Germline HOXB13 mutations p.G84E and p.R217C do not confer an increased breast cancer risk

Jingjing Liu^{1

2}, Wendy J C Prager-van der Smissen¹, J Margriet Collée³, Manjeet K Bolla⁴, Qin Wang⁴, Kyriaki Michailidou^{4

5

6}, Joe Dennis⁴, Thomas U Ahearn⁷, Kristiina Aittomäki⁸, Christine B Ambrosone⁹, Irene L Andrulis^{10

11}, Hoda Anton-Culver¹², Natalia N Antonenkova¹³, Volker Arndt¹⁴, Norbert Arnold^{15

16}, Kristan J Aronson¹⁷, Annelie Augustinsson¹⁸, Päivi Auvinen^{19

20

21}, Heiko Becher^{22

23}, Matthias W Beckmann²⁴, Sabine Behrens²⁵, Marina Bermisheva²⁶, Leslie Bernstein²⁷, Natalia V Bogdanova^{13

28

29}, Nadja Bogdanova-Markov³⁰, Stig E Bojesen^{31

32

33}, Hiltrud Brauch^{34

35

36}, Hermann Brenner^{14

36

37}, Ignacio Briceno^{38

39}, Sara Y Brucker⁴⁰, Thomas Brüning⁴¹, Barbara Burwinkel^{42

43}, Qiuyin Cai⁴⁴, Hui Cai⁴⁴, Daniele Campa^{25

45}, Federico Canzian⁴⁶, Jose E Castelao⁴⁷, Jenny Chang-Claude^{25

48}, Stephen J Chanock⁷, Ji-Yeob Choi^{49

50}, Melissa Christiaens⁵¹, Christine L Clarke⁵²; NBCS Collaborators; Fergus J Couch⁵³, Kamila Czene⁵⁴, Mary B Daly⁵⁵, Peter Devilee^{56

57}, Isabel Dos-Santos-Silva⁵⁸, Miriam Dwek⁵⁹, Diana M Eccles⁶⁰, A Heather Eliassen^{61

62}, Peter A Fasching^{24

63}, Jonine Figueroa^{7

64

65}, Henrik Flyger⁶⁶, Lin Fritschi⁶⁷, Manuela Gago-Dominguez^{68

69}, Susan M Gapstur⁷⁰, Montserrat García-Closas⁷, José A García-Sáenz⁷¹, Mia M Gaudet⁷⁰, Graham G Giles^{72

73

74}, Mark S Goldberg^{75

76}, David E Goldgar⁷⁷, Pascal Guénel⁷⁸, Christopher A Haiman⁷⁹, Niclas Håkansson⁸⁰, Per Hall^{54

81}, Patricia A Harrington⁸², Steven N Hart⁸³, Mikael Hartman^{84

85}, Peter Hillemanns²⁹, John L Hopper⁷³, Ming-Feng Hou⁸⁶, David J Hunter^{62

87

88}, Dezheng Huo⁸⁹; ABCTB Investigators; Hidemi Ito^{90

91}, Motoki Iwasaki⁹², Milena Jakimovska⁹³, Anna Jakubowska^{94

95}, Esther M John⁹⁶, Rudolf Kaaks²⁵, Daehee Kang^{49

50

97}, Renske Keeman⁹⁸, Elza Khusnutdinova^{26

99}, Sung-Won Kim¹⁰⁰, Peter Kraft^{62

87}, Vessela N Kristensen¹⁰¹, Allison W Kurian^{96

102}, Loic Le Marchand¹⁰³, Jingmei Li¹⁰⁴, Annika Lindblom^{105

106}, Artitaya Lophatananon¹⁰⁷, Robert N Luben¹⁰⁸, Jan Lubiński⁹⁴, Arto Mannermaa^{21

109

110}, Mehdi Manoochehri¹¹¹, Siranoush Manoukian¹¹², Sara Margolin^{81

113}, Shivaani Mariapun¹¹⁴, Keitaro Matsuo^{90

91}, Tabea Maurer⁴⁸, Dimitrios Mavroudis¹¹⁵, Alfons Meindl¹¹⁶, Usha Menon¹¹⁷, Roger L Milne^{72

