Mendelian randomisation study of smoking exposure in relation to breast cancer risk,British Journal of Cancer

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Mendelian randomisation study of smoking exposure in relation to breast cancer risk
British Journal of Cancer ( IF 6.4 ) Pub Date : 2021-08-02 , DOI: 10.1038/s41416-021-01432-8
Hanla A Park _{1,

2} , Sonja Neumeyer ₁ , Kyriaki Michailidou _{3,

4,

5} , Manjeet K Bolla ₅ , Qin Wang ₅ , Joe Dennis ₅ , Thomas U Ahearn ₆ , Irene L Andrulis _{7,

8} , Hoda Anton-Culver ₉ , Natalia N Antonenkova ₁₀ , Volker Arndt ₁₁ , Kristan J Aronson ₁₂ , Annelie Augustinsson ₁₃ , Adinda Baten ₁₄ , Laura E Beane Freeman ₆ , Heiko Becher _{15,

16} , Matthias W Beckmann ₁₇ , Sabine Behrens ₁ , Javier Benitez _{18,

19} , Marina Bermisheva ₂₀ , Natalia V Bogdanova _{10,

21,

22} , Stig E Bojesen _{23,

24,

25} , Hiltrud Brauch _{26,

27,

28} , Hermann Brenner _{11,

29,

30} , Sara Y Brucker ₃₁ , Barbara Burwinkel _{32,

33} , Daniele Campa _{1,

34} , Federico Canzian ₃₅ , Jose E Castelao ₃₆ , Stephen J Chanock ₆ , Georgia Chenevix-Trench ₃₇ , Christine L Clarke ₃₈ , , Don M Conroy ₃₉ , Fergus J Couch ₄₀ , Angela Cox ₄₁ , Simon S Cross _{41,

42} , Kamila Czene ₄₃ , Mary B Daly ₄₄ , Peter Devilee _{45,

46} , Thilo Dörk ₂₂ , Isabel Dos-Santos-Silva ₄₇ , Miriam Dwek ₄₈ , Diana M Eccles ₄₉ , A Heather Eliassen _{50,

51} , Christoph Engel ₅₂ , Mikael Eriksson ₄₃ , D Gareth Evans _{53,

54} , Peter A Fasching _{17,

55} , Henrik Flyger ₅₆ , Lin Fritschi ₅₇ , Montserrat García-Closas ₆ , José A García-Sáenz ₅₈ , Mia M Gaudet ₅₉ , Graham G Giles _{60,

61,

62} , Gord Glendon ₇ , Mark S Goldberg _{63,

64} , David E Goldgar ₆₅ , Anna González-Neira ₁₉ , Mervi Grip ₆₆ , Pascal Guénel ₆₇ , Eric Hahnen _{68,

69} , Christopher A Haiman ₇₀ , Niclas Håkansson ₇₁ , Per Hall _{43,

72} , Ute Hamann ₇₃ , Sileny Han ₁₄ , Elaine F Harkness _{74,

75,

76} , Steven N Hart ₇₇ , Wei He ₄₃ , Bernadette A M Heemskerk-Gerritsen ₇₈ , John L Hopper ₆₁ , David J Hunter _{51,

79,

80} , , , Agnes Jager ₇₈ , Anna Jakubowska _{81,

82} , Esther M John _{83,

84} , Audrey Jung ₁ , Rudolf Kaaks ₁ , Pooja Middha Kapoor _{1,

2} , Renske Keeman ₈₅ , Elza Khusnutdinova _{20,

86} , Cari M Kitahara ₈₇ , Linetta B Koppert ₈₈ , Stella Koutros ₆ , Vessela N Kristensen ₈₉ , Allison W Kurian _{83,

84} , James Lacey _{90,

91} , Diether Lambrechts _{92,

93} , Loic Le Marchand ₉₄ , Wing-Yee Lo _{26,

95} , Jan Lubiński ₈₁ , Arto Mannermaa _{96,

97,

98} , Mehdi Manoochehri ₇₃ , Sara Margolin _{72,

99} , Maria Elena Martinez _{100,

101} , Dimitrios Mavroudis ₁₀₂ , Alfons Meindl ₁₀₃ , Usha Menon ₁₀₄ , Roger L Milne _{60,

61,

62} , Taru A Muranen ₁₀₅ , Heli Nevanlinna ₁₀₅ , William G Newman _{53,

54} , Børge G Nordestgaard _{23,

24,

25} , Kenneth Offit _{106,

107} , Andrew F Olshan ₁₀₈ , Håkan Olsson ₁₃ , Tjoung-Won Park-Simon ₂₂ , Paolo Peterlongo ₁₀₉ , Julian Peto ₄₇ , Dijana Plaseska-Karanfilska ₁₁₀ , Nadege Presneau ₄₈ , Paolo Radice ₁₁₁ , Gad Rennert ₁₁₂ , Hedy S Rennert ₁₁₂ , Atocha Romero ₁₁₃ , Emmanouil Saloustros ₁₁₄ , Elinor J Sawyer ₁₁₅ , Marjanka K Schmidt _{85,

