Mendelian randomisation study of smoking exposure in relation to breast cancer risk

Hanla A Park^{1

2}, Sonja Neumeyer¹, Kyriaki Michailidou^{3

4

5}, Manjeet K Bolla⁵, Qin Wang⁵, Joe Dennis⁵, Thomas U Ahearn⁶, Irene L Andrulis^{7

8}, Hoda Anton-Culver⁹, Natalia N Antonenkova¹⁰, Volker Arndt¹¹, Kristan J Aronson¹², Annelie Augustinsson¹³, Adinda Baten¹⁴, Laura E Beane Freeman⁶, Heiko Becher^{15

16}, Matthias W Beckmann¹⁷, Sabine Behrens¹, Javier Benitez^{18

19}, Marina Bermisheva²⁰, Natalia V Bogdanova^{10

21

22}, Stig E Bojesen^{23

24

25}, Hiltrud Brauch^{26

27

28}, Hermann Brenner^{11

29

30}, Sara Y Brucker³¹, Barbara Burwinkel^{32

33}, Daniele Campa^{1

34}, Federico Canzian³⁵, Jose E Castelao³⁶, Stephen J Chanock⁶, Georgia Chenevix-Trench³⁷, Christine L Clarke³⁸; NBCS Collaborators; Don M Conroy³⁹, Fergus J Couch⁴⁰, Angela Cox⁴¹, Simon S Cross^{41

42}, Kamila Czene⁴³, Mary B Daly⁴⁴, Peter Devilee^{45

46}, Thilo Dörk²², Isabel Dos-Santos-Silva⁴⁷, Miriam Dwek⁴⁸, Diana M Eccles⁴⁹, A Heather Eliassen^{50

51}, Christoph Engel⁵², Mikael Eriksson⁴³, D Gareth Evans^{53

54}, Peter A Fasching^{17

55}, Henrik Flyger⁵⁶, Lin Fritschi⁵⁷, Montserrat García-Closas⁶, José A García-Sáenz⁵⁸, Mia M Gaudet⁵⁹, Graham G Giles^{60

61

62}, Gord Glendon⁷, Mark S Goldberg^{63

64}, David E Goldgar⁶⁵, Anna González-Neira¹⁹, Mervi Grip⁶⁶, Pascal Guénel⁶⁷, Eric Hahnen^{68

69}, Christopher A Haiman⁷⁰, Niclas Håkansson⁷¹, Per Hall^{43

72}, Ute Hamann⁷³, Sileny Han¹⁴, Elaine F Harkness^{74

75

76}, Steven N Hart⁷⁷, Wei He⁴³, Bernadette A M Heemskerk-Gerritsen⁷⁸, John L Hopper⁶¹, David J Hunter^{51

79

80}; ABCTB Investigators; kConFab Investigators; Agnes Jager⁷⁸, Anna Jakubowska^{81

82}, Esther M John^{83

84}, Audrey Jung¹, Rudolf Kaaks¹, Pooja Middha Kapoor^{1

2}, Renske Keeman⁸⁵, Elza Khusnutdinova^{20

86}, Cari M Kitahara⁸⁷, Linetta B Koppert⁸⁸, Stella Koutros⁶, Vessela N Kristensen⁸⁹, Allison W Kurian^{83

84}, James Lacey^{90

91}, Diether Lambrechts^{92

93}, Loic Le Marchand⁹⁴, Wing-Yee Lo^{26

95}, Jan Lubiński⁸¹, Arto Mannermaa^{96

97

98}, Mehdi Manoochehri⁷³, Sara Margolin^{72

99}, Maria Elena Martinez^{100

101}, Dimitrios Mavroudis¹⁰², Alfons Meindl¹⁰³, Usha Menon¹⁰⁴, Roger L Milne^{60

61

62}, Taru A Muranen¹⁰⁵, Heli Nevanlinna¹⁰⁵, William G Newman^{53

54}, Børge G Nordestgaard^{23

24

25}, Kenneth Offit^{106

107}, Andrew F Olshan¹⁰⁸, Håkan Olsson¹³, Tjoung-Won Park-Simon²², Paolo Peterlongo¹⁰⁹, Julian Peto⁴⁷, Dijana Plaseska-Karanfilska¹¹⁰, Nadege Presneau⁴⁸, Paolo Radice¹¹¹, Gad Rennert¹¹², Hedy S Rennert¹¹², Atocha Romero¹¹³, Emmanouil Saloustros¹¹⁴, Elinor J Sawyer¹¹⁵, Marjanka K Schmidt^{85

116}, Rita K Schmutzler^{68

69

117}, Minouk J Schoemaker¹¹⁸, Lukas Schwentner¹¹⁹, Christopher Scott⁷⁷, Mitul Shah³⁹, Xiao-Ou Shu¹²⁰, Jacques Simard¹²¹, Ann Smeets¹²², Melissa C Southey^{60

62

123}, John J Spinelli^{124

125}, Victoria Stevens⁵⁹, Anthony J Swerdlow^{118

126}, Rulla M Tamimi^{50

51

79}, William J Tapper⁴⁹, Jack A Taylor^{127

128}, Mary Beth Terry¹²⁹, Ian Tomlinson^{130

131}, Melissa A Troester¹⁰⁸, Thérèse Truong⁶⁷, Celine M Vachon¹³², Elke M van Veen^{53

