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

About this Publication
Title
Physical activity, sedentary time and breast cancer risk: a Mendelian randomisation study.
Pubmed ID
36328784 (View this publication on the PubMed website)
Digital Object Identifier
Publication
Br J Sports Med. 2022 Oct; Volume 56 (Issue 20): Pages 1157-1170
Authors
Dixon-Suen SC , Lewis SJ , Martin RM , English DR , Boyle T , Giles GG , Michailidou K , Bolla MK , Wang Q , Dennis J , Lush M , Investigators A , Ahearn TU , Ambrosone CB , Andrulis IL , Anton-Culver H , Arndt V , Aronson KJ , Augustinsson A , Auvinen P , ...show more Beane Freeman LE , Becher H , Beckmann MW , Behrens S , Bermisheva M , Blomqvist C , Bogdanova NV , Bojesen SE , Bonanni B , Brenner H , Brüning T , Buys SS , Camp NJ , Campa D , Canzian F , Castelao JE , Cessna MH , Chang-Claude J , Chanock SJ , Clarke CL , Conroy DM , Couch FJ , Cox A , Cross SS , Czene K , Daly MB , Devilee P , Dörk T , Dwek M , Eccles DM , Eliassen AH , Engel C , Eriksson M , Evans DG , Fasching PA , Fletcher O , Flyger H , Fritschi L , Gabrielson M , Gago-Dominguez M , García-Closas M , García-Sáenz JA , Goldberg MS , Guénel P , Gündert M , Hahnen E , Haiman CA , Häberle L , Håkansson N , Hall P , Hamann U , Hart SN , Harvie M , Hillemanns P , Hollestelle A , Hooning MJ , Hoppe R , Hopper J , Howell A , Hunter DJ , Jakubowska A , Janni W , John EM , Jung A , Kaaks R , Keeman R , Kitahara CM , Koutros S , Kraft P , Kristensen VN , Kubelka-Sabit K , Kurian AW , Lacey JV , Lambrechts D , Le Marchand L , Lindblom A , Loibl S , Lubiński J , Mannermaa A , Manoochehri M , Margolin S , Martinez ME , Mavroudis D , Menon U , Mulligan AM , Murphy RA , Collaborators N , Nevanlinna H , Nevelsteen I , Newman WG , Offit K , Olshan AF , Olsson H , Orr N , Patel A , Peto J , Plaseska-Karanfilska D , Presneau N , Rack B , Radice P , Rees-Punia E , Rennert G , Rennert HS , Romero A , Saloustros E , Sandler DP , Schmidt MK , Schmutzler RK , Schwentner L , Scott C , Shah M , Shu XO , Simard J , Southey MC , Stone J , Surowy H , Swerdlow AJ , Tamimi RM , Tapper WJ , Taylor JA , Terry MB , Tollenaar RAEM , Troester MA , Truong T , Untch M , Vachon CM , Joseph V , Wappenschmidt B , Weinberg CR , Wolk A , Yannoukakos D , Zheng W , Ziogas A , Dunning AM , Pharoah PDP , Easton DF , Milne RL , Lynch BM , Breast Cancer Association Consortium
Affiliations
  • Cancer Epidemiology Division, Cancer Council Victoria, Melbourne, Victoria, Australia.
  • Bristol Medical School, Department of Population Health Sciences, University of Bristol, Bristol, UK.
  • Allied Health and Human Performance, University of South Australia, Adelaide, South Australia, Australia.
  • Biostatistics Unit, The Cyprus Institute of Neurology and Genetics, Nicosia, Cyprus.
  • Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.
  • Australian Breast Cancer Tissue Bank, Westmead Institute for Medical Research, The University of Sydney, Sydney, New South Wales, Australia.
  • Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA.
  • Roswell Park Comprehensive Cancer Center, Buffalo, New York, USA.
  • Fred A. Litwin Center for Cancer Genetics, Lunenfeld-Tanenbaum Research Institute of Mount Sinai Hospital, Toronto, Ontario, Canada.
  • Department of Medicine, Genetic Epidemiology Research Institute, University of California Irvine, Irvine, California, USA.
...show more
  • Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany.
  • Department of Public Health Sciences, and Cancer Research Institute, Queen's University, Kingston, Ontario, Canada.
