jolla, California, USA.
¹⁰⁸ Department of Medical Oncology, University Hospital of Heraklion, Heraklion, Greece.
¹⁰⁹ MRC Clinical Trials Unit, Institute of Clinical Trials & Methodology, University College London, London, UK.
¹¹⁰ Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada.
¹¹¹ Laboratory Medicine Program, University Health Network, Toronto, Ontario, Canada.
¹¹² Cancer Control Research, BC Cancer, Vancouver, British Columbia, Canada.
¹¹³ School of Population and Public Health, The University of British Columbia, Vancouver, British Columbia, Canada.
¹¹⁴ Department of Obstetrics and Gynecology, Helsinki University Hospital, University of Helsinki, Helsinki, Finland.
¹¹⁵ Leuven Multidisciplinary Breast Center, Department of Oncology, Leuven Cancer Institute, University Hospitals Leuven, Leuven, Belgium.
¹¹⁶ Clinical Genetics Research Lab, Department of Cancer Biology and Genetics, Memorial Sloan Kettering Cancer Center, New York City, New York, USA.
¹¹⁷ Clinical Genetics Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York City, New York, USA.
¹¹⁸ Department of Epidemiology, Gillings School of Global Public Health and UNC Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
¹¹⁹ Centre for Cancer Research and Cell Biology, Queen's University Belfast, Belfast, UK.
¹²⁰ Department of Population Science, American Cancer Society, Atlanta, Georgia, USA.
¹²¹ Department of Non-Communicable Disease Epidemiology, London School of Hygiene and Tropical Medicine, London, UK.
¹²² Research Centre for Genetic Engineering and Biotechnology 'Georgi D. Efremov', MASA, Skopje, Macedonia (the former Yugoslav Republic of).
¹²³ Unit of Molecular Bases of Genetic Risk and Genetic Testing, Department of Research, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
¹²⁴ Clalit National Cancer Control Center, Carmel Medical Center and Technion Faculty of Medicine, Haifa, Israel.
¹²⁵ Medical Oncology Department, Hospital Universitario Puerta de Hierro, Madrid, Spain.
¹²⁶ Department of Oncology, University Hospital of Larissa, Larissa, Greece.
¹²⁷ Epidemiology Branch, National Institute of Environmental Health Sciences, NIH, Research Triangle Park, North Carolina, USA.
¹²⁸ Division of Psychosocial Research and Epidemiology, The Netherlands Cancer Institute - Antoni van Leeuwenhoek Hospital, Amsterdam, The Netherlands.
¹²⁹ Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, Tennessee, USA.
¹³⁰ Genomics Center, Centre Hospitalier Universitaire de Québec - Université Laval Research Center, Québec City, Québec, Canada.
¹³¹ Genetic Epidemiology Group, School of Population and Global Health, The University of Western Australia, Perth, Western Australia, Australia.
¹³² Division of Genetics and Epidemiology, The Institute of Cancer Research, London, UK.
¹³³ Division of Breast Cancer Research, The Institute of Cancer Research, London, UK.
¹³⁴ Department of Population Health Sciences, Weill Cornell Medicine, New York City, New York, USA.
¹³⁵ Epigenetic and Stem Cell Biology Laboratory, National Institute of Environmental Health Sciences, NIH, Research Triangle Park, North Carolina, USA.
¹³⁶ Department of Epidemiology, Mailman School of Public Health, Columbia University, New York City, New York, USA.
¹³⁷ Department of Surgery, Leiden University Medical Center, Leiden, The Netherlands.
¹³⁸ Department of Gynecology and Obstetrics, Helios Clinics Berlin-Buch, Berlin, Germany.
¹³⁹ Department of Quantitative Health Sciences, Division of Epidemiology, Mayo Clinic, Rochester, Minnesota, USA.
¹⁴⁰ Biostatistics and Computational Biology Branch, National Institute of Environmental Health Sciences, NIH, Research Triangle Park, North Carolina, USA.
¹⁴¹ Department of Surgical Sciences, Uppsala University, Uppsala, Sweden.
¹⁴² Molecular Diagnostics Laboratory, INRASTES, National Centre for Scientific Research-Demokritos, Athens, Greece.
¹⁴³ Cancer Epidemiology Division, Cancer Council Victoria, Melbourne, Victoria, Australia brigid.lynch@cancervic.org.au.
¹⁴⁴ Physical Activity Laboratory, Baker Heart and Diabetes Institute, Melbourne, Victoria, Australia.