54}, Joseph Vijai^{106

107}, Sophia Wang^{90

91}, Camilla Wendt⁹⁹, Robert Winqvist^{133

134}, Alicja Wolk^{71

135}, Argyrios Ziogas⁹, Alison M Dunning³⁹, Paul D P Pharoah^{5

39}, Douglas F Easton^{5

39}, Wei Zheng¹²⁰, Peter Kraft^{51

79}, Jenny Chang-Claude^{136

137}

Collaborators, Affiliations

Collaborators

Anne-Lise Børresen-Dale, Grethe I Grenaker Alnæs, Kristine K Sahlberg, Lars Ottestad, Rolf Kåresen, Ellen Schlichting, Marit Muri Holmen, Toril Sauer, Vilde Haakensen, Olav Engebråten, Bjørn Naume, Alexander Fosså, Cecile E Kiserud, Kristin V Reinertsen, Åslaug Helland, Margit Riis, Jürgen Geisler, Christine Clarke, Deborah Marsh, Rodney Scott, Robert Baxter, Desmond Yip, Jane Carpenter, Alison Davis, Nirmala Pathmanathan, Peter Simpson, Dinny Graham, Mythily Sachchithananthan, David Amor, Lesley Andrews, Yoland Antill, Rosemary Balleine, Jonathan Beesley, Ian Bennett, Michael Bogwitz, Leon Botes, Meagan Brennan, Melissa Brown, Michael Buckley, Jo Burke, Phyllis Butow, Liz Caldon, Ian Campbell, Deepa Chauhan, Manisha Chauhan, Georgia Chenevix-Trench, Alice Christian, Paul Cohen, Alison Colley, Ashley Crook, James Cui, Margaret Cummings, Sarah-Jane Dawson, Anna DeFazio, Martin Delatycki, Rebecca Dickson, Joanne Dixon, Ted Edkins, Stacey Edwards, Gelareh Farshid, Andrew Fellows, Georgina Fenton, Michael Field, James Flanagan, Peter Fong, Laura Forrest, Stephen Fox, Juliet French, Michael Friedlander, Clara Gaff, Mike Gattas, Peter George, Sian Greening, Marion Harris, Stewart Hart, Nick Hayward, John Hopper, Cass Hoskins, Clare Hunt, Paul James, Mark Jenkins, Alexa Kidd, Judy Kirk, Jessica Koehler, James Kollias, Sunil Lakhani, Mitchell Lawrence, Geoff Lindeman, Lara Lipton, Liz Lobb, Graham Mann, Deborah Marsh, Sue Anne McLachlan, Bettina Meiser, Roger Milne, Sophie Nightingale, Shona O'Connell, Sarah O'Sullivan, David Gallego Ortega, Nick Pachter, Briony Patterson, Amy Pearn, Kelly Phillips, Ellen Pieper, Edwina Rickard, Bridget Robinson, Mona Saleh, Elizabeth Salisbury, Christobel Saunders, Jodi Saunus, Rodney Scott, Clare Scott, Adrienne Sexton, Andrew Shelling, Peter Simpson, Melissa Southey, Amanda Spurdle, Jessica Taylor, Renea Taylor, Heather Thorne, Alison Trainer, Kathy Tucker, Jane Visvader, Logan Walker, Rachael Williams, Ingrid Winship, Mary Ann Young