  • Department of Cancer Epidemiology, Clinical Sciences, Lund University, Lund, Sweden.
  • Department of Oncology, Cancer Center, Kuopio University Hospital, Kuopio, Finland.
  • Institute of Medical Biometry and Epidemiology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
  • Department of Gynecology and Obstetrics, Comprehensive Cancer Center ER-EMN, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nuremberg, Erlangen, Germany.
  • Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
  • Institute of Biochemistry and Genetics, FSBSI Ufa Federal Research Centre of the Russian Academy of Sciences, Ufa, Russian Federation.
  • Department of Oncology, Helsinki University Hospital, University of Helsinki, Helsinki, Finland.
  • Department of Radiation Oncology, Hannover Medical School, Hannover, Germany.
  • Copenhagen General Population Study, Herlev and Gentofte Hospital, Copenhagen University Hospital, Herlev, Denmark.
  • Division of Cancer Prevention and Genetics, European Institute of Oncology IRCCS, Milan, Italy.
  • Institute for Prevention and Occupational Medicine of the German Social Accident Insurance (IPA), Institute of the Ruhr University Bochum, Bochum, Germany.
  • Department of Internal Medicine and Huntsman Cancer Institute, The University of Utah, Salt Lake City, Utah, USA.
  • Genomic Epidemiology Group, German Cancer Research Center (DKFZ), Heidelberg, Germany.
  • Oncology and Genetics Unit, Instituto de Investigación Sanitaria Galicia Sur (IISGS), Xerencia de Xestion Integrada de Vigo-SERGAS, Vigo, Spain.
  • Department of Pathology, Intermountain Medical Center, Intermountain Healthcare, Salt Lake City, Utah, USA.
  • Westmead Institute for Medical Research, The University of Sydney, Sydney, New South Wales, Australia.
  • Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Cambridge, UK.
  • Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota, USA.
  • Sheffield Institute for Nucleic Acids (SInFoNiA), Department of Oncology and Metabolism, The University of Sheffield, Sheffield, UK.
  • Academic Unit of Pathology, Department of Neuroscience, The University of Sheffield, Sheffield, UK.
  • Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
  • Department of Clinical Genetics, Fox Chase Cancer Center, Philadelphia, Pennsylvania, USA.
  • Department of Pathology, Leiden University Medical Center, Leiden, The Netherlands.
  • Gynaecology Research Unit, Hannover Medical School, Hannover, Germany.
  • School of Life Sciences, University of Westminster, London, UK.
  • Faculty of Medicine, University of Southampton, Southampton, UK.
  • Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA.
  • Institute for Medical Informatics, Statistics and Epidemiology, University of Leipzig, Leipzig, Germany.
  • 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.
  • The Breast Cancer Now Toby Robins Research Centre, The Institute of Cancer Research, London, UK.
  • Department of Breast Surgery, Herlev and Gentofte Hospital, Copenhagen University Hospital, Herlev, Denmark.
  • School of Population Health, Curtin University, Perth, Western Australia, Australia.
  • 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.
  • Medical Oncology Department, Hospital Clínico San Carlos, Instituto de Investigación Sanitaria San Carlos (IdISSC), Centro de Investigación Biomédica en Red de Cáncer, Madrid, Spain.
  • Department of Medicine, McGill University, Montréal, Québec, Canada.
  • Team 'Exposome and Heredity', Center for Research in Epidemiology and Population Health (CESP), Gustave Roussy, INSERM, University Paris-Saclay, Villejuif, France.
  • Molecular Epidemiology Group, C080, German Cancer Research Center (DKFZ), Heidelberg, Germany.
  • Center for Familial Breast and Ovarian Cancer, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany.
  • Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California, USA.
  • Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.
  • Molecular Genetics of Breast Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany.
  • Department of Health Sciences Research, Mayo Clinic, Rochester, Minnesota, USA.
  • Prevent Breast Cancer Research Unit, Manchester University Hospital Foundation NHS Trust, Manchester, UK.
  • Department of Medical Oncology, Erasmus MC Cancer Institute, Rotterdam, The Netherlands.
  • Dr Margarete Fischer Bosch Institute of Clinical Pharmacology, Stuttgart, Germany.
  • Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, Victoria, Australia.
  • Division of Cancer Sciences, The University of Manchester, Manchester, UK.
  • Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA.
  • Department of Genetics and Pathology, Pomeranian Medical University in Szczecin, Szczecin, Poland.
  • Department of Gynaecology and Obstetrics, University Hospital Ulm, Ulm, Germany.
  • Department of Epidemiology and Population Health, Stanford University School of Medicine, Stanford, California, USA.
  • Division of Molecular Pathology, Netherlands Cancer Institute, Amsterdam, The Netherlands.
  • Radiation Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland, USA.
  • Department of Medical Genetics, Oslo University Hospital and University of Oslo, Oslo, Norway.
  • Department of Histopathology and Cytology, Clinical Hospital Acibadem Sistina, Skopje, Macedonia (the former Yugoslav Republic of).
  • Department of Computational and Quantitative Medicine, City of Hope, Duarte, California, USA.
  • VIB Center for Cancer Biology, VIB, Gent, Oost-Vlaanderen, Belgium.
  • Epidemiology Program, University of Hawai'i Cancer Center, Honolulu, Hawaii, USA.
  • Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.
  • German Breast Group, Neu-Isenburg, Germany.
  • Translational Cancer Research Area, University of Eastern Finland, Kuopio, Finland.
  • Department of Oncology, Södersjukhuset, Stockholm, Sweden.
  • Moores Cancer Center, University of California San Diego, La Jolla, California, USA.
  • Department of Medical Oncology, University Hospital of Heraklion, Heraklion, Greece.
  • MRC Clinical Trials Unit, Institute of Clinical Trials & Methodology, University College London, London, UK.
  • Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada.
  • Cancer Control Research, BC Cancer, Vancouver, British Columbia, Canada.
  • Department of Obstetrics and Gynecology, Helsinki University Hospital, University of Helsinki, Helsinki, Finland.
  • Leuven Multidisciplinary Breast Center, Department of Oncology, Leuven Cancer Institute, University Hospitals Leuven, Leuven, Belgium.
  • Clinical Genetics Research Lab, Department of Cancer Biology and Genetics, Memorial Sloan Kettering Cancer Center, New York City, New York, USA.
  • 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.
  • Centre for Cancer Research and Cell Biology, Queen's University Belfast, Belfast, UK.
  • Department of Population Science, American Cancer Society, Atlanta, Georgia, USA.
  • Department of Non-Communicable Disease Epidemiology, London School of Hygiene and Tropical Medicine, London, UK.
  • Research Centre for Genetic Engineering and Biotechnology 'Georgi D. Efremov', MASA, Skopje, Macedonia (the former Yugoslav Republic of).
  • Unit of Molecular Bases of Genetic Risk and Genetic Testing, Department of Research, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
  • Clalit National Cancer Control Center, Carmel Medical Center and Technion Faculty of Medicine, Haifa, Israel.
  • Medical Oncology Department, Hospital Universitario Puerta de Hierro, Madrid, Spain.
  • Department of Oncology, University Hospital of Larissa, Larissa, Greece.
  • Epidemiology Branch, National Institute of Environmental Health Sciences, NIH, Research Triangle Park, North Carolina, USA.
  • Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, Tennessee, USA.
  • Genomics Center, Centre Hospitalier Universitaire de Québec - Université Laval Research Center, Québec City, Québec, Canada.
  • Division of Genetics and Epidemiology, The Institute of Cancer Research, London, UK.
  • Department of Epidemiology, Mailman School of Public Health, Columbia University, New York City, New York, USA.
  • Department of Surgery, Leiden University Medical Center, Leiden, The Netherlands.
  • Department of Gynecology and Obstetrics, Helios Clinics Berlin-Buch, Berlin, Germany.
  • Department of Quantitative Health Sciences, Division of Epidemiology, Mayo Clinic, Rochester, Minnesota, USA.
  • Biostatistics and Computational Biology Branch, National Institute of Environmental Health Sciences, NIH, Research Triangle Park, North Carolina, USA.
  • Molecular Diagnostics Laboratory, INRASTES, National Centre for Scientific Research-Demokritos, Athens, Greece.
  • Cancer Epidemiology Division, Cancer Council Victoria, Melbourne, Victoria, Australia brigid.lynch@cancervic.org.au.
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 (nsnps=5) or sedentary time (nsnps=6), or accelerometer-measured (nsnps=1) or self-reported (nsnps=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.

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