73

74}, Kenneth Muir¹⁰⁷, Anna Marie Mulligan^{118

119}, Susan L Neuhausen²⁷, Heli Nevanlinna¹²⁰, Kenneth Offit^{121

122}, Olufunmilayo I Olopade⁸⁹, Janet E Olson⁸³, Håkan Olsson¹⁸, Nick Orr^{123

124}, Sue K Park^{49

50

97}, Paolo Peterlongo¹²⁵, Julian Peto⁵⁸, Dijana Plaseska-Karanfilska⁹³, Nadege Presneau⁵⁹, Brigitte Rack¹²⁶, Rohini Rau-Murthy¹²², Gad Rennert¹²⁷, Hedy S Rennert¹²⁷, Valerie Rhenius⁸², Atocha Romero¹²⁸, Matthias Ruebner¹²⁹, Emmanouil Saloustros¹³⁰, Rita K Schmutzler^{131

132

133}, Andreas Schneeweiss^{43

134}, Christopher Scott⁸³, Mitul Shah⁸², Chen-Yang Shen^{135

136}, Xiao-Ou Shu⁴⁴, Jacques Simard¹³⁷, Christof Sohn¹³⁴, Melissa C Southey^{72

74

138}, John J Spinelli^{139

140}, Rulla M Tamimi^{61

62

87}, William J Tapper⁶⁰, Soo H Teo^{141

142}, Mary Beth Terry¹⁴³, Diana Torres^{38

111}, Thérèse Truong⁷⁸, Michael Untch¹⁴⁴, Celine M Vachon¹⁴⁵, Christi J van Asperen¹⁴⁶, Alicja Wolk^{80

147}, Taiki Yamaji⁹², Wei Zheng⁴⁴, Argyrios Ziogas¹², Elad Ziv¹⁴⁸, Gabriela Torres-Mejía¹⁴⁹, Thilo Dörk²⁹, Anthony J Swerdlow^{150

151}, Ute Hamann¹¹¹, Marjanka K Schmidt^{98

152}, Alison M Dunning⁸², Paul D P Pharoah^{4

82}, Douglas F Easton^{4

82}, Maartje J Hooning¹, John W M Martens¹, Antoinette Hollestelle¹⁵³

Collaborators, Affiliations

Collaborators

Kristine K Sahlberg, Anne-Lise Børresen-Dale, 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, Tone F Bathen, Elin Borgen, Britt Fritzman, Øystein Garred, Gry Aarum Geitvik, Solveig Hofvind, Anita Langerød, Ole Christian Lingjærde, Gunhild Mari Mælandsmo, Hege G Russnes, Helle Kristine Skjerven, Therese Sørlie, Grethe I Grenaker Alnæs, Christine Clarke, Deborah Marsh, Rodney Scott, Robert Baxter, Desmond Yip, Jane Carpenter, Alison Davis, Nirmala Pathmanathan, Peter Simpson, Dinny Graham, Mythily Sachchithananthan