Affiliations

¹ Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
² Faculty of Medicine, University of Heidelberg, Heidelberg, Germany.
³ Biostatistics Unit, The Cyprus Institute of Neurology & Genetics, Nicosia, Cyprus.
⁴ Cyprus School of Molecular Medicine, The Cyprus Institute of Neurology & Genetics, Nicosia, Cyprus.
⁵ Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.
⁶ Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Department of Health and Human Services, Bethesda, MD, USA.
⁷ Fred A. Litwin Center for Cancer Genetics, Lunenfeld-Tanenbaum Research Institute of Mount Sinai Hospital, Toronto, ON, Canada.
⁸ Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada.
⁹ Department of Epidemiology, Genetic Epidemiology Research Institute, University of California Irvine, Irvine, CA, USA.
¹⁰ N.N. Alexandrov Research Institute of Oncology and Medical Radiology, Minsk, Belarus.
¹¹ Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany.
¹² Department of Public Health Sciences, and Cancer Research Institute, Queen's University, Kingston, ON, Canada.
¹³ Department of Cancer Epidemiology, Clinical Sciences, Lund University, Lund, Sweden.
¹⁴ Leuven Multidisciplinary Breast Center, Department of Oncology, Leuven Cancer Institute, University Hospitals Leuven, Leuven, Belgium.
¹⁵ Institute of Medical Biometry and Epidemiology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
¹⁶ Institute of Biometry and Clinical Epidemiology, Charité -Universitätsmedizin Berlin, Berlin, Germany.
¹⁷ Department of Gynecology and Obstetrics, Comprehensive Cancer Center ER-EMN, University Hospital Erlangen, Friedrich-Alexander-University Erlangen-Nuremberg, Erlangen, Germany.
¹⁸ Centro de Investigación en Red de Enfermedades Raras (CIBERER), Madrid, Spain.
¹⁹ Human Cancer Genetics Programme, Spanish National Cancer Research Centre (CNIO), Madrid, Spain.
²⁰ Institute of Biochemistry and Genetics, Ufa Federal Research Centre of the Russian Academy of Sciences, Ufa, Russia.
²¹ Department of Radiation Oncology, Hannover Medical School, Hannover, Germany.
²² Gynaecology Research Unit, Hannover Medical School, Hannover, Germany.
²³ Copenhagen General Population Study, Herlev and Gentofte Hospital, Copenhagen University Hospital, Herlev, Denmark.
²⁴ Department of Clinical Biochemistry, Herlev and Gentofte Hospital, Copenhagen University Hospital, Herlev, Denmark.
²⁵ Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
²⁶ Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology, Stuttgart, Germany.
²⁷ iFIT-Cluster of Excellence, University of Tübingen, Tübingen, Germany.
²⁸ German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Partner Site Tübingen, Tübingen, Germany.
²⁹ Division of Preventive Oncology, German Cancer Research Center (DKFZ) and National Center for Tumor Diseases (NCT), Heidelberg, Germany.
³⁰ German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany.
³¹ Department of Gynecology and Obstetrics, University of Tübingen, Tübingen, Germany.
³² Molecular Epidemiology Group, C080, German Cancer Research Center (DKFZ), Heidelberg, Germany.
³³ Molecular Biology of Breast Cancer, University Womens Clinic Heidelberg, University of Heidelberg, Heidelberg, Germany.
³⁴ Department of Biology, University of Pisa, Pisa, Italy.
³⁵ Genomic Epidemiology Group, German Cancer Research Center (DKFZ), Heidelberg, Germany.
³⁶ Oncology and Genetics Unit, Instituto de Investigacion Sanitaria Galicia Sur (IISGS), Xerencia de Xestion Integrada de Vigo-SERGAS, Vigo, Spain.
³⁷ Department of Genetics and Computational Biology, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia.
³⁸ Westmead Institute for Medical Research, University of Sydney, Sydney, NSW, Australia.
³⁹ Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Cambridge, UK.
⁴⁰ Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA.
⁴¹ Sheffield Institute for Nucleic Acids (SInFoNiA), Department of Oncology and Metabolism, University of Sheffield, Sheffield, UK.
⁴² Academic Unit of Pathology, Department of Neuroscience, University of Sheffield, Sheffield, UK.
⁴³ Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
⁴⁴ Department of Clinical Genetics, Fox Chase Cancer Center, Philadelphia, PA, USA.
⁴⁵ Department of Pathology, Leiden University Medical Center, Leiden, The Netherlands.
⁴⁶ Department of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands.
⁴⁷ Department of Non-Communicable Disease Epidemiology, London School of Hygiene and Tropical Medicine, London, UK.
⁴⁸ School of Life Sciences, University of Westminster, London, UK.
⁴⁹ Faculty of Medicine, University of Southampton, Southampton, UK.
⁵⁰ Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
⁵¹ Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
⁵² Institute for Medical Informatics, Statistics and Epidemiology, University of Leipzig, Leipzig, Germany.
⁵³ 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.
⁵⁴ 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.
⁵⁵ David Geffen School of Medicine, Department of Medicine Division of Hematology and Oncology, University of California at Los Angeles, Los Angeles, CA, USA.
⁵⁶ Department of Breast Surgery, Herlev and Gentofte Hospital, Copenhagen University Hospital, Herlev, Denmark.
⁵⁷ School of Public Health, Curtin University, Perth, WA, Australia.
⁵⁸ Medical Oncology Department, Hospital Clínico San Carlos, Instituto de Investigación Sanitaria San Carlos (IdISSC), Centro Investigación Biomédica en Red de Cáncer (CIBERONC), Madrid, Spain.
⁵⁹ Behavioral and Epidemiology Research Group, American Cancer Society, Atlanta, GA, USA.
⁶⁰ Cancer Epidemiology Division, Cancer Council Victoria, Melbourne, VIC, Australia.
⁶¹ Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, VIC, Australia.
⁶² Precision Medicine, School of Clinical Sciences at Monash Health, Monash University, Clayton, VIC, Australia.
⁶³ Department of Medicine, McGill University, Montréal, QC, Canada.
⁶⁴ Division of Clinical Epidemiology, Royal Victoria Hospital, McGill University, Montréal, QC, Canada.
⁶⁵ Department of Dermatology, Huntsman Cancer Institute, University of Utah School of Medicine, Salt Lake City, UT, USA.
⁶⁶ Department of Surgery, Oulu University Hospital, University of Oulu, Oulu, Finland.
⁶⁷ Cancer & Environment Group, Center for Research in Epidemiology and Population Health (CESP), INSERM, University Paris-Sud, University Paris-Saclay, Villejuif, France.
⁶⁸ Center for Familial Breast and Ovarian Cancer, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany.
⁶⁹ Center for Integrated Oncology (CIO), Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany.
⁷⁰ Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
⁷¹ Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.
⁷² Department of Oncology, Södersjukhuset, Stockholm, Sweden.
⁷³ Molecular Genetics of Breast Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany.
⁷⁴ Division of Informatics, Imaging and Data Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester Academic Health Science Centre, Manchester, UK.
⁷⁵ Nightingale & Genesis Prevention Centre, Wythenshawe Hospital, Manchester University NHS Foundation Trust, Manchester, UK.
⁷⁶ NIHR Manchester Biomedical Research Unit, Manchester University NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester, UK.
⁷⁷ Department of Health Sciences Research, Mayo Clinic, Rochester, MN, USA.
⁷⁸ Department of Medical Oncology, Erasmus MC Cancer Institute, Rotterdam, The Netherlands.
⁷⁹ Program in Genetic Epidemiology and Statistical Genetics, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
⁸⁰ Nuffield Department of Population Health, University of Oxford, Oxford, UK.
⁸¹ Department of Genetics and Pathology, Pomeranian Medical University, Szczecin, Poland.
⁸² Independent Laboratory of Molecular Biology and Genetic Diagnostics, Pomeranian Medical University, Szczecin, Poland.
⁸³ Department of Epidemiology and Population Health, Stanford University School of Medicine, Stanford, CA, USA.
⁸⁴ Department of Medicine, Division of Oncology, Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA, USA.
⁸⁵ Division of Molecular Pathology, The Netherlands Cancer Institute - Antoni van Leeuwenhoek Hospital, Amsterdam, The Netherlands.
⁸⁶ Department of Genetics and Fundamental Medicine, Bashkir State University, Ufa, Russia.
⁸⁷ Radiation Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, USA.
⁸⁸ Department of Surgical Oncology, Family Cancer Clinic, Erasmus MC Cancer Institute, Rotterdam, The Netherlands.
⁸⁹ Medical Genetics, Oslo University Hospital and University of Oslo, Oslo, Norway.
⁹⁰ Department of Computational and Quantitative Medicine, City of Hope, Duarte, CA, USA.
⁹¹ City of Hope Comprehensive Cancer Center, City of Hope, Duarte, CA, USA.
⁹² VIB Center for Cancer Biology, Leuven, Belgium.
⁹³ Laboratory for Translational Genetics, Department of Human Genetics, University of Leuven, Leuven, Belgium.
⁹⁴ Epidemiology Program, University of Hawaii Cancer Center, Honolulu, HI, USA.
⁹⁵ University of Tübingen, Tübingen, Germany.
⁹⁶ Translational Cancer Research Area, University of Eastern Finland, Kuopio, Finland.
⁹⁷ Institute of Clinical Medicine, Pathology and Forensic Medicine, University of Eastern Finland, Kuopio, Finland.
⁹⁸ Biobank of Eastern Finland, Kuopio University Hospital, Kuopio, Finland.
⁹⁹ Department of Clinical Science and Education, Södersjukhuset, Karolinska Institutet, Stockholm, Sweden.
¹⁰⁰ Moores Cancer Center, University of California San Diego, La Jolla, CA, USA.
¹⁰¹ Department of Family Medicine and Public Health, University of California San Diego, La Jolla, CA, USA.
¹⁰² Department of Medical Oncology, University Hospital of Heraklion, Heraklion, Greece.
¹⁰³ Department of Gynecology and Obstetrics, University of Munich, Campus Großhadern, Munich, Germany.
¹⁰⁴ MRC Clinical Trials Unit at UCL, Institute of Clinical Trials & Methodology, University College London, London, UK.
¹⁰⁵ Department of Obstetrics and Gynecology, Helsinki University Hospital, University of Helsinki, Helsinki, Finland.
¹⁰⁶ Clinical Genetics Research Lab, Department of Cancer Biology and Genetics, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
¹⁰⁷ Clinical Genetics Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
¹⁰⁸ Department of Epidemiology, Gillings School of Global Public Health and UNC Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
¹⁰⁹ Genome Diagnostics Program, IFOM - the FIRC Institute of Molecular Oncology, Milan, Italy.
¹¹⁰ Research Centre for Genetic Engineering and Biotechnology 'Georgi D, Efremov', MASA, Skopje, Republic of North Macedonia.
¹¹¹ Unit of Molecular Bases of Genetic Risk and Genetic Testing, Department of Research, Fondazione IRCCS Istituto Nazionale dei Tumori (INT), Milan, Italy.
¹¹² Clalit National Cancer Control Center, Carmel Medical Center and Technion Faculty of Medicine, Haifa, Israel.
¹¹³ Medical Oncology Department, Hospital Universitario Puerta de Hierro, Madrid, Spain.
¹¹⁴ Department of Oncology, University Hospital of Larissa, Larissa, Greece.
¹¹⁵ School of Cancer & Pharmaceutical Sciences, Comprehensive Cancer Centre, Guy's Campus, King's College London, London, UK.
¹¹⁶ Division of Psychosocial Research and Epidemiology, The Netherlands Cancer Institute - Antoni van Leeuwenhoek hospital, Amsterdam, The Netherlands.
¹¹⁷ Center for Molecular Medicine Cologne (CMMC), Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany.
¹¹⁸ Division of Genetics and Epidemiology, The Institute of Cancer Research, London, UK.
¹¹⁹ Department of Gynaecology and Obstetrics, University Hospital Ulm, Ulm, Germany.
¹²⁰ Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, TN, USA.
¹²¹ Genomics Center, Centre Hospitalier Universitaire de Québec - Université Laval Research Center, Québec City, QC, Canada.
¹²² Department of Surgical Oncology, University Hospitals Leuven, Leuven, Belgium.
¹²³ Department of Clinical Pathology, The University of Melbourne, Melbourne, VIC, Australia.
¹²⁴ Population Oncology, BC Cancer, Vancouver, BC, Canada.
¹²⁵ School of Population and Public Health, University of British Columbia, Vancouver, BC, Canada.
¹²⁶ Division of Breast Cancer Research, The Institute of Cancer Research, London, UK.
¹²⁷ Epidemiology Branch, National Institute of Environmental Health Sciences, NIH, Research Triangle Park, NC, USA.
¹²⁸ Epigenetic and Stem Cell Biology Laboratory, National Institute of Environmental Health Sciences, NIH, Research Triangle Park, NC, USA.
¹²⁹ Department of Epidemiology, Mailman School of Public Health, Columbia University, New York, NY, USA.
¹³⁰ Institute of Cancer and Genomic Sciences, University of Birmingham, Birmingham, UK.
¹³¹ Wellcome Trust Centre for Human Genetics and Oxford NIHR Biomedical Research Centre, University of Oxford, Oxford, UK.
¹³² Department of Health Science Research, Division of Epidemiology, Mayo Clinic, Rochester, MN, USA.
¹³³ Laboratory of Cancer Genetics and Tumor Biology, Cancer and Translational Medicine Research Unit, Biocenter Oulu, University of Oulu, Oulu, Finland.
¹³⁴ Laboratory of Cancer Genetics and Tumor Biology, Northern Finland Laboratory Centre Oulu, Oulu, Finland.
¹³⁵ Department of Surgical Sciences, Uppsala University, Uppsala, Sweden.
¹³⁶ Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany. j.chang-claude@dkfz.de.
¹³⁷ Cancer Epidemiology Group, University Cancer Center Hamburg (UCCH), University Medical Center Hamburg-Eppendorf, Hamburg, Germany. j.chang-claude@dkfz.de.

PMID: 34341517
PMCID: PMC8505411
DOI: 10.1038/s41416-021-01432-8

Mendelian randomisation study of smoking exposure in relation to breast cancer risk

Hanla A Park et al. Br J Cancer. 2021 Oct.

. 2021 Oct;125(8):1135-1145.

doi: 10.1038/s41416-021-01432-8. Epub 2021 Aug 2.

Authors

Collaborators

Anne-Lise Børresen-Dale, Grethe I Grenaker Alnæs, Kristine K Sahlberg, Lars Ottestad, Rolf Kåresen, Ellen Schlichting, Marit Muri Holmen, Toril Sauer, Vilde Haakensen, Olav Engebråten, Bjørn Naume, Alexander Fosså, Cecile E Kiserud, Kristin V Reinertsen, Åslaug Helland, Margit Riis, Jürgen Geisler, Christine Clarke, Deborah Marsh, Rodney Scott, Robert Baxter, Desmond Yip, Jane Carpenter, Alison Davis, Nirmala Pathmanathan, Peter Simpson, Dinny Graham, Mythily Sachchithananthan, David Amor, Lesley Andrews, Yoland Antill, Rosemary Balleine, Jonathan Beesley, Ian Bennett, Michael Bogwitz, Leon Botes, Meagan Brennan, Melissa Brown, Michael Buckley, Jo Burke, Phyllis Butow, Liz Caldon, Ian Campbell, Deepa Chauhan, Manisha Chauhan, Georgia Chenevix-Trench, Alice Christian, Paul Cohen, Alison Colley, Ashley Crook, James Cui, Margaret Cummings, Sarah-Jane Dawson, Anna DeFazio, Martin Delatycki, Rebecca Dickson, Joanne Dixon, Ted Edkins, Stacey Edwards, Gelareh Farshid, Andrew Fellows, Georgina Fenton, Michael Field, James Flanagan, Peter Fong, Laura Forrest, Stephen Fox, Juliet French, Michael Friedlander, Clara Gaff, Mike Gattas, Peter George, Sian Greening, Marion Harris, Stewart Hart, Nick Hayward, John Hopper, Cass Hoskins, Clare Hunt, Paul James, Mark Jenkins, Alexa Kidd, Judy Kirk, Jessica Koehler, James Kollias, Sunil Lakhani, Mitchell Lawrence, Geoff Lindeman, Lara Lipton, Liz Lobb, Graham Mann, Deborah Marsh, Sue Anne McLachlan, Bettina Meiser, Roger Milne, Sophie Nightingale, Shona O'Connell, Sarah O'Sullivan, David Gallego Ortega, Nick Pachter, Briony Patterson, Amy Pearn, Kelly Phillips, Ellen Pieper, Edwina Rickard, Bridget Robinson, Mona Saleh, Elizabeth Salisbury, Christobel Saunders, Jodi Saunus, Rodney Scott, Clare Scott, Adrienne Sexton, Andrew Shelling, Peter Simpson, Melissa Southey, Amanda Spurdle, Jessica Taylor, Renea Taylor, Heather Thorne, Alison Trainer, Kathy Tucker, Jane Visvader, Logan Walker, Rachael Williams, Ingrid Winship, Mary Ann Young

