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

Breast Cancer Association Consortium (BCAC); Suzanne C. Dixon-Suen; Sarah J. Lewis; Richard M. Martin; Dallas R. English; Terry Boyle; Graham G. Giles; Kyriaki Michailidou; Manjeet K. Bolla; Qin Wang; Joe Dennis; Michael Lush; Abctb Investigators; Thomas U. Ahearn; Christine B. Ambrosone; Irene L. Andrulis; Hoda Anton-Culver; Volker Arndt; Kristan J. Aronson; Annelie 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; José A. García-Sáenz; 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 Hopper; Anthony Howell; David J. Hunter; Anna Jakubowska; Wolfgang Janni; Esther M. John; Audrey 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; Nbcs Collaborators; Heli Nevanlinna; Ines Nevelsteen; William G. Newman; Kenneth Offit; Andrew F. Olshan; Håkan Olsson; Nick Orr; Alpa 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

doi:10.1136/bjsports-2021-105132

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

Breast Cancer Association Consortium (BCAC), Suzanne C. Dixon-Suen, Sarah J. Lewis, Richard M. Martin, Dallas R. English, Terry Boyle, Graham G. Giles, Kyriaki Michailidou, Manjeet K. Bolla, Qin Wang, Joe Dennis, Michael Lush, Abctb Investigators, Thomas U. Ahearn, Christine B. Ambrosone, Irene L. Andrulis, Hoda Anton-Culver, Volker Arndt, Kristan J. Aronson, Annelie AugustinssonPäivi 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, José A. García-Sáenz, 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 Hopper, Anthony Howell, David J. Hunter, Anna Jakubowska, Wolfgang Janni, Esther M. John, Audrey 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, Nbcs Collaborators, Heli Nevanlinna, Ines Nevelsteen, William G. Newman, Kenneth Offit, Andrew F. Olshan, Håkan Olsson, Nick Orr, Alpa 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

Population and Public Health

Research output: Contribution to journal › Article › peer-review

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 language	English
Pages (from-to)	1157-1170
Number of pages	14
Journal	British Journal of Sports Medicine
Volume	56
Issue number	20
DOIs	https://doi.org/10.1136/bjsports-2021-105132
Publication status	Published - 6 Sep 2022

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10.1136/bjsports-2021-105132

Cite this

Breast Cancer Association Consortium (BCAC), Dixon-Suen, S. C., Lewis, S. J., Martin, R. M., English, D. R., Boyle, T., Giles, G. G., Michailidou, K., Bolla, M. K., Wang, Q., Dennis, J., Lush, M., Investigators, A., Ahearn, T. U., Ambrosone, C. B., Andrulis, I. L., Anton-Culver, H., Arndt, V., Aronson, K. J., ... Lynch, B. M. (2022). Physical activity, sedentary time and breast cancer risk: a Mendelian randomisation study. British Journal of Sports Medicine, 56(20), 1157-1170. https://doi.org/10.1136/bjsports-2021-105132

@article{3cb2c2af2ce6419e91e843fbf10dfdfd,

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

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",

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

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 Qu{\'e}bec, 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) Publisher Copyright: {\textcopyright} ",

year = "2022",

month = sep,

day = "6",

doi = "10.1136/bjsports-2021-105132",

language = "English",

volume = "56",

pages = "1157--1170",

journal = "British Journal of Sports Medicine",

issn = "0306-3674",

publisher = "BMJ Publishing Group",

number = "20",

}

Breast Cancer Association Consortium (BCAC), 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, Freeman, LEB, 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 2022, 'Physical activity, sedentary time and breast cancer risk: a Mendelian randomisation study', British Journal of Sports Medicine, vol. 56, no. 20, pp. 1157-1170. https://doi.org/10.1136/bjsports-2021-105132

TY - JOUR

T1 - Physical activity, sedentary time and breast cancer risk

T2 - a Mendelian randomisation study

AU - Breast Cancer Association Consortium (BCAC)

AU - Dixon-Suen, Suzanne C.

AU - Lewis, Sarah J.

AU - Martin, Richard M.

AU - English, Dallas R.

AU - Boyle, Terry

AU - Giles, Graham G.

AU - Michailidou, Kyriaki

AU - Bolla, Manjeet K.

AU - Wang, Qin

AU - Dennis, Joe

AU - Lush, Michael

AU - Investigators, Abctb

AU - Ahearn, Thomas U.

AU - Ambrosone, Christine B.

AU - Andrulis, Irene L.

AU - Anton-Culver, Hoda

AU - Arndt, Volker

AU - Aronson, Kristan J.

AU - Augustinsson, Annelie

AU - Auvinen, Päivi

AU - Freeman, Laura E.Beane

AU - Becher, Heiko

AU - Beckmann, Matthias W.

AU - Behrens, Sabine

AU - Bermisheva, Marina

AU - Blomqvist, Carl

AU - Bogdanova, Natalia V.

AU - Bojesen, Stig E.

AU - Bonanni, Bernardo

AU - Brenner, Hermann

AU - Brüning, Thomas

AU - Buys, Saundra S.