^# Contributed equally.

PMID: 36328784
PMCID: PMC9876601
DOI: 10.1136/bjsports-2021-105132

Abstract

Objectives: Physical inactivity and sedentary behaviour are associated with higher breast cancer risk in observational studies, but ascribing causality is difficult. Mendelian randomisation (MR) assesses causality by simulating randomised trial groups using genotype. We assessed whether lifelong physical activity or sedentary time, assessed using genotype, may be causally associated with breast cancer risk overall, pre/post-menopause, and by case-groups defined by tumour characteristics.

Methods: We performed two-sample inverse-variance-weighted MR using individual-level Breast Cancer Association Consortium case-control data from 130 957 European-ancestry women (69 838 invasive cases), and published UK Biobank data (n=91 105-377 234). Genetic instruments were single nucleotide polymorphisms (SNPs) associated in UK Biobank with wrist-worn accelerometer-measured overall physical activity (n_snps=5) or sedentary time (n_snps=6), or accelerometer-measured (n_snps=1) or self-reported (n_snps=5) vigorous physical activity.

Results: Greater genetically-predicted overall activity was associated with lower breast cancer overall risk (OR=0.59; 95% confidence interval (CI) 0.42 to 0.83 per-standard deviation (SD;~8 milligravities acceleration)) and for most case-groups. Genetically-predicted vigorous activity was associated with lower risk of pre/perimenopausal breast cancer (OR=0.62; 95% CI 0.45 to 0.87,≥3 vs. 0 self-reported days/week), with consistent estimates for most case-groups. Greater genetically-predicted sedentary time was associated with higher hormone-receptor-negative tumour risk (OR=1.77; 95% CI 1.07 to 2.92 per-SD (~7% time spent sedentary)), with elevated estimates for most case-groups. Results were robust to sensitivity analyses examining pleiotropy (including weighted-median-MR, MR-Egger).

Conclusion: Our study provides strong evidence that greater overall physical activity, greater vigorous activity, and lower sedentary time are likely to reduce breast cancer risk. More widespread adoption of active lifestyles may reduce the burden from the most common cancer in women.

Keywords: Breast; Genetics; Physical activity; Sedentary Behaviour.

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Conflict of interest statement

Competing interests: MWB conducts research funded by Amgen, Novartis and Pfizer. PAF conducts research funded by Amgen, Novartis and Pfizer. He received honoraria from Roche, Novartis and Pfizer. AWK declares research funding to her institution from Myriad Genetics for an unrelated project (funding dates 2017-2019). SL declares grants and honoraria paid to her institution from Amgen, Novartis, Pfizer, Roche, and, outside the submitted work, grants and/or honoraria paid to her institution from AbbVie, Celgene, Seattle Genetics, PrIME/Medscape, Daiichi-Sankyo, Lilly, Samsung, BMS, Puma, Immunomedics, AstraZeneca, Pierre Fabre, Merck, GlaxoSmithKlein, EirGenix, and Bayer, and personal fees from Chugai; SL also has a patent EP14153692.0 pending. UM declares stock ownership in Abcodia Ltd. RAM has been a consultant for Pharmavite. No other authors have conflicts to declare.

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1. World Cancer Research Fund International / American Institute for Cancer Research. Continuous Update Project Report: Diet, Nutrition, Physical Activity and Breast Cancer. 2017.
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1. Chong F, Wang Y, Song M, Sun Q, Xie W, Song C. Sedentary behavior and risk of breast cancer: a dose-response meta-analysis from prospective studies. Breast cancer (Tokyo, Japan). 2020. - PubMed

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Physical activity, sedentary time and breast cancer risk: a Mendelian randomisation study

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Physical activity, sedentary time and breast cancer risk: a Mendelian randomisation study

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