Affiliations

¹ Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
² Faculty of Medicine, University of Heidelberg, Heidelberg, Germany.
³ Biostatistics Unit, The Cyprus Institute of Neurology & Genetics, Nicosia, Cyprus.
⁴ Cyprus School of Molecular Medicine, The Cyprus Institute of Neurology & Genetics, Nicosia, Cyprus.
⁵ Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.
⁶ Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Department of Health and Human Services, Bethesda, MD, USA.
⁷ Fred A. Litwin Center for Cancer Genetics, Lunenfeld-Tanenbaum Research Institute of Mount Sinai Hospital, Toronto, ON, Canada.
⁸ Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada.
⁹ Department of Epidemiology, Genetic Epidemiology Research Institute, University of California Irvine, Irvine, CA, USA.
¹⁰ N.N. Alexandrov Research Institute of Oncology and Medical Radiology, Minsk, Belarus.
¹¹ Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany.
¹² Department of Public Health Sciences, and Cancer Research Institute, Queen's University, Kingston, ON, Canada.
¹³ Department of Cancer Epidemiology, Clinical Sciences, Lund University, Lund, Sweden.
¹⁴ Leuven Multidisciplinary Breast Center, Department of Oncology, Leuven Cancer Institute, University Hospitals Leuven, Leuven, Belgium.
¹⁵ Institute of Medical Biometry and Epidemiology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
¹⁶ Institute of Biometry and Clinical Epidemiology, Charité -Universitätsmedizin Berlin, Berlin, Germany.
¹⁷ Department of Gynecology and Obstetrics, Comprehensive Cancer Center ER-EMN, University Hospital Erlangen, Friedrich-Alexander-University Erlangen-Nuremberg, Erlangen, Germany.
¹⁸ Centro de Investigación en Red de Enfermedades Raras (CIBERER), Madrid, Spain.
¹⁹ Human Cancer Genetics Programme, Spanish National Cancer Research Centre (CNIO), Madrid, Spain.
²⁰ Institute of Biochemistry and Genetics, Ufa Federal Research Centre of the Russian Academy of Sciences, Ufa, Russia.
²¹ Department of Radiation Oncology, Hannover Medical School, Hannover, Germany.
²² Gynaecology Research Unit, Hannover Medical School, Hannover, Germany.
²³ Copenhagen General Population Study, Herlev and Gentofte Hospital, Copenhagen University Hospital, Herlev, Denmark.
²⁴ Department of Clinical Biochemistry, Herlev and Gentofte Hospital, Copenhagen University Hospital, Herlev, Denmark.
²⁵ Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
²⁶ Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology, Stuttgart, Germany.
²⁷ iFIT-Cluster of Excellence, University of Tübingen, Tübingen, Germany.
²⁸ German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Partner Site Tübingen, Tübingen, Germany.
²⁹ Division of Preventive Oncology, German Cancer Research Center (DKFZ) and National Center for Tumor Diseases (NCT), Heidelberg, Germany.
³⁰ German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany.
³¹ Department of Gynecology and Obstetrics, University of Tübingen, Tübingen, Germany.
³² Molecular Epidemiology Group, C080, German Cancer Research Center (DKFZ), Heidelberg, Germany.
³³ Molecular Biology of Breast Cancer, University Womens Clinic Heidelberg, University of Heidelberg, Heidelberg, Germany.
³⁴ Department of Biology, University of Pisa, Pisa, Italy.
³⁵ Genomic Epidemiology Group, German Cancer Research Center (DKFZ), Heidelberg, Germany.
³⁶ Oncology and Genetics Unit, Instituto de Investigacion Sanitaria Galicia Sur (IISGS), Xerencia de Xestion Integrada de Vigo-SERGAS, Vigo, Spain.
³⁷ Department of Genetics and Computational Biology, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia.
³⁸ Westmead Institute for Medical Research, University of Sydney, Sydney, NSW, Australia.
³⁹ Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Cambridge, UK.
⁴⁰ Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA.
⁴¹ Sheffield Institute for Nucleic Acids (SInFoNiA), Department of Oncology and Metabolism, University of Sheffield, Sheffield, UK.
⁴² Academic Unit of Pathology, Department of Neuroscience, University of Sheffield, Sheffield, UK.
⁴³ Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
⁴⁴ Department of Clinical Genetics, Fox Chase Cancer Center, Philadelphia, PA, USA.
⁴⁵ Department of Pathology, Leiden University Medical Center, Leiden, The Netherlands.
⁴⁶ Department of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands.
⁴⁷ Department of Non-Communicable Disease Epidemiology, London School of Hygiene and Tropical Medicine, London, UK.
⁴⁸ School of Life Sciences, University of Westminster, London, UK.
⁴⁹ Faculty of Medicine, University of Southampton, Southampton, UK.
⁵⁰ Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
⁵¹ Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
⁵² Institute for Medical Informatics, Statistics and Epidemiology, University of Leipzig, Leipzig, Germany.
⁵³ 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.
⁵⁴ 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.
⁵⁵ David Geffen School of Medicine, Department of Medicine Division of Hematology and Oncology, University of California at Los Angeles, Los Angeles, CA, USA.
⁵⁶ Department of Breast Surgery, Herlev and Gentofte Hospital, Copenhagen University Hospital, Herlev, Denmark.
⁵⁷ School of Public Health, Curtin University, Perth, WA, Australia.
⁵⁸ Medical Oncology Department, Hospital Clínico San Carlos, Instituto de Investigación Sanitaria San Carlos (IdISSC), Centro Investigación Biomédica en Red de Cáncer (CIBERONC), Madrid, Spain.
⁵⁹ Behavioral and Epidemiology Research Group, American Cancer Society, Atlanta, GA, USA.
⁶⁰ Cancer Epidemiology Division, Cancer Council Victoria, Melbourne, VIC, Australia.
⁶¹ Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, VIC, Australia.
⁶² Precision Medicine, School of Clinical Sciences at Monash Health, Monash University, Clayton, VIC, Australia.
⁶³ Department of Medicine, McGill University, Montréal, QC, Canada.
⁶⁴ Division of Clinical Epidemiology, Royal Victoria Hospital, McGill University, Montréal, QC, Canada.
⁶⁵ Department of Dermatology, Huntsman Cancer Institute, University of Utah School of Medicine, Salt Lake City, UT, USA.
⁶⁶ Department of Surgery, Oulu University Hospital, University of Oulu, Oulu, Finland.
⁶⁷ Cancer & Environment Group, Center for Research in Epidemiology and Population Health (CESP), INSERM, University Paris-Sud, University Paris-Saclay, Villejuif, France.
⁶⁸ Center for Familial Breast and Ovarian Cancer, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany.
⁶⁹ Center for Integrated Oncology (CIO), Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany.
⁷⁰ Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
⁷¹ Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.