AU - Camp, Nicola J.

AU - Campa, Daniele

AU - Canzian, Federico

AU - Castelao, Jose E.

AU - Cessna, Melissa H.

AU - Chang-Claude, Jenny

AU - Chanock, Stephen J.

AU - Clarke, Christine L.

AU - Conroy, Don M.

AU - Couch, Fergus J.

AU - Cox, Angela

AU - Cross, Simon S.

AU - Czene, Kamila

AU - Daly, Mary B.

AU - Devilee, Peter

AU - Dörk, Thilo

AU - Dwek, Miriam

AU - Eccles, Diana M.

AU - Eliassen, A. Heather

AU - Engel, Christoph

AU - Eriksson, Mikael

AU - Evans, D. Gareth

AU - Fasching, Peter A.

AU - Fletcher, Olivia

AU - Flyger, Henrik

AU - Fritschi, Lin

AU - Gabrielson, Marike

AU - Gago-Dominguez, Manuela

AU - García-Closas, Montserrat

AU - García-Sáenz, José A.

AU - Goldberg, Mark S.

AU - Guénel, Pascal

AU - Gündert, Melanie

AU - Hahnen, Eric

AU - Haiman, Christopher A.

AU - Häberle, Lothar

AU - Håkansson, Niclas

AU - Hall, Per

AU - Hamann, Ute

AU - Hart, Steven N.

AU - Harvie, Michelle

AU - Hillemanns, Peter

AU - Hollestelle, Antoinette

AU - Hooning, Maartje J.

AU - Hoppe, Reiner

AU - Hopper, John

AU - Howell, Anthony

AU - Hunter, David J.

AU - Jakubowska, Anna

AU - Janni, Wolfgang

AU - John, Esther M.

AU - Jung, Audrey

AU - Kaaks, Rudolf

AU - Keeman, Renske

AU - Kitahara, Cari M.

AU - Koutros, Stella

AU - Kraft, Peter

AU - Kristensen, Vessela N.

AU - Kubelka-Sabit, Katerina

AU - Kurian, Allison W.

AU - Lacey, James V.

AU - Lambrechts, Diether

AU - Le Marchand, Loic

AU - Lindblom, Annika

AU - Loibl, Sibylle

AU - Lubiński, Jan

AU - Mannermaa, Arto

AU - Manoochehri, Mehdi

AU - Margolin, Sara

AU - Martinez, Maria Elena

AU - Mavroudis, Dimitrios

AU - Menon, Usha

AU - Mulligan, Anna Marie

AU - Murphy, Rachel A.

AU - Collaborators, Nbcs

AU - Nevanlinna, Heli

AU - Nevelsteen, Ines

AU - Newman, William G.

AU - Offit, Kenneth

AU - Olshan, Andrew F.

AU - Olsson, Håkan

AU - Orr, Nick

AU - Patel, Alpa

AU - Peto, Julian

AU - Plaseska-Karanfilska, Dijana

AU - Presneau, Nadege

AU - Rack, Brigitte

AU - Radice, Paolo

AU - Rees-Punia, Erika

AU - Rennert, Gad

AU - Rennert, Hedy S.

AU - Romero, Atocha

AU - Saloustros, Emmanouil

AU - Sandler, Dale P.

AU - Schmidt, Marjanka K.

AU - Schmutzler, Rita K.

AU - Schwentner, Lukas

AU - Scott, Christopher

AU - Shah, Mitul

AU - Shu, Xiao Ou

AU - Simard, Jacques

AU - Southey, Melissa C.

AU - Stone, Jennifer

AU - Surowy, Harald

AU - Swerdlow, Anthony J.

AU - Tamimi, Rulla M.

AU - Tapper, William J.

AU - Taylor, Jack A.

AU - Terry, Mary Beth

AU - Tollenaar, Rob A.E.M.

AU - Troester, Melissa A.

AU - Truong, Thérèse

AU - Untch, Michael

AU - Vachon, Celine M.

AU - Joseph, Vijai

AU - Wappenschmidt, Barbara

AU - Weinberg, Clarice R.

AU - Wolk, Alicja

AU - Yannoukakos, Drakoulis

AU - Zheng, Wei

AU - Ziogas, Argyrios

AU - Dunning, Alison M.

AU - Pharoah, Paul D.P.

AU - Easton, Douglas F.

AU - Milne, Roger L.

AU - Lynch, Brigid M.

N1 - 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) Publisher Copyright: ©

PY - 2022/9/6

Y1 - 2022/9/6

N2 - 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.

AB - 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.

KW - Breast

KW - Genetics

KW - Physical activity

KW - Sedentary Behaviour

UR - http://www.scopus.com/inward/record.url?scp=85137660444&partnerID=8YFLogxK

U2 - 10.1136/bjsports-2021-105132

DO - 10.1136/bjsports-2021-105132

M3 - Article

C2 - 36328784

AN - SCOPUS:85137660444

VL - 56

SP - 1157

EP - 1170

JO - British Journal of Sports Medicine

JF - British Journal of Sports Medicine

SN - 0306-3674

IS - 20

ER -

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

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