. 2021 Feb;124(4):842-854.

doi: 10.1038/s41416-020-01185-w. Epub 2021 Jan 26.

CYP3A7*1C allele: linking premenopausal oestrone and progesterone levels with risk of hormone receptor-positive breast cancers

Nichola Johnson^#¹, Sarah Maguire^#², Anna Morra^#³, Pooja Middha Kapoor^#^{4

5}, Katarzyna Tomczyk⁶, Michael E Jones⁷, Minouk J Schoemaker⁷, Clare Gilham⁸, Manjeet K Bolla⁹, Qin Wang⁹, Joe Dennis⁹, Thomas U Ahearn¹⁰, Irene L Andrulis^{11

12}, Hoda Anton-Culver¹³, Natalia N Antonenkova¹⁴, Volker Arndt¹⁵, Kristan J Aronson¹⁶, Annelie Augustinsson¹⁷, Caroline Baynes¹⁸, Laura E Beane Freeman¹⁰, Matthias W Beckmann¹⁹, Javier Benitez^{20

21}, Marina Bermisheva²², Carl Blomqvist^{23

24}, Bram Boeckx^{25

26}, Natalia V Bogdanova^{14

27

28}, Stig E Bojesen^{29

30

31}, Hiltrud Brauch^{32

33

34}, Hermann Brenner^{15

34

35}, Barbara Burwinkel^{36

37}, Daniele Campa^{4

38}, Federico Canzian³⁹, Jose E Castelao⁴⁰, Stephen J Chanock¹⁰, Georgia Chenevix-Trench⁴¹, Christine L Clarke⁴²; NBCS Collaborators; Don M Conroy¹⁸, Fergus J Couch⁴³, Angela Cox⁴⁴, Simon S Cross⁴⁵, Kamila Czene⁴⁶, Thilo Dörk²⁸, A Heather Eliassen^{47

48}, Christoph Engel^{49

50}, D Gareth Evans^{51

52}, Peter A Fasching^{19

53}, Jonine Figueroa^{10

54

55}, Giuseppe Floris⁵⁶, Henrik Flyger⁵⁷, Manuela Gago-Dominguez^{58

59}, Susan M Gapstur⁶⁰, Montserrat García-Closas¹⁰, Mia M Gaudet⁶⁰, Graham G Giles^{61

62

63}, Mark S Goldberg^{64

65}, Anna González-Neira²¹; AOCS Group; Pascal Guénel⁶⁶, Eric Hahnen^{67

68}, Christopher A Haiman⁶⁹, Niclas Håkansson⁷⁰, Per Hall^{46

71}, Ute Hamann⁷², Patricia A Harrington¹⁸, Steven N Hart⁷³, Maartje J Hooning⁷⁴, John L Hopper⁶², Anthony Howell⁷⁵, David J Hunter^{48

76}; ABCTB Investigators; kConFab Investigators; Agnes Jager⁷⁴, Anna Jakubowska^{77

78}, Esther M John^{79

80}, Rudolf Kaaks⁴, Renske Keeman³, Elza Khusnutdinova^{22

81}, Cari M Kitahara⁸², Veli-Matti Kosma^{83

84

85}, Stella Koutros¹⁰, Peter Kraft^{48

86}, Vessela N Kristensen^{87

88}, Allison W Kurian^{79

80}, Diether Lambrechts^{25

26}, Loic Le Marchand⁸⁹, Martha Linet⁸², Jan Lubiński⁷⁷, Arto Mannermaa^{83

84

85}, Siranoush Manoukian⁹⁰, Sara Margolin^{71

91}, John W M Martens⁷⁴, Dimitrios Mavroudis⁹², Rebecca Mayes¹⁸, Alfons Meindl⁹³, Roger L Milne^{61

62

63}, Susan L Neuhausen⁹⁴, Heli Nevanlinna⁹⁵, William G Newman^{51

52}, Sune F Nielsen^{29

30}, Børge G Nordestgaard^{29

30

31}, Nadia Obi⁹⁶, Andrew F Olshan⁹⁷, Janet E Olson⁷³, Håkan Olsson¹⁷, Ester Orban⁹⁸, Tjoung-Won Park-Simon²⁸, Paolo Peterlongo⁹⁹, Dijana Plaseska-Karanfilska¹⁰⁰, Katri Pylkäs^{101

102}, Gad Rennert¹⁰³, Hedy S Rennert¹⁰³, Kathryn J Ruddy¹⁰⁴, Emmanouil Saloustros¹⁰⁵, Dale P Sandler¹⁰⁶, Elinor J Sawyer¹⁰⁷, Rita K Schmutzler^{67

