A genome-wide gene-environment interaction study of breast cancer risk for women of European ancestry

doi:10.1186/s13058-023-01691-8

. 2023 Aug 9;25(1):93.

doi: 10.1186/s13058-023-01691-8.

A genome-wide gene-environment interaction study of breast cancer risk for women of European ancestry

Pooja Middha¹, Xiaoliang Wang^{2

3}, Sabine Behrens⁴, Manjeet K Bolla⁵, Qin Wang⁵, Joe Dennis⁵, Kyriaki Michailidou^{5

6}, Thomas U Ahearn⁷, Irene L Andrulis^{8

9}, Hoda Anton-Culver¹⁰, Volker Arndt¹¹, Kristan J Aronson¹², Paul L Auer¹³, Annelie Augustinsson¹⁴, Thaïs Baert¹⁵, Laura E Beane Freeman⁷, Heiko Becher¹⁶, Matthias W Beckmann¹⁷, Javier Benitez^{18

19}, Stig E Bojesen^{20

21

22}, Hiltrud Brauch^{23

24

25}, Hermann Brenner^{11

26

27}, Angela Brooks-Wilson²⁸, Daniele Campa^{4

29}, Federico Canzian³⁰, Angel Carracedo^{31

32}, Jose E Castelao³³, Stephen J Chanock⁷, Georgia Chenevix-Trench³⁴; CTS Consortium; Emilie Cordina-Duverger³⁵, Fergus J Couch³⁶, Angela Cox³⁷, Simon S Cross³⁸, Kamila Czene³⁹, Laure Dossus⁴⁰, Pierre-Antoine Dugué^{41

42}, A Heather Eliassen^{43

44

45}, Mikael Eriksson³⁹, D Gareth Evans^{46

47}, Peter A Fasching¹⁷, Jonine D Figueroa^{7

48

49}, Olivia Fletcher⁵⁰, Henrik Flyger⁵¹, Marike Gabrielson³⁹, Manuela Gago-Dominguez³¹, Graham G Giles^{41

42

52}, Anna González-Neira⁵³, Felix Grassmann^{39

54}, Anne Grundy⁵⁵, Pascal Guénel³⁵, Christopher A Haiman⁵⁶, Niclas Håkansson⁵⁷, Per Hall^{39

58}, Ute Hamann⁵⁹, Susan E Hankinson^{43

60}, Elaine F Harkness^{61

62

63}, Bernd Holleczek⁶⁴, Reiner Hoppe^{23

65}, John L Hopper⁵², Richard S Houlston⁶⁶, Anthony Howell⁶⁷, David J Hunter^{44

68}, Christian Ingvar⁶⁹; ABCTB Investigators; kConFab Investigators; Karolin Isaksson⁷⁰, Helena Jernström¹⁴, Esther M John^{71

72}, Michael E Jones⁶⁶, Rudolf Kaaks⁴, Renske Keeman⁷³, Cari M Kitahara⁷⁴, Yon-Dschun Ko⁷⁵, Stella Koutros⁷, Allison W Kurian^{71

72}, James V Lacey^{76

77}, Diether Lambrechts^{78

79}, Nicole L Larson⁸⁰, Susanna Larsson^{57

81}, Loic Le Marchand⁸², Flavio Lejbkowicz⁸³, Shuai Li^{5

41

52}, Martha Linet⁷⁴, Jolanta Lissowska⁸⁴, Maria Elena Martinez⁸⁵, Tabea Maurer⁸⁶, Anna Marie Mulligan^{87

88}, Claire Mulot⁸⁹, Rachel A Murphy^{90

91}, William G Newman^{46

47}, Sune F Nielsen^{20

21}, Børge G Nordestgaard^{20

21

22}, Aaron Norman⁸⁰, Katie M O'Brien⁹², Janet E Olson⁸⁰, Alpa V Patel⁹³, Ross Prentice⁹⁴, Erika Rees-Punia⁹³, Gad Rennert⁸³, Valerie Rhenius⁹⁵, Kathryn J Ruddy⁹⁶, Dale P Sandler⁹², Christopher G Scott⁹⁷, Mitul Shah⁹⁵, Xiao-Ou Shu⁹⁸, Ann Smeets⁹⁹, Melissa C Southey^{41

42

100}, Jennifer Stone^{52

101}, Rulla M Tamimi^{44

102}, Jack A Taylor^{92

103}, Lauren R Teras⁹³, Katarzyna Tomczyk⁵⁰, Melissa A Troester¹⁰⁴, Thérèse Truong³⁵, Celine M Vachon⁸⁰, Sophia S Wang^{76