116} , Rita K Schmutzler _{68,

69,

117} , Minouk J Schoemaker ₁₁₈ , Lukas Schwentner ₁₁₉ , Christopher Scott ₇₇ , Mitul Shah ₃₉ , Xiao-Ou Shu ₁₂₀ , Jacques Simard ₁₂₁ , Ann Smeets ₁₂₂ , Melissa C Southey _{60,

62,

123} , John J Spinelli _{124,

125} , Victoria Stevens ₅₉ , Anthony J Swerdlow _{118,

126} , Rulla M Tamimi _{50,

51,

79} , William J Tapper ₄₉ , Jack A Taylor _{127,

128} , Mary Beth Terry ₁₂₉ , Ian Tomlinson _{130,

131} , Melissa A Troester ₁₀₈ , Thérèse Truong ₆₇ , Celine M Vachon ₁₃₂ , Elke M van Veen _{53,

54} , Joseph Vijai _{106,

107} , Sophia Wang _{90,

91} , Camilla Wendt ₉₉ , Robert Winqvist _{133,

134} , Alicja Wolk _{71,

135} , Argyrios Ziogas ₉ , Alison M Dunning ₃₉ , Paul D P Pharoah _{5,

39} , Douglas F Easton _{5,

39} , Wei Zheng ₁₂₀ , Peter Kraft _{51,

79} , Jenny Chang-Claude _{1,

136}

Affiliation

Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
Faculty of Medicine, University of Heidelberg, Heidelberg, Germany.
Biostatistics Unit, The Cyprus Institute of Neurology & Genetics, Nicosia, Cyprus.
Cyprus School of Molecular Medicine, The Cyprus Institute of Neurology & Genetics, Nicosia, Cyprus.
Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.
Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Department of Health and Human Services, Bethesda, MD, USA.
Fred A. Litwin Center for Cancer Genetics, Lunenfeld-Tanenbaum Research Institute of Mount Sinai Hospital, Toronto, ON, Canada.
Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada.
Department of Epidemiology, Genetic Epidemiology Research Institute, University of California Irvine, Irvine, CA, USA.
N.N. Alexandrov Research Institute of Oncology and Medical Radiology, Minsk, Belarus.
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, ON, Canada.
Department of Cancer Epidemiology, Clinical Sciences, Lund University, Lund, Sweden.
Leuven Multidisciplinary Breast Center, Department of Oncology, Leuven Cancer Institute, University Hospitals Leuven, Leuven, Belgium.
Institute of Medical Biometry and Epidemiology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
Institute of Biometry and Clinical Epidemiology, Charité -Universitätsmedizin Berlin, Berlin, Germany.
Department of Gynecology and Obstetrics, Comprehensive Cancer Center ER-EMN, University Hospital Erlangen, Friedrich-Alexander-University Erlangen-Nuremberg, Erlangen, Germany.
Centro de Investigación en Red de Enfermedades Raras (CIBERER), Madrid, Spain.
Human Cancer Genetics Programme, Spanish National Cancer Research Centre (CNIO), Madrid, Spain.
Institute of Biochemistry and Genetics, Ufa Federal Research Centre of the Russian Academy of Sciences, Ufa, Russia.
Department of Radiation Oncology, Hannover Medical School, Hannover, Germany.
Gynaecology Research Unit, Hannover Medical School, Hannover, Germany.
Copenhagen General Population Study, Herlev and Gentofte Hospital, Copenhagen University Hospital, Herlev, Denmark.
Department of Clinical Biochemistry, Herlev and Gentofte Hospital, Copenhagen University Hospital, Herlev, Denmark.
Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology, Stuttgart, Germany.
iFIT-Cluster of Excellence, University of Tübingen, Tübingen, Germany.
German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Partner Site Tübingen, Tübingen, Germany.
Division of Preventive Oncology, German Cancer Research Center (DKFZ) and National Center for Tumor Diseases (NCT), Heidelberg, Germany.
German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany.
Department of Gynecology and Obstetrics, University of Tübingen, Tübingen, Germany.
Molecular Epidemiology Group, C080, German Cancer Research Center (DKFZ), Heidelberg, Germany.
Molecular Biology of Breast Cancer, University Womens Clinic Heidelberg, University of Heidelberg, Heidelberg, Germany.
Department of Biology, University of Pisa, Pisa, Italy.
Genomic Epidemiology Group, German Cancer Research Center (DKFZ), Heidelberg, Germany.
Oncology and Genetics Unit, Instituto de Investigacion Sanitaria Galicia Sur (IISGS), Xerencia de Xestion Integrada de Vigo-SERGAS, Vigo, Spain.
Department of Genetics and Computational Biology, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia.
Westmead Institute for Medical Research, University of Sydney, Sydney, NSW, Australia.
Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Cambridge, UK.
Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA.
Sheffield Institute for Nucleic Acids (SInFoNiA), Department of Oncology and Metabolism, University of Sheffield, Sheffield, UK.