Affiliations

¹ Department of Medical Oncology, Family Cancer Clinic, Erasmus MC Cancer Institute, Rotterdam, The Netherlands.
² Institute of Medical and Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, China.
³ Department of Clinical Genetics, Erasmus University Medical Center, Rotterdam, The Netherlands.
⁴ Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.
⁵ Biostatistics Unit, The Cyprus Institute of Neurology & Genetics, Nicosia, Cyprus.
⁶ Cyprus School of Molecular Medicine, The Cyprus Institute of Neurology & Genetics, Nicosia, Cyprus.
⁷ Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Department of Health and Human Services, Bethesda, MD, USA.
⁸ Department of Clinical Genetics, Helsinki University Hospital, University of Helsinki, Helsinki, Finland.
⁹ Roswell Park Cancer Institute, Buffalo, NY, USA.
¹⁰ Fred A. Litwin Center for Cancer Genetics, Lunenfeld-Tanenbaum Research Institute of Mount Sinai Hospital, Toronto, ON, Canada.
¹¹ Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada.
¹² Department of Epidemiology, Genetic Epidemiology Research Institute, University of California Irvine, Irvine, CA, USA.
¹³ N.N. Alexandrov Research Institute of Oncology and Medical Radiology, Minsk, Belarus.
¹⁴ Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany.
¹⁵ Department of Gynaecology and Obstetrics, University Hospital of Schleswig-Holstein, Campus Kiel, Christian-Albrechts University Kiel, Kiel, Germany.
¹⁶ Institute of Clinical Molecular Biology, University Hospital of Schleswig-Holstein, Campus Kiel, Christian-Albrechts University Kiel, Kiel, Germany.
¹⁷ Department of Public Health Sciences, and Cancer Research Institute, Queen's University, Kingston, ON, Canada.
¹⁸ Department of Cancer Epidemiology, Clinical Sciences, Lund University, Lund, Sweden.
¹⁹ Cancer Center, Kuopio University Hospital, Kuopio, Finland.
²⁰ Institute of Clinical Medicine, Oncology, University of Eastern Finland, Kuopio, Finland.
²¹ Translational Cancer Research Area, University of Eastern Finland, Kuopio, Finland.
²² Institute of Medical Biometry and Epidemiology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
²³ Institute of Biometry and Clinical Epidemiology, Charité -Universitätsmedizin Berlin, Berlin, Germany.
²⁴ Department of Gynecology and Obstetrics, Comprehensive Cancer Center ER-EMN, University Hospital Erlangen, Friedrich-Alexander-University Erlangen-Nuremberg, Erlangen, Germany.
²⁵ Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
²⁶ Institute of Biochemistry and Genetics, Ufa Federal Research Centre of the Russian Academy of Sciences, Ufa, Russia.
²⁷ Department of Population Sciences, Beckman Research Institute of City of Hope, Duarte, CA, USA.
²⁸ Department of Radiation Oncology, Hannover Medical School, Hannover, Germany.
²⁹ Gynaecology Research Unit, Hannover Medical School, Hannover, Germany.
³⁰ Institute of Human Genetics, University of Münster, Münster, Germany.
³¹ Copenhagen General Population Study, Herlev and Gentofte Hospital, Copenhagen University Hospital, Herlev, Denmark.
³² Department of Clinical Biochemistry, Herlev and Gentofte Hospital, Copenhagen University Hospital, Herlev, Denmark.
³³ Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
³⁴ Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology, Stuttgart, Germany.
³⁵ iFIT-Cluster of Excellence, University of Tübingen, Tübingen, Germany.
³⁶ German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Partner Site Tübingen, Tübingen, Germany.
³⁷ Division of Preventive Oncology, German Cancer Research Center (DKFZ) and National Center for Tumor Diseases (NCT), Heidelberg, Germany.
³⁸ Institute of Human Genetics, Pontificia Universidad Javeriana, Bogota, Colombia.
³⁹ Medical Faculty, Universidad de La Sabana, Bogota, Colombia.
⁴⁰ Department of Gynecology and Obstetrics, University of Tübingen, Tübingen, Germany.
⁴¹ Institute for Prevention and Occupational Medicine of the German Social Accident Insurance, Institute of the Ruhr University Bochum (IPA), Bochum, Germany.
⁴² Molecular Epidemiology Group, C080, German Cancer Research Center (DKFZ), Heidelberg, Germany.
⁴³ Molecular Biology of Breast Cancer, University Womens Clinic Heidelberg, University of Heidelberg, Heidelberg, Germany.
⁴⁴ Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, TN, USA.
⁴⁵ Department of Biology, University of Pisa, Pisa, Italy.
⁴⁶ Genomic Epidemiology Group, German Cancer Research Center (DKFZ), Heidelberg, Germany.
⁴⁷ Oncology and Genetics Unit, Instituto de Investigacion Sanitaria Galicia Sur (IISGS), Xerencia de Xestion Integrada de Vigo-SERGAS, Vigo, Spain.
⁴⁸ Cancer Epidemiology Group, University Cancer Center Hamburg (UCCH), University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
⁴⁹ Department of Biomedical Sciences, Seoul National University Graduate School, Seoul, Korea.
⁵⁰ Cancer Research Institute, Seoul National University, Seoul, Korea.
⁵¹ Leuven Multidisciplinary Breast Center, Department of Oncology, Leuven Cancer Institute, University Hospitals Leuven, Leuven, Belgium.
⁵² Westmead Institute for Medical Research, University of Sydney, Sydney, New South Wales, Australia.
⁵³ Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA.
⁵⁴ Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