77}, Clarice R Weinberg¹⁰⁵, Hans Wildiers¹⁵, Walter Willett^{43

44

45}, Stacey J Winham¹⁰⁶, Alicja Wolk^{57

81}, Xiaohong R Yang⁷, M Pilar Zamora¹⁰⁷, Wei Zheng⁹⁸, Argyrios Ziogas¹⁰, Alison M Dunning⁹⁵, Paul D P Pharoah^{5

95}, Montserrat García-Closas⁷, Marjanka K Schmidt^{73

108}, Peter Kraft^{44

109}, Roger L Milne^{41

42

52}, Sara Lindström^{2

3}, Douglas F Easton^#^{5

95}, Jenny Chang-Claude^#^{4

86}

Affiliations

¹ Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany. pooja.middha@ucsf.edu.
² Department of Epidemiology, University of Washington School of Public Health, Seattle, WA, USA.
³ Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
⁴ Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
⁵ Department of Public Health and Primary Care, Centre for Cancer Genetic Epidemiology, University of Cambridge, Cambridge, UK.
⁶ Biostatistics Unit, The Cyprus Institute of Neurology and Genetics, Nicosia, Cyprus.
⁷ Division of Cancer Epidemiology and Genetics, Department of Health and Human Services, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
⁸ Fred A. Litwin Center for Cancer Genetics, Lunenfeld-Tanenbaum Research Institute of Mount Sinai Hospital, Toronto, ON, Canada.
⁹ Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada.
¹⁰ Department of Medicine, Genetic Epidemiology Research Institute, University of California Irvine, Irvine, CA, USA.
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 Division of Biostatistics, Institute for Health and Equity, and Cancer Center, Medical College of Wisconsin, Milwaukee, WI, USA.
¹⁴ Oncology, Clinical Sciences in Lund, Lund University, Lund, Sweden.
¹⁵ Department of Oncology, Leuven Multidisciplinary Breast Center, Leuven Cancer Institute, University Hospitals Leuven, Leuven, Belgium.
¹⁶ Institute of Medical Biometry and Epidemiology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
¹⁷ Department of Gynecology and Obstetrics, Comprehensive Cancer Center Erlangen-EMN, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nuremberg, Erlangen, Germany.
¹⁸ Human Genetics Group, Spanish National Cancer Research Centre (CNIO), Madrid, Spain.
¹⁹ Centre for Biomedical Network Research on Rare Diseases (CIBERER), Instituto de Salud Carlos III, Madrid, Spain.
²⁰ Copenhagen General Population Study, Herlev and Gentofte Hospital, Copenhagen University Hospital, Herlev, Denmark.
²¹ Department of Clinical Biochemistry, Herlev and Gentofte Hospital, Copenhagen University Hospital, Herlev, Denmark.
²² Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
²³ Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology, Stuttgart, Germany.
²⁴ iFIT-Cluster of Excellence, University of Tübingen, Tübingen, Germany.
²⁵ German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), Partner Site Tübingen, Tübingen, Germany.
²⁶ Division of Preventive Oncology, German Cancer Research Center (DKFZ) and National Center for Tumor Diseases (NCT), Heidelberg, Germany.
²⁷ German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany.
²⁸ Canada's Michael Smith Genome Sciences Centre, BC Cancer, Vancouver, BC, Canada.
²⁹ Department of Biology, University of Pisa, Pisa, Italy.
³⁰ Genomic Epidemiology Group, German Cancer Research Center (DKFZ), Heidelberg, Germany.
³¹ Genomic Medicine Group, International Cancer Genetics and Epidemiology Group, Fundación Pública Galega de Medicina Xenómica, Instituto de Investigación Sanitaria de Santiago de Compostela (IDIS), Complejo Hospitalario Universitario de Santiago, SERGAS, Santiago de Compostela, Spain.
³² Grupo de Medicina Xenómica, Centro de Investigación en Red de Enfermedades Raras (CIBERER) y Centro Nacional de Genotipado (CEGEN-PRB2), Universidad de Santiago de Compostela, Santiago de Compostela, Spain.