Academic Unit of Pathology, Department of Neuroscience, University of Sheffield, Sheffield, UK.
Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
Department of Clinical Genetics, Fox Chase Cancer Center, Philadelphia, PA, USA.
Department of Pathology, Leiden University Medical Center, Leiden, The Netherlands.
Department of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands.
Department of Non-Communicable Disease Epidemiology, London School of Hygiene and Tropical Medicine, London, UK.
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, MA, USA.
Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, 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.
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.
David Geffen School of Medicine, Department of Medicine Division of Hematology and Oncology, University of California at Los Angeles, Los Angeles, CA, USA.
Department of Breast Surgery, Herlev and Gentofte Hospital, Copenhagen University Hospital, Herlev, Denmark.
School of Public Health, Curtin University, Perth, WA, Australia.
Medical Oncology Department, Hospital Clínico San Carlos, Instituto de Investigación Sanitaria San Carlos (IdISSC), Centro Investigación Biomédica en Red de Cáncer (CIBERONC), Madrid, Spain.
Behavioral and Epidemiology Research Group, American Cancer Society, Atlanta, GA, USA.
Cancer Epidemiology Division, Cancer Council Victoria, Melbourne, VIC, Australia.
Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, VIC, Australia.
Precision Medicine, School of Clinical Sciences at Monash Health, Monash University, Clayton, VIC, Australia.
Department of Medicine, McGill University, Montréal, QC, Canada.
Division of Clinical Epidemiology, Royal Victoria Hospital, McGill University, Montréal, QC, Canada.
Department of Dermatology, Huntsman Cancer Institute, University of Utah School of Medicine, Salt Lake City, UT, USA.
Department of Surgery, Oulu University Hospital, University of Oulu, Oulu, Finland.
Cancer & Environment Group, Center for Research in Epidemiology and Population Health (CESP), INSERM, University Paris-Sud, University Paris-Saclay, Villejuif, France.
Center for Familial Breast and Ovarian Cancer, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany.
Center for Integrated Oncology (CIO), 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, CA, USA.
Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.
Department of Oncology, Södersjukhuset, Stockholm, Sweden.
Molecular Genetics of Breast Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany.
Division of Informatics, Imaging and Data Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester Academic Health Science Centre, Manchester, UK.
Nightingale & Genesis Prevention Centre, Wythenshawe Hospital, Manchester University NHS Foundation Trust, Manchester, UK.
NIHR Manchester Biomedical Research Unit, Manchester University NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester, UK.
Department of Health Sciences Research, Mayo Clinic, Rochester, MN, USA.
Department of Medical Oncology, Erasmus MC Cancer Institute, Rotterdam, The Netherlands.
Program in Genetic Epidemiology and Statistical Genetics, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
Nuffield Department of Population Health, University of Oxford, Oxford, UK.
Department of Genetics and Pathology, Pomeranian Medical University, Szczecin, Poland.
Independent Laboratory of Molecular Biology and Genetic Diagnostics, Pomeranian Medical University, Szczecin, Poland.
Department of Epidemiology and Population Health, Stanford University School of Medicine, Stanford, CA, USA.
Department of Medicine, Division of Oncology, Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA, USA.
Division of Molecular Pathology, The Netherlands Cancer Institute - Antoni van Leeuwenhoek Hospital, Amsterdam, The Netherlands.
Department of Genetics and Fundamental Medicine, Bashkir State University, Ufa, Russia.
Radiation Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, USA.
Department of Surgical Oncology, Family Cancer Clinic, Erasmus MC Cancer Institute, Rotterdam, The Netherlands.
Medical Genetics, Oslo University Hospital and University of Oslo, Oslo, Norway.
Department of Computational and Quantitative Medicine, City of Hope, Duarte, CA, USA.
City of Hope Comprehensive Cancer Center, City of Hope, Duarte, CA, USA.
VIB Center for Cancer Biology, Leuven, Belgium.
Laboratory for Translational Genetics, Department of Human Genetics, University of Leuven, Leuven, Belgium.
Epidemiology Program, University of Hawaii Cancer Center, Honolulu, HI, USA.
University of Tübingen, Tübingen, Germany.
Translational Cancer Research Area, University of Eastern Finland, Kuopio, Finland.
Institute of Clinical Medicine, Pathology and Forensic Medicine, University of Eastern Finland, Kuopio, Finland.
Biobank of Eastern Finland, Kuopio University Hospital, Kuopio, Finland.
Department of Clinical Science and Education, Södersjukhuset, Karolinska Institutet, Stockholm, Sweden.
Moores Cancer Center, University of California San Diego, La Jolla, CA, USA.
Department of Family Medicine and Public Health, University of California San Diego, La Jolla, CA, USA.
Department of Medical Oncology, University Hospital of Heraklion, Heraklion, Greece.
Department of Gynecology and Obstetrics, University of Munich, Campus Großhadern, Munich, Germany.
MRC Clinical Trials Unit at UCL, Institute of Clinical Trials & Methodology, University College London, London, UK.
Department of Obstetrics and Gynecology, Helsinki University Hospital, University of Helsinki, Helsinki, Finland.
Clinical Genetics Research Lab, Department of Cancer Biology and Genetics, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
Clinical Genetics Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, 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, NC, USA.
Genome Diagnostics Program, IFOM - the FIRC Institute of Molecular Oncology, Milan, Italy.
Research Centre for Genetic Engineering and Biotechnology 'Georgi D, Efremov', MASA, Skopje, Republic of North Macedonia.
Unit of Molecular Bases of Genetic Risk and Genetic Testing, Department of Research, Fondazione IRCCS Istituto Nazionale dei Tumori (INT), 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.
School of Cancer & Pharmaceutical Sciences, Comprehensive Cancer Centre, Guy's Campus, King's College London, London, UK.
Division of Psychosocial Research and Epidemiology, The Netherlands Cancer Institute - Antoni van Leeuwenhoek hospital, Amsterdam, The Netherlands.
Center for Molecular Medicine Cologne (CMMC), Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany.
Division of Genetics and Epidemiology, The Institute of Cancer Research, London, UK.
Department of Gynaecology and Obstetrics, University Hospital Ulm, Ulm, Germany.
Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, TN, USA.
Genomics Center, Centre Hospitalier Universitaire de Québec - Université Laval Research Center, Québec City, QC, Canada.
Department of Surgical Oncology, University Hospitals Leuven, Leuven, Belgium.
Department of Clinical Pathology, The University of Melbourne, Melbourne, VIC, Australia.
Population Oncology, BC Cancer, Vancouver, BC, Canada.
School of Population and Public Health, University of British Columbia, Vancouver, BC, Canada.
Division of Breast Cancer Research, The Institute of Cancer Research, London, UK.
Epidemiology Branch, National Institute of Environmental Health Sciences, NIH, Research Triangle Park, NC, USA.
Epigenetic and Stem Cell Biology Laboratory, National Institute of Environmental Health Sciences, NIH, Research Triangle Park, NC, USA.
Department of Epidemiology, Mailman School of Public Health, Columbia University, New York, NY, USA.
Institute of Cancer and Genomic Sciences, University of Birmingham, Birmingham, UK.
Wellcome Trust Centre for Human Genetics and Oxford NIHR Biomedical Research Centre, University of Oxford, Oxford, UK.
Department of Health Science Research, Division of Epidemiology, Mayo Clinic, Rochester, MN, USA.
Laboratory of Cancer Genetics and Tumor Biology, Cancer and Translational Medicine Research Unit, Biocenter Oulu, University of Oulu, Oulu, Finland.
Laboratory of Cancer Genetics and Tumor Biology, Northern Finland Laboratory Centre Oulu, Oulu, Finland.
Department of Surgical Sciences, Uppsala University, Uppsala, Sweden.
Cancer Epidemiology Group, University Cancer Center Hamburg (UCCH), University Medical Center Hamburg-Eppendorf, Hamburg, Germany.

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.

中文翻译：

吸烟暴露与乳腺癌风险相关的孟德尔随机研究

背景

尽管最近的流行病学研究报告吸烟与乳腺癌风险之间存在适度的关联，但吸烟是否与乳腺癌风险存在因果关系仍然是模棱两可的。

方法

我们应用孟德尔随机化 (MR) 来评估吸烟对乳腺癌风险的潜在因果影响。使用个体水平数据以及终生吸烟指数 (LSI) 或每天吸烟量 (CPD) 的全基因组关联研究中报告的 164 个单核苷酸多态性 (SNP) 的汇总统计数据来获得 MR 效应估计。来自 108,420 名浸润性乳腺癌病例和 87,681 名对照者的数据被用于 LSI 分析，以及对来自 26,147 名癌症病例和 26,072 名对照者的曾经吸烟者进行的 CPD 分析。进行敏感性分析以解决多效性。

结果

基因预测的 LSI 与乳腺癌风险增加相关（OR 1.18/SD，95% CI：1.07–1.30， P = 0.11 × 10 ^–2 ），但没有证据表明与基因预测的 CPD 相关（OR 1.02，95% CI：0.78–1.19， P = 0.85）。敏感性分析得出了类似的结果，并且没有显示出多效性的有力证据。