68

108}, Christopher Scott⁷³, Xiao-Ou Shu¹⁰⁹, Jacques Simard¹¹⁰, Snezhana Smichkoska¹¹¹, Christof Sohn¹¹², Melissa C Southey^{61

63

113}, John J Spinelli^{114

115}, Jennifer Stone^{62

116}, Rulla M Tamimi^{48

117}, Jack A Taylor^{106

118}, Rob A E M Tollenaar¹¹⁹, Ian Tomlinson^{120

121}, Melissa A Troester⁹⁷, Thérèse Truong⁶⁶, Celine M Vachon¹²², Elke M van Veen^{51

52}, Sophia S Wang^{123

124}, Clarice R Weinberg¹²⁵, Camilla Wendt⁹¹, Hans Wildiers⁵⁶, Robert Winqvist^{101

102}, Alicja Wolk^{70

126}, Wei Zheng¹⁰⁹, Argyrios Ziogas¹³, Alison M Dunning¹⁸, Paul D P Pharoah^{9

18}, Douglas F Easton^{9

18}, A Forbes Howie¹²⁷, Julian Peto⁸, Isabel Dos-Santos-Silva⁸, Anthony J Swerdlow^{7

128}, Jenny Chang-Claude^{4

98}, Marjanka K Schmidt^{3

129}, Nick Orr², Olivia Fletcher⁶

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

^# Contributed equally.

PMID: 33495599
PMCID: PMC7884683
DOI: 10.1038/s41416-020-01185-w

CYP3A7*1C allele: linking premenopausal oestrone and progesterone levels with risk of hormone receptor-positive breast cancers

Nichola Johnson et al. Br J Cancer. 2021 Feb.

. 2021 Feb;124(4):842-854.

doi: 10.1038/s41416-020-01185-w. Epub 2021 Jan 26.

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

^# Contributed equally.

PMID: 33495599
PMCID: PMC7884683
DOI: 10.1038/s41416-020-01185-w

Abstract

Background: Epidemiological studies provide strong evidence for a role of endogenous sex hormones in the aetiology of breast cancer. The aim of this analysis was to identify genetic variants that are associated with urinary sex-hormone levels and breast cancer risk.

Methods: We carried out a genome-wide association study of urinary oestrone-3-glucuronide and pregnanediol-3-glucuronide levels in 560 premenopausal women, with additional analysis of progesterone levels in 298 premenopausal women. To test for the association with breast cancer risk, we carried out follow-up genotyping in 90,916 cases and 89,893 controls from the Breast Cancer Association Consortium. All women were of European ancestry.

Results: For pregnanediol-3-glucuronide, there were no genome-wide significant associations; for oestrone-3-glucuronide, we identified a single peak mapping to the CYP3A locus, annotated by rs45446698. The minor rs45446698-C allele was associated with lower oestrone-3-glucuronide (-49.2%, 95% CI -56.1% to -41.1%, P = 3.1 × 10^-18); in follow-up analyses, rs45446698-C was also associated with lower progesterone (-26.7%, 95% CI -39.4% to -11.6%, P = 0.001) and reduced risk of oestrogen and progesterone receptor-positive breast cancer (OR = 0.86, 95% CI 0.82-0.91, P = 6.9 × 10^-8).

Conclusions: The CYP3A7*1C allele is associated with reduced risk of hormone receptor-positive breast cancer possibly mediated via an effect on the metabolism of endogenous sex hormones in premenopausal women.

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Conflict of interest statement

M.W.B. conducts research funded by Amgen, Novartis and Pfizer. P.A.F. conducts research funded by Amgen, Novartis and Pfizer. He received honoraria from Roche, Novartis and Pfizer. A.W.K.’s institution has received research funding from Myriad Genetics for an unrelated project (funding dates 2017–2019). P.H., .P.D.P.P., O.F., K.C. and A.C. are members of the Editorial Board of BJC. The remaining authors declare no competing interests.

Figures

**Fig. 1. Manhattan plot of single-nucleotide polymorphism (SNP) associations with luteal-phase urinary oestrone-3-glucuronide levels in 560 premenopausal women.**
–log₁₀ P values for SNP associations are plotted against the genomic coordinates (hg19). The red line indicates the conventionally accepted threshold for genome-wide significance (P = 1 × 10⁻⁸).

See this image and copyright information in PMC

References

1. Chen WY. Exogenous and endogenous hormones and breast cancer. Best. Pr. Res Clin. Endocrinol. Metab. 2008;22:573–585. doi: 10.1016/j.beem.2008.08.001. - DOI - PMC - PubMed
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CYP3A7*1C allele: linking premenopausal oestrone and progesterone levels with risk of hormone receptor-positive breast cancers

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CYP3A7*1C allele: linking premenopausal oestrone and progesterone levels with risk of hormone receptor-positive breast cancers

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