³³ Oncology and Genetics Unit, Instituto de Investigación Sanitaria Galicia Sur (IISGS), Xerencia de Xestion Integrada de Vigo-SERGAS, Vigo, Spain.
³⁴ Department of Genetics and Computational Biology, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia.
³⁵ Team 'Exposome and Heredity', CESP, Gustave Roussy, INSERM, University Paris-Saclay, UVSQ, Villejuif, France.
³⁶ Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA.
³⁷ Department of Oncology and Metabolism, Sheffield Institute for Nucleic Acids (SInFoNiA), University of Sheffield, Sheffield, UK.
³⁸ Academic Unit of Pathology, Department of Neuroscience, University of Sheffield, Sheffield, UK.
³⁹ Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
⁴⁰ Nutrition and Metabolism Section, International Agency for Research on Cancer (IARC-WHO), Lyon, France.
⁴¹ Precision Medicine, School of Clinical Sciences at Monash Health, Monash University, Clayton, VIC, Australia.
⁴² Cancer Epidemiology Division, Cancer Council Victoria, Melbourne, VIC, Australia.
⁴³ Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
⁴⁴ Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
⁴⁵ Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
⁴⁶ Division of Evolution and Genomic Sciences, Faculty of Biology, Medicine and Health, Manchester Academic Health Science Centre, School of Biological Sciences, University of Manchester, Manchester, UK.
⁴⁷ North West Genomics Laboratory Hub, Manchester Centre for Genomic Medicine, Manchester Academic Health Science Centre, St Mary's Hospital, Manchester University NHS Foundation Trust, Manchester, UK.
⁴⁸ Usher Institute of Population Health Sciences and Informatics, The University of Edinburgh, Edinburgh, UK.
⁴⁹ Cancer Research UK Edinburgh Centre, The University of Edinburgh, Edinburgh, UK.
⁵⁰ The Breast Cancer Now Toby Robins Research Centre, The Institute of Cancer Research, London, UK.
⁵¹ Department of Breast Surgery, Herlev and Gentofte Hospital, Copenhagen University Hospital, Herlev, Denmark.
⁵² Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, VIC, Australia.
⁵³ Human Cancer Genetics Programme, Spanish National Cancer Research Centre (CNIO), Madrid, Spain.
⁵⁴ Institute for Clinical Research and Systems Medicine, Health and Medical University, Potsdam, Germany.
⁵⁵ Department of Public Health Sciences, Queen's University, Kingston, ON, Canada.
⁵⁶ Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
⁵⁷ Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.
⁵⁸ Department of Oncology, Södersjukhuset, Stockholm, Sweden.
⁵⁹ Molecular Genetics of Breast Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany.
⁶⁰ Department of Biostatistics and Epidemiology, University of Massachusetts, Amherst, Amherst, MA, USA.
⁶¹ Division of Informatics, Imaging and Data Sciences, Faculty of Biology, Medicine and Health, Manchester Academic Health Science Centre, University of Manchester, Manchester, UK.
⁶² Nightingale and Genesis Prevention Centre, Wythenshawe Hospital, Manchester University NHS Foundation Trust, Manchester, UK.
⁶³ NIHR Manchester Biomedical Research Unit, Manchester Academic Health Science Centre, Manchester University NHS Foundation Trust, Manchester, UK.
⁶⁴ Saarland Cancer Registry, Saarbrücken, Germany.
⁶⁵ University of Tübingen, Tübingen, Germany.
⁶⁶ Division of Genetics and Epidemiology, The Institute of Cancer Research, London, UK.
⁶⁷ Division of Cancer Sciences, University of Manchester, Manchester, UK.
⁶⁸ Nuffield Department of Population Health, University of Oxford, Oxford, UK.
⁶⁹ Surgery, Clinical Sciences in Lund, Lund University, Lund, Sweden.
⁷⁰ Department of Surgery, Kristianstad Hospital, Kristianstad, Sweden.
⁷¹ Department of Epidemiology and Population Health, Stanford University School of Medicine, Stanford, CA, USA.