⁷² Department of Oncology, Södersjukhuset, Stockholm, Sweden.
⁷³ Molecular Genetics of Breast Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany.
⁷⁴ Division of Informatics, Imaging and Data Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester Academic Health Science Centre, Manchester, UK.
⁷⁵ Nightingale & Genesis Prevention Centre, Wythenshawe Hospital, Manchester University NHS Foundation Trust, Manchester, UK.
⁷⁶ NIHR Manchester Biomedical Research Unit, Manchester University NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester, UK.
⁷⁷ Department of Health Sciences Research, Mayo Clinic, Rochester, MN, USA.
⁷⁸ Department of Medical Oncology, Erasmus MC Cancer Institute, Rotterdam, The Netherlands.
⁷⁹ Program in Genetic Epidemiology and Statistical Genetics, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
⁸⁰ Nuffield Department of Population Health, University of Oxford, Oxford, UK.
⁸¹ Department of Genetics and Pathology, Pomeranian Medical University, Szczecin, Poland.
⁸² Independent Laboratory of Molecular Biology and Genetic Diagnostics, Pomeranian Medical University, Szczecin, Poland.
⁸³ Department of Epidemiology and Population Health, Stanford University School of Medicine, Stanford, CA, USA.
⁸⁴ Department of Medicine, Division of Oncology, Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA, USA.
⁸⁵ Division of Molecular Pathology, The Netherlands Cancer Institute - Antoni van Leeuwenhoek Hospital, Amsterdam, The Netherlands.
⁸⁶ Department of Genetics and Fundamental Medicine, Bashkir State University, Ufa, Russia.
⁸⁷ Radiation Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, USA.
⁸⁸ Department of Surgical Oncology, Family Cancer Clinic, Erasmus MC Cancer Institute, Rotterdam, The Netherlands.
⁸⁹ Medical Genetics, Oslo University Hospital and University of Oslo, Oslo, Norway.
⁹⁰ Department of Computational and Quantitative Medicine, City of Hope, Duarte, CA, USA.
⁹¹ City of Hope Comprehensive Cancer Center, City of Hope, Duarte, CA, USA.
⁹² VIB Center for Cancer Biology, Leuven, Belgium.
⁹³ Laboratory for Translational Genetics, Department of Human Genetics, University of Leuven, Leuven, Belgium.
⁹⁴ Epidemiology Program, University of Hawaii Cancer Center, Honolulu, HI, USA.
⁹⁵ University of Tübingen, Tübingen, Germany.
⁹⁶ Translational Cancer Research Area, University of Eastern Finland, Kuopio, Finland.
⁹⁷ Institute of Clinical Medicine, Pathology and Forensic Medicine, University of Eastern Finland, Kuopio, Finland.
⁹⁸ Biobank of Eastern Finland, Kuopio University Hospital, Kuopio, Finland.
⁹⁹ Department of Clinical Science and Education, Södersjukhuset, Karolinska Institutet, Stockholm, Sweden.
¹⁰⁰ Moores Cancer Center, University of California San Diego, La Jolla, CA, USA.
¹⁰¹ Department of Family Medicine and Public Health, University of California San Diego, La Jolla, CA, USA.
¹⁰² Department of Medical Oncology, University Hospital of Heraklion, Heraklion, Greece.
¹⁰³ Department of Gynecology and Obstetrics, University of Munich, Campus Großhadern, Munich, Germany.
¹⁰⁴ MRC Clinical Trials Unit at UCL, Institute of Clinical Trials & Methodology, University College London, London, UK.
¹⁰⁵ Department of Obstetrics and Gynecology, Helsinki University Hospital, University of Helsinki, Helsinki, Finland.
¹⁰⁶ Clinical Genetics Research Lab, Department of Cancer Biology and Genetics, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
¹⁰⁷ Clinical Genetics Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
¹⁰⁸ Department of Epidemiology, Gillings School of Global Public Health and UNC Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
¹⁰⁹ Genome Diagnostics Program, IFOM - the FIRC Institute of Molecular Oncology, Milan, Italy.
¹¹⁰ Research Centre for Genetic Engineering and Biotechnology 'Georgi D, Efremov', MASA, Skopje, Republic of North Macedonia.
¹¹¹ Unit of Molecular Bases of Genetic Risk and Genetic Testing, Department of Research, Fondazione IRCCS Istituto Nazionale dei Tumori (INT), Milan, Italy.
¹¹² Clalit National Cancer Control Center, Carmel Medical Center and Technion Faculty of Medicine, Haifa, Israel.
¹¹³ Medical Oncology Department, Hospital Universitario Puerta de Hierro, Madrid, Spain.
¹¹⁴ Department of Oncology, University Hospital of Larissa, Larissa, Greece.
¹¹⁵ School of Cancer & Pharmaceutical Sciences, Comprehensive Cancer Centre, Guy's Campus, King's College London, London, UK.
¹¹⁶ Division of Psychosocial Research and Epidemiology, The Netherlands Cancer Institute - Antoni van Leeuwenhoek hospital, Amsterdam, The Netherlands.
¹¹⁷ Center for Molecular Medicine Cologne (CMMC), Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany.
¹¹⁸ Division of Genetics and Epidemiology, The Institute of Cancer Research, London, UK.
¹¹⁹ Department of Gynaecology and Obstetrics, University Hospital Ulm, Ulm, Germany.
¹²⁰ Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, TN, USA.
¹²¹ Genomics Center, Centre Hospitalier Universitaire de Québec - Université Laval Research Center, Québec City, QC, Canada.
¹²² Department of Surgical Oncology, University Hospitals Leuven, Leuven, Belgium.
¹²³ Department of Clinical Pathology, The University of Melbourne, Melbourne, VIC, Australia.
¹²⁴ Population Oncology, BC Cancer, Vancouver, BC, Canada.
¹²⁵ School of Population and Public Health, University of British Columbia, Vancouver, BC, Canada.
¹²⁶ Division of Breast Cancer Research, The Institute of Cancer Research, London, UK.
¹²⁷ Epidemiology Branch, National Institute of Environmental Health Sciences, NIH, Research Triangle Park, NC, USA.
¹²⁸ Epigenetic and Stem Cell Biology Laboratory, National Institute of Environmental Health Sciences, NIH, Research Triangle Park, NC, USA.
¹²⁹ Department of Epidemiology, Mailman School of Public Health, Columbia University, New York, NY, USA.
¹³⁰ Institute of Cancer and Genomic Sciences, University of Birmingham, Birmingham, UK.
¹³¹ Wellcome Trust Centre for Human Genetics and Oxford NIHR Biomedical Research Centre, University of Oxford, Oxford, UK.
¹³² Department of Health Science Research, Division of Epidemiology, Mayo Clinic, Rochester, MN, USA.
¹³³ Laboratory of Cancer Genetics and Tumor Biology, Cancer and Translational Medicine Research Unit, Biocenter Oulu, University of Oulu, Oulu, Finland.
¹³⁴ Laboratory of Cancer Genetics and Tumor Biology, Northern Finland Laboratory Centre Oulu, Oulu, Finland.
¹³⁵ Department of Surgical Sciences, Uppsala University, Uppsala, Sweden.
¹³⁶ Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany. j.chang-claude@dkfz.de.
¹³⁷ Cancer Epidemiology Group, University Cancer Center Hamburg (UCCH), University Medical Center Hamburg-Eppendorf, Hamburg, Germany. j.chang-claude@dkfz.de.

PMID: 34341517
PMCID: PMC8505411
DOI: 10.1038/s41416-021-01432-8

Abstract

Background: Despite a modest association between tobacco smoking and breast cancer risk reported by recent epidemiological studies, it is still equivocal whether smoking is causally related to breast cancer risk.

Methods: We applied Mendelian randomisation (MR) to evaluate a potential causal effect of cigarette smoking on breast cancer risk. Both individual-level data as well as summary statistics for 164 single-nucleotide polymorphisms (SNPs) reported in genome-wide association studies of lifetime smoking index (LSI) or cigarette per day (CPD) were used to obtain MR effect estimates. Data from 108,420 invasive breast cancer cases and 87,681 controls were used for the LSI analysis and for the CPD analysis conducted among ever-smokers from 26,147 cancer cases and 26,072 controls. Sensitivity analyses were conducted to address pleiotropy.

Results: Genetically predicted LSI was associated with increased breast cancer risk (OR 1.18 per SD, 95% CI: 1.07-1.30, P = 0.11 × 10^-2), but there was no evidence of association for genetically predicted CPD (OR 1.02, 95% CI: 0.78-1.19, P = 0.85). The sensitivity analyses yielded similar results and showed no strong evidence of pleiotropic effect.

Conclusion: Our MR study provides supportive evidence for a potential causal association with breast cancer risk for lifetime smoking exposure but not cigarettes per day among smokers.

PubMed Disclaimer

Conflict of interest statement

U.Me. has reported a conflict of interest outside of the submitted work (owing stocks in Abcodia awarded to her by University College London). P.H., R.M.T. and A.Cox. are subject editors for the British Journal of Cancer. P.D.P. P., E.J.S. and K.Cz. are editorial board members for the British Journal of Cancer. The remaining authors declare no competing interests.

References

1. Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J. Clin. 2018;68:394–424. doi: 10.3322/caac.21492. - DOI - PubMed
1. Tobacco smoke and involuntary smoking, IARC Monographs on the Evaluation of Carcinogenic Risks to Humans. 83, 1–1438 (2004). - PMC - PubMed
1. Centers for Disease C, Prevention, National Center for Chronic Disease P, Health P, Office on S, Health. Publications and reports of the surgeon general. in How Tobacco Smoke Causes Disease: The Biology and Behavioral Basis for Smoking-Attributable Disease: A Report of the Surgeon General Centers for Disease Control and Prevention (US): Atlanta (GA) (2010). - PubMed
1. Hecht SS. Tobacco smoke carcinogens and breast cancer. Environ. Mol. Mutagen. 2002;39:119–126. doi: 10.1002/em.10071. - DOI - PubMed
1. Petrakis NL, Gruenke LD, Beelen TC, Castagnoli N, Jr., Craig JC. Nicotine in breast fluid of nonlactating women. Science. 1978;199:303–305. doi: 10.1126/science.619458. - DOI - PubMed

Publication types

Actions
Actions

MeSH terms

Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions

Save citation to file

Email citation

Add to Collections

Add to My Bibliography

Your saved search

Create a file for external citation management software

Your RSS Feed

Mendelian randomisation study of smoking exposure in relation to breast cancer risk

Collaborators

Affiliations

Mendelian randomisation study of smoking exposure in relation to breast cancer risk

Authors

Collaborators

Affiliations

Abstract

Conflict of interest statement

References

Publication types

MeSH terms

Grants and funding

LinkOut - more resources

Full Text Sources

Medical