⁵⁵ Department of Clinical Genetics, Fox Chase Cancer Center, Philadelphia, PA, USA.
⁵⁶ Department of Pathology, Leiden University Medical Center, Leiden, The Netherlands.
⁵⁷ Department of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands.
⁵⁸ Department of Non-Communicable Disease Epidemiology, London School of Hygiene and Tropical Medicine, London, UK.
⁵⁹ School of Life Sciences, University of Westminster, London, UK.
⁶⁰ Faculty of Medicine, University of Southampton, Southampton, UK.
⁶¹ Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
⁶² Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
⁶³ David Geffen School of Medicine, Department of Medicine Division of Hematology and Oncology, University of California at Los Angeles, Los Angeles, CA, USA.
⁶⁴ Usher Institute of Population Health Sciences and Informatics, The University of Edinburgh, Edinburgh, UK.
⁶⁵ Cancer Research UK Edinburgh Centre, The University of Edinburgh, Edinburgh, UK.
⁶⁶ Department of Breast Surgery, Herlev and Gentofte Hospital, Copenhagen University Hospital, Herlev, Denmark.
⁶⁷ School of Public Health, Curtin University, Perth, Western Australia, Australia.
⁶⁸ Genomic Medicine Group, Galician Foundation of Genomic Medicine, Instituto de Investigación Sanitaria de Santiago de Compostela (IDIS), Complejo Hospitalario Universitario de Santiago, SERGAS, Santiago de Compostela, Spain.
⁶⁹ Moores Cancer Center, University of California San Diego, La Jolla, CA, USA.
⁷⁰ Behavioral and Epidemiology Research Group, American Cancer Society, Atlanta, GA, USA.
⁷¹ Medical Oncology Department, Hospital Clínico San Carlos, Instituto de Investigación Sanitaria San Carlos (IdISSC), Centro Investigación Biomédica en Red de Cáncer (CIBERONC), Madrid, Spain.
⁷² Cancer Epidemiology Division, Cancer Council Victoria, Melbourne, Victoria, Australia.
⁷³ Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, Victoria, Australia.
⁷⁴ Precision Medicine, School of Clinical Sciences at Monash Health, Monash University, Clayton, Victoria, Australia.
⁷⁵ Department of Medicine, McGill University, Montréal, QC, Canada.
⁷⁶ Division of Clinical Epidemiology, Royal Victoria Hospital, McGill University, Montréal, QC, Canada.
⁷⁷ Department of Dermatology, Huntsman Cancer Institute, University of Utah School of Medicine, Salt Lake City, UT, USA.
⁷⁸ Cancer & Environment Group, Center for Research in Epidemiology and Population Health (CESP), INSERM, University Paris-Sud, University Paris-Saclay, Villejuif, France.
⁷⁹ Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
⁸⁰ Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.
⁸¹ Department of Oncology, Södersjukhuset, Stockholm, Sweden.
⁸² Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Cambridge, UK.
⁸³ Department of Health Sciences Research, Mayo Clinic, Rochester, MN, USA.
⁸⁴ Saw Swee Hock School of Public Health, National University of Singapore and National University Health System, Singapore, Singapore.
⁸⁵ Department of Surgery, National University Health System, Singapore, Singapore.
⁸⁶ Department of Surgery, Kaohsiung Municipal Hsiao-Kang Hospital, Kaohsiung, Taiwan.
⁸⁷ Program in Genetic Epidemiology and Statistical Genetics, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
⁸⁸ Nuffield Department of Population Health, University of Oxford, Oxford, UK.
⁸⁹ Center for Clinical Cancer Genetics, The University of Chicago, Chicago, IL, USA.
⁹⁰ Division of Cancer Epidemiology and Prevention, Aichi Cancer Center Research Institute, Nagoya, Japan.
⁹¹ Division of Cancer Epidemiology, Nagoya University Graduate School of Medicine, Nagoya, Japan.
⁹² Division of Epidemiology, Center for Public Health Sciences, National Cancer Center, Tokyo, Japan.
⁹³ Research Centre for Genetic Engineering and Biotechnology 'Georgi D. Efremov', MASA, Skopje, Republic of North Macedonia.
⁹⁴ Department of Genetics and Pathology, Pomeranian Medical University, Szczecin, Poland.
⁹⁵ Independent Laboratory of Molecular Biology and Genetic Diagnostics, Pomeranian Medical University, Szczecin, Poland.
⁹⁶ Department of Medicine, Division of Oncology, Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA, USA.
⁹⁷ Department of Preventive Medicine, Seoul National University College of Medicine, Seoul, Korea.
⁹⁸ Division of Molecular Pathology, The Netherlands Cancer Institute - Antoni van Leeuwenhoek Hospital, Amsterdam, The Netherlands.
⁹⁹ Saint Petersburg State University, Saint-Petersburg, Russia.
¹⁰⁰ Department of Surgery, Daerim Saint Mary's Hospital, Seoul, Korea.
¹⁰¹ Department of Medical Genetics, Oslo University Hospital and University of Oslo, Oslo, Norway.
¹⁰² Department of Health Research and Policy, Stanford University School of Medicine, Stanford, CA, USA.
¹⁰³ Epidemiology Program, University of Hawaii Cancer Center, Honolulu, HI, USA.
¹⁰⁴ Human Genetics Division, Genome Institute of Singapore, Singapore, Singapore.
¹⁰⁵ Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.
¹⁰⁶ Department of Clinical Genetics, Karolinska University Hospital, Stockholm, Sweden.
¹⁰⁷ Division of Population Health, Health Services Research and Primary Care, School of Health Sciences, Faculty of Biology, Medicine and Health, The University of Manchester, Manchester, