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

Suzanne C. Dixon-Suen, Sarah J. Lewis, on behalf of the Breast Cancer Association Consortium, ABCTB Investigators, NBCS Collaborators, Richard M. Martin, Dallas R. English, Terry Boyle, Graham G. Giles, Kyriaki Michailidou, Manjeet K. Bolla, Qin Wang, Joe Dennis, Michael Lush, Thomas U. Ahearn, Christine B. Ambrosone, Irene L. Andrulis, Hoda Anton-Culver, Volker Arndt, Kristan J. AronsonAnnelie Augustinsson, Päivi Auvinen, Laura E.Beane Freeman, Heiko Becher, Matthias W. Beckmann, Sabine Behrens, Marina Bermisheva, Carl Blomqvist, Natalia V. Bogdanova, Stig E. Bojesen, Bernardo Bonanni, Hermann Brenner, Thomas Brüning, Saundra S. Buys, Nicola J. Camp, Daniele Campa, Federico Canzian, Jose E. Castelao, Melissa H. Cessna, Jenny Chang-Claude, Stephen J. Chanock, Christine L. Clarke, Don M. Conroy, Fergus J. Couch, Angela Cox, Simon S. Cross, Kamila Czene, Mary B. Daly, Peter Devilee, Thilo Dörk, Miriam Dwek, Diana M. Eccles, A. Heather Eliassen, Christoph Engel, Mikael Eriksson, D. Gareth Evans, Peter A. Fasching, Olivia Fletcher, Henrik Flyger, Lin Fritschi, Marike Gabrielson, Manuela Gago-Dominguez, Montserrat García-Closas, Mark S. Goldberg, Pascal Guénel, Melanie Gündert, Eric Hahnen, Christopher A. Haiman, Lothar Häberle, Niclas Håkansson, Per Hall, Ute Hamann, Steven N. Hart, Michelle Harvie, Peter Hillemanns, Antoinette Hollestelle, Maartje J. Hooning, Reiner Hoppe, John L. Hopper, Anthony Howell, David J. Hunter, Anna Jakubowska, Wolfgang Janni, Esther M. John, Audrey Y. Jung, Rudolf Kaaks, Renske Keeman, Cari M. Kitahara, Stella Koutros, Peter Kraft, Vessela N. Kristensen, Katerina Kubelka-Sabit, Allison W. Kurian, James V. Lacey, Diether Lambrechts, Loic Le Marchand, Annika Lindblom, Sibylle Loibl, Jan Lubiński, Arto Mannermaa, Mehdi Manoochehri, Sara Margolin, Maria Elena Martinez, Dimitrios Mavroudis, Usha Menon, Anna Marie Mulligan, Rachel A. Murphy, Heli Nevanlinna, Ines Nevelsteen, William G. Newman, Kenneth Offit, Andrew F. Olshan, Håkan Olsson, Nick Orr, Alpa V. Patel, Julian Peto, Dijana Plaseska-Karanfilska, Nadege Presneau, Brigitte Rack, Paolo Radice, Erika Rees-Punia, Gad Rennert, Hedy S. Rennert, Atocha Romero, Emmanouil Saloustros, Dale P. Sandler, Marjanka K Schmidt, Rita K. Schmutzler, Lukas Schwentner, Christopher Scott, Mitul Shah, Xiao Ou Shu, Jacques Simard, Melissa C. Southey, Jennifer Stone, Harald Surowy, Anthony J. Swerdlow, Rulla M. Tamimi, William J. Tapper, Jack A. Taylor, Mary Beth Terry, Rob A.E.M. Tollenaar, Melissa A. Troester, Thérèse Truong, Michael Untch, Celine M. Vachon, Vijai Joseph, Barbara Wappenschmidt, Clarice R. Weinberg, Alicja Wolk, Drakoulis Yannoukakos, Wei Zheng, Argyrios Ziogas, Alison M. Dunning, Paul D.P. Pharoah, Douglas F. Easton, Roger L. Milne, Brigid M. Lynch*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

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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.

Original languageEnglish
Pages (from-to)1157-1170
Number of pages14
JournalBritish Journal of Sports Medicine
Volume56
Issue number20
Early online date6 Sept 2022
DOIs
Publication statusPublished - 29 Sept 2022

Bibliographical note

Funding Information:
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.

Funding Information:
This work was supported by the following agencies. Funders had no role in study design, data collection, analysis, interpretation, writing of the report, or the decision to submit the paper for publication. BCAC is funded by the European Union's Horizon 2020 Research and Innovation Programme (grant numbers 634935 and 633784 for BRIDGES and B-CAST respectively), and the PERSPECTIVE IandI project, funded by the Government of Canada through Genome Canada and the Canadian Institutes of Health Research, the Ministere de l'Economie et de l'Innovation du Quebec through Genome Québec, the Quebec Breast Cancer Foundation. The EU Horizon 2020 Research and Innovation Programme funding source had no role in study design, data collection, data analysis, data interpretation or writing of the report. Additional funding for BCAC is provided via the Confluence project which is funded with intramural funds from the National Cancer Institute Intramural Research Program, National Institutes of Health. Genotyping of the OncoArray was funded by the NIH Grant U19 CA148065, and Cancer Research UK Grant C1287/A16563 and the PERSPECTIVE project supported by the Government of Canada through Genome Canada and the Canadian Institutes of Health Research (grant GPH-129344) and, the Ministere de l'Economie, Science et Innovation du Quebec through Genome Quebec and the PSRSIIRI-701 grant, and the Quebec Breast Cancer Foundation. Funding for iCOGS came from: the European Community's Seventh Framework Programme under grant agreement no 223175 (HEALTH-F2- 2009-223175) (COGS), Cancer Research UK (C1287/A10118, C1287/A10710, C12292/A11174, C1281/A12014, C5047/A8384, C5047/A15007, C5047/A10692, C8197/A16565), the National Institutes of Health (CA128978) and Post-Cancer GWAS initiative (1U19 CA148537, 1U19 CA148065 and 1U19 CA148112 - the GAME-ON initiative), the Department of Defence (W81XWH-10-1-0341), the Canadian Institutes of Health Research (CIHR) for the CIHR Team in Familial Risks of Breast Cancer, and Komen Foundation for the Cure, the Breast Cancer Research Foundation, and the Ovarian Cancer Research Fund. The BRIDGES panel sequencing was supported by the European Union Horizon 2020 research and innovation program BRIDGES (grant number, 634935) and the Wellcome Trust (v203477/Z/16/Z). The Australian Breast Cancer Family Study (ABCFS) was supported by grant UM1 CA164920 from the National Cancer Institute (USA)

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