⁷² Division of Oncology, Department of Medicine, Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA, USA.
⁷³ Division of Molecular Pathology, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
⁷⁴ Radiation Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, USA.
⁷⁵ Department of Internal Medicine, Johanniter GmbH Bonn, Johanniter Krankenhaus, Bonn, Germany.
⁷⁶ Department of Computational and Quantitative Medicine, City of Hope, Duarte, CA, USA.
⁷⁷ City of Hope Comprehensive Cancer Center, City of Hope, Duarte, CA, USA.
⁷⁸ Laboratory for Translational Genetics, Department of Human Genetics, KU Leuven, Leuven, Belgium.
⁷⁹ VIB Center for Cancer Biology, VIB, Leuven, Belgium.
⁸⁰ Department of Quantitative Health Sciences, Division of Epidemiology, Mayo Clinic, Rochester, MN, USA.
⁸¹ Department of Surgical Sciences, Uppsala University, Uppsala, Sweden.
⁸² Epidemiology Program, University of Hawaii Cancer Center, Honolulu, HI, USA.
⁸³ Clalit National Cancer Control Center, Carmel Medical Center and Technion Faculty of Medicine, Haifa, Israel.
⁸⁴ Department of Cancer Epidemiology and Prevention, M. Sklodowska-Curie National Research Oncology Institute, Warsaw, Poland.
⁸⁵ Moores Cancer Center and Herbert Wertheim School of Public Health and Human Longevity Science, University of California, San Diego, La Jolla, CA, USA.
⁸⁶ Cancer Epidemiology Group, University Cancer Center Hamburg (UCCH), University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
⁸⁷ Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada.
⁸⁸ Laboratory Medicine Program, University Health Network, Toronto, ON, Canada.
⁸⁹ INSERM UMR-S1138. CRB EPIGENETEC, Université Paris Cité, Paris, France.
⁹⁰ School of Population and Public Health, University of British Columbia, Vancouver, BC, Canada.
⁹¹ Cancer Control Research, BC Cancer, Vancouver, BC, Canada.
⁹² Epidemiology Branch, National Institute of Environmental Health Sciences, NIH, Research Triangle Park, NC, USA.
⁹³ Department of Population Science, American Cancer Society, Atlanta, GA, USA.
⁹⁴ Cancer Prevention Program, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
⁹⁵ Department of Oncology, Centre for Cancer Genetic Epidemiology, University of Cambridge, Cambridge, UK.
⁹⁶ Department of Oncology, Mayo Clinic, Rochester, MN, USA.
⁹⁷ Department of Quantitative Health Sciences, Division of Clinical Trials and Biostatistics, Mayo Clinic, Rochester, MN, USA.
⁹⁸ Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, TN, USA.
⁹⁹ Department of Surgical Oncology, University Hospitals Leuven, Leuven, Belgium.
¹⁰⁰ Department of Clinical Pathology, The University of Melbourne, Melbourne, VIC, Australia.
¹⁰¹ Genetic Epidemiology Group, School of Population and Global Health, University of Western Australia, Perth, WA, Australia.
¹⁰² Department of Population Health Sciences, Weill Cornell Medicine, New York, NY, USA.
¹⁰³ Epigenetic and Stem Cell Biology Laboratory, National Institute of Environmental Health Sciences, NIH, Research Triangle Park, NC, USA.
¹⁰⁴ 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.
¹⁰⁵ Biostatistics and Computational Biology Branch, National Institute of Environmental Health Sciences, NIH, Research Triangle Park, NC, USA.
¹⁰⁶ Division of Computational Biology, Department of Quantitative Health Sciences, Mayo Clinic, Rochester, MN, USA.
¹⁰⁷ Servicio de Oncología Médica, Hospital Universitario La Paz, Madrid, Spain.
¹⁰⁸ Division of Psychosocial Research and Epidemiology, The Netherlands Cancer Institute - Antoni Van Leeuwenhoek Hospital, Amsterdam, the Netherlands.
¹⁰⁹ Program in Genetic Epidemiology and Statistical Genetics, Harvard T.H. Chan School of Public Health, Boston, MA, USA.

^# Contributed equally.

PMID: 37559094
PMCID: PMC10411002
DOI: 10.1186/s13058-023-01691-8

A genome-wide gene-environment interaction study of breast cancer risk for women of European ancestry

Pooja Middha et al. Breast Cancer Res. 2023.

. 2023 Aug 9;25(1):93.

doi: 10.1186/s13058-023-01691-8.

Authors

Affiliations

¹ Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany. pooja.middha@ucsf.edu.
² Department of Epidemiology, University of Washington School of Public Health, Seattle, WA, USA.
³ Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
⁴ Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
⁵ Department of Public Health and Primary Care, Centre for Cancer Genetic Epidemiology, University of Cambridge, Cambridge, UK.
⁶ Biostatistics Unit, The Cyprus Institute of Neurology and Genetics, Nicosia, Cyprus.
⁷ Division of Cancer Epidemiology and Genetics, Department of Health and Human Services, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
⁸ Fred A. Litwin Center for Cancer Genetics, Lunenfeld-Tanenbaum Research Institute of Mount Sinai Hospital, Toronto, ON, Canada.
⁹ Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada.
¹⁰ Department of Medicine, Genetic Epidemiology Research Institute, University of California Irvine, Irvine, CA, USA.
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 Division of Biostatistics, Institute for Health and Equity, and Cancer Center, Medical College of Wisconsin, Milwaukee, WI, USA.
¹⁴ Oncology, Clinical Sciences in Lund, Lund University, Lund, Sweden.
¹⁵ Department of Oncology, Leuven Multidisciplinary Breast Center, Leuven Cancer Institute, University Hospitals Leuven, Leuven, Belgium.
¹⁶ Institute of Medical Biometry and Epidemiology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
¹⁷ Department of Gynecology and Obstetrics, Comprehensive Cancer Center Erlangen-EMN, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nuremberg, Erlangen, Germany.
¹⁸ Human Genetics Group, Spanish National Cancer Research Centre (CNIO), Madrid, Spain.
¹⁹ Centre for Biomedical Network Research on Rare Diseases (CIBERER), Instituto de Salud Carlos III, Madrid, Spain.
²⁰ Copenhagen General Population Study, Herlev and Gentofte Hospital, Copenhagen University Hospital, Herlev, Denmark.
²¹ Department of Clinical Biochemistry, Herlev and Gentofte Hospital, Copenhagen University Hospital, Herlev, Denmark.
²² Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
²³ Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology, Stuttgart, Germany.
²⁴ iFIT-Cluster of Excellence, University of Tübingen, Tübingen, Germany.
²⁵ German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), Partner Site Tübingen, Tübingen, Germany.
²⁶ Division of Preventive Oncology, German Cancer Research Center (DKFZ) and National Center for Tumor Diseases (NCT), Heidelberg, Germany.
²⁷ German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany.
²⁸ Canada's Michael Smith Genome Sciences Centre, BC Cancer, Vancouver, BC, Canada.
²⁹ Department of Biology, University of Pisa, Pisa, Italy.
³⁰ Genomic Epidemiology Group, German Cancer Research Center (DKFZ), Heidelberg, Germany.
³¹ Genomic Medicine Group, International Cancer Genetics and Epidemiology Group, Fundación Pública Galega de Medicina Xenómica, Instituto de Investigación Sanitaria de Santiago de Compostela (IDIS), Complejo Hospitalario Universitario de Santiago, SERGAS, Santiago de Compostela, Spain.
³² Grupo de Medicina Xenómica, Centro de Investigación en Red de Enfermedades Raras (CIBERER) y Centro Nacional de Genotipado (CEGEN-PRB2), Universidad de Santiago de Compostela, Santiago de Compostela, Spain.
³³ Oncology and Genetics Unit, Instituto de Investigación Sanitaria Galicia Sur (IISGS), Xerencia de Xestion Integrada de Vigo-SERGAS, Vigo, Spain.
³⁴ Department of Genetics and Computational Biology, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia.
³⁵ Team 'Exposome and Heredity', CESP, Gustave Roussy, INSERM, University Paris-Saclay, UVSQ, Villejuif, France.
³⁶ Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA.
³⁷ Department of Oncology and Metabolism, Sheffield Institute for Nucleic Acids (SInFoNiA), University of Sheffield, Sheffield, UK.
³⁸ Academic Unit of Pathology, Department of Neuroscience, University of Sheffield, Sheffield, UK.
³⁹ Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
⁴⁰ Nutrition and Metabolism Section, International Agency for Research on Cancer (IARC-WHO), Lyon, France.
⁴¹ Precision Medicine, School of Clinical Sciences at Monash Health, Monash University, Clayton, VIC, Australia.
⁴² Cancer Epidemiology Division, Cancer Council Victoria, Melbourne, VIC, Australia.
⁴³ Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
⁴⁴ Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
⁴⁵ Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
⁴⁶ Division of Evolution and Genomic Sciences, Faculty of Biology, Medicine and Health, Manchester Academic Health Science Centre, School of Biological Sciences, University of Manchester, Manchester, UK.
⁴⁷ North West Genomics Laboratory Hub, Manchester Centre for Genomic Medicine, Manchester Academic Health Science Centre, St Mary's Hospital, Manchester University NHS Foundation Trust, Manchester, UK.
⁴⁸ Usher Institute of Population Health Sciences and Informatics, The University of Edinburgh, Edinburgh, UK.
⁴⁹ Cancer Research UK Edinburgh Centre, The University of Edinburgh, Edinburgh, UK.
⁵⁰ The Breast Cancer Now Toby Robins Research Centre, The Institute of Cancer Research, London, UK.
⁵¹ Department of Breast Surgery, Herlev and Gentofte Hospital, Copenhagen University Hospital, Herlev, Denmark.
⁵² Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, VIC, Australia.
⁵³ Human Cancer Genetics Programme, Spanish National Cancer Research Centre (CNIO), Madrid, Spain.
⁵⁴ Institute for Clinical Research and Systems Medicine, Health and Medical University, Potsdam, Germany.
⁵⁵ Department of Public Health Sciences, Queen's University, Kingston, ON, Canada.
⁵⁶ Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
⁵⁷ Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.
⁵⁸ Department of Oncology, Södersjukhuset, Stockholm, Sweden.
⁵⁹ Molecular Genetics of Breast Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany.
⁶⁰ Department of Biostatistics and Epidemiology, University of Massachusetts, Amherst, Amherst, MA, USA.
⁶¹ Division of Informatics, Imaging and Data Sciences, Faculty of Biology, Medicine and Health, Manchester Academic Health Science Centre, University of Manchester, Manchester, UK.
⁶² Nightingale and Genesis Prevention Centre, Wythenshawe Hospital, Manchester University NHS Foundation Trust, Manchester, UK.
⁶³ NIHR Manchester Biomedical Research Unit, Manchester Academic Health Science Centre, Manchester University NHS Foundation Trust, Manchester, UK.
⁶⁴ Saarland Cancer Registry, Saarbrücken, Germany.
⁶⁵ University of Tübingen, Tübingen, Germany.
⁶⁶ Division of Genetics and Epidemiology, The Institute of Cancer Research, London, UK.
⁶⁷ Division of Cancer Sciences, University of Manchester, Manchester, UK.
⁶⁸ Nuffield Department of Population Health, University of Oxford, Oxford, UK.
⁶⁹ Surgery, Clinical Sciences in Lund, Lund University, Lund, Sweden.
⁷⁰ Department of Surgery, Kristianstad Hospital, Kristianstad, Sweden.
⁷¹ Department of Epidemiology and Population Health, Stanford University School of Medicine, Stanford, CA, USA.
⁷² Division of Oncology, Department of Medicine, Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA, USA.
⁷³ Division of Molecular Pathology, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
⁷⁴ Radiation Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, USA.
⁷⁵ Department of Internal Medicine, Johanniter GmbH Bonn, Johanniter Krankenhaus, Bonn, Germany.
⁷⁶ Department of Computational and Quantitative Medicine, City of Hope, Duarte, CA, USA.
⁷⁷ City of Hope Comprehensive Cancer Center, City of Hope, Duarte, CA, USA.
⁷⁸ Laboratory for Translational Genetics, Department of Human Genetics, KU Leuven, Leuven, Belgium.
⁷⁹ VIB Center for Cancer Biology, VIB, Leuven, Belgium.
⁸⁰ Department of Quantitative Health Sciences, Division of Epidemiology, Mayo Clinic, Rochester, MN, USA.
⁸¹ Department of Surgical Sciences, Uppsala University, Uppsala, Sweden.
⁸² Epidemiology Program, University of Hawaii Cancer Center, Honolulu, HI, USA.
⁸³ Clalit National Cancer Control Center, Carmel Medical Center and Technion Faculty of Medicine, Haifa, Israel.
⁸⁴ Department of Cancer Epidemiology and Prevention, M. Sklodowska-Curie National Research Oncology Institute, Warsaw, Poland.
⁸⁵ Moores Cancer Center and Herbert Wertheim School of Public Health and Human Longevity Science, University of California, San Diego, La Jolla, CA, USA.
⁸⁶ Cancer Epidemiology Group, University Cancer Center Hamburg (UCCH), University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
⁸⁷ Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada.
⁸⁸ Laboratory Medicine Program, University Health Network, Toronto, ON, Canada.
⁸⁹ INSERM UMR-S1138. CRB EPIGENETEC, Université Paris Cité, Paris, France.
⁹⁰ School of Population and Public Health, University of British Columbia, Vancouver, BC, Canada.
⁹¹ Cancer Control Research, BC Cancer, Vancouver, BC, Canada.
⁹² Epidemiology Branch, National Institute of Environmental Health Sciences, NIH, Research Triangle Park, NC, USA.
⁹³ Department of Population Science, American Cancer Society, Atlanta, GA, USA.
⁹⁴ Cancer Prevention Program, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
⁹⁵ Department of Oncology, Centre for Cancer Genetic Epidemiology, University of Cambridge, Cambridge, UK.
⁹⁶ Department of Oncology, Mayo Clinic, Rochester, MN, USA.
⁹⁷ Department of Quantitative Health Sciences, Division of Clinical Trials and Biostatistics, Mayo Clinic, Rochester, MN, USA.
⁹⁸ Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, TN, USA.
⁹⁹ Department of Surgical Oncology, University Hospitals Leuven, Leuven, Belgium.
¹⁰⁰ Department of Clinical Pathology, The University of Melbourne, Melbourne, VIC, Australia.
¹⁰¹ Genetic Epidemiology Group, School of Population and Global Health, University of Western Australia, Perth, WA, Australia.
¹⁰² Department of Population Health Sciences, Weill Cornell Medicine, New York, NY, USA.
¹⁰³ Epigenetic and Stem Cell Biology Laboratory, National Institute of Environmental Health Sciences, NIH, Research Triangle Park, NC, USA.
¹⁰⁴ 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.
¹⁰⁵ Biostatistics and Computational Biology Branch, National Institute of Environmental Health Sciences, NIH, Research Triangle Park, NC, USA.
¹⁰⁶ Division of Computational Biology, Department of Quantitative Health Sciences, Mayo Clinic, Rochester, MN, USA.
¹⁰⁷ Servicio de Oncología Médica, Hospital Universitario La Paz, Madrid, Spain.
¹⁰⁸ Division of Psychosocial Research and Epidemiology, The Netherlands Cancer Institute - Antoni Van Leeuwenhoek Hospital, Amsterdam, the Netherlands.
¹⁰⁹ Program in Genetic Epidemiology and Statistical Genetics, Harvard T.H. Chan School of Public Health, Boston, MA, USA.

^# Contributed equally.

PMID: 37559094
PMCID: PMC10411002
DOI: 10.1186/s13058-023-01691-8

Abstract

Background: Genome-wide studies of gene-environment interactions (G×E) may identify variants associated with disease risk in conjunction with lifestyle/environmental exposures. We conducted a genome-wide G×E analysis of ~ 7.6 million common variants and seven lifestyle/environmental risk factors for breast cancer risk overall and for estrogen receptor positive (ER +) breast cancer.

Methods: Analyses were conducted using 72,285 breast cancer cases and 80,354 controls of European ancestry from the Breast Cancer Association Consortium. Gene-environment interactions were evaluated using standard unconditional logistic regression models and likelihood ratio tests for breast cancer risk overall and for ER + breast cancer. Bayesian False Discovery Probability was employed to assess the noteworthiness of each SNP-risk factor pairs.

Results: Assuming a 1 × 10^-5 prior probability of a true association for each SNP-risk factor pairs and a Bayesian False Discovery Probability < 15%, we identified two independent SNP-risk factor pairs: rs80018847(9p13)-LINGO2 and adult height in association with overall breast cancer risk (OR_int = 0.94, 95% CI 0.92-0.96), and rs4770552(13q12)-SPATA13 and age at menarche for ER + breast cancer risk (OR_int = 0.91, 95% CI 0.88-0.94).

Conclusions: Overall, the contribution of G×E interactions to the heritability of breast cancer is very small. At the population level, multiplicative G×E interactions do not make an important contribution to risk prediction in breast cancer.

Keywords: Breast cancer; European ancestry; Gene-environment interactions; Genetic epidemiology.

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Conflict of interest statement

The authors do not have any conflict of interest.

Figures

**Fig. 1**
Manhattan plot of genome-wide interactions of adult height on overall breast cancer risk. The genome-wide significance threshold of P < 5 x 10⁻⁸ is indicated by the dashed black line. Genome-wide significant findings are highlighted in blue

**Fig. 2**
Manhattan plot of genome-wide interaction of age at menarche for ER + breast cancer risk. The genome-wide significance threshold of P < 5 x 10⁻⁸ is indicated by the dashed black line. Genome-wide significant findings are highlighted in blue.

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References

1. Baer HJ, et al. Adult height, age at attained height, and incidence of breast cancer in premenopausal women. Int J Cancer. 2006;119:2231–2235. doi: 10.1002/ijc.22096. - DOI - PubMed
1. Collaborative Group on Hormonal Factors in Breast Cancer Breast cancer and breastfeeding: collaborative reanalysis of individual data from 47 epidemiological studies in 30 countries, including 50 302 women with breast cancer and 96 973 women without the disease. Lancet. 2002;360:187–195. doi: 10.1016/S0140-6736(02)09454-0. - DOI - PubMed
1. Collaborative Group on Hormonal Factors in Breast Cancer Menarche, menopause, and breast cancer risk: individual participant meta-analysis, including 118 964 women with breast cancer from 117 epidemiological studies. Lancet Oncol. 2012;13:1141–1151. doi: 10.1016/S1470-2045(12)70425-4. - DOI - PMC - PubMed
1. Hunter DJ, et al. Oral contraceptive use and breast cancer: a prospective study of young women. Cancer Epidemiol Biomark Prev Publ Am Assoc Cancer Res Cosponsored Am Soc Prev Oncol. 2010;19:2496–2502. doi: 10.1158/1055-9965.EPI-10-0747. - DOI - PMC - PubMed
1. Jung S, et al. Alcohol consumption and breast cancer risk by estrogen receptor status: in a pooled analysis of 20 studies. Int J Epidemiol. 2016;45:916–928. doi: 10.1093/ije/dyv156. - DOI - PMC - PubMed

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[1] Baer HJ, et al. Adult height, age at attained height, and incidence of breast cancer in premenopausal women. Int J Cancer. 2006;119:2231–2235. doi: 10.1002/ijc.22096. - DOI - PubMed

[2] Baer HJ, et al. Adult height, age at attained height, and incidence of breast cancer in premenopausal women. Int J Cancer. 2006;119:2231–2235. doi: 10.1002/ijc.22096. - DOI - PubMed

[3] Collaborative Group on Hormonal Factors in Breast Cancer Breast cancer and breastfeeding: collaborative reanalysis of individual data from 47 epidemiological studies in 30 countries, including 50 302 women with breast cancer and 96 973 women without the disease. Lancet. 2002;360:187–195. doi: 10.1016/S0140-6736(02)09454-0. - DOI - PubMed

[4] Collaborative Group on Hormonal Factors in Breast Cancer Breast cancer and breastfeeding: collaborative reanalysis of individual data from 47 epidemiological studies in 30 countries, including 50 302 women with breast cancer and 96 973 women without the disease. Lancet. 2002;360:187–195. doi: 10.1016/S0140-6736(02)09454-0. - DOI - PubMed

[5] Collaborative Group on Hormonal Factors in Breast Cancer Menarche, menopause, and breast cancer risk: individual participant meta-analysis, including 118 964 women with breast cancer from 117 epidemiological studies. Lancet Oncol. 2012;13:1141–1151. doi: 10.1016/S1470-2045(12)70425-4. - DOI - PMC - PubMed

[6] Collaborative Group on Hormonal Factors in Breast Cancer Menarche, menopause, and breast cancer risk: individual participant meta-analysis, including 118 964 women with breast cancer from 117 epidemiological studies. Lancet Oncol. 2012;13:1141–1151. doi: 10.1016/S1470-2045(12)70425-4. - DOI - PMC - PubMed

[7] Hunter DJ, et al. Oral contraceptive use and breast cancer: a prospective study of young women. Cancer Epidemiol Biomark Prev Publ Am Assoc Cancer Res Cosponsored Am Soc Prev Oncol. 2010;19:2496–2502. doi: 10.1158/1055-9965.EPI-10-0747. - DOI - PMC - PubMed

[8] Hunter DJ, et al. Oral contraceptive use and breast cancer: a prospective study of young women. Cancer Epidemiol Biomark Prev Publ Am Assoc Cancer Res Cosponsored Am Soc Prev Oncol. 2010;19:2496–2502. doi: 10.1158/1055-9965.EPI-10-0747. - DOI - PMC - PubMed

[9] Jung S, et al. Alcohol consumption and breast cancer risk by estrogen receptor status: in a pooled analysis of 20 studies. Int J Epidemiol. 2016;45:916–928. doi: 10.1093/ije/dyv156. - DOI - PMC - PubMed

[10] Jung S, et al. Alcohol consumption and breast cancer risk by estrogen receptor status: in a pooled analysis of 20 studies. Int J Epidemiol. 2016;45:916–928. doi: 10.1093/ije/dyv156. - DOI - PMC - PubMed

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A genome-wide gene-environment interaction study of breast cancer risk for women of European ancestry

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A genome-wide gene-environment interaction study of breast cancer risk for women of European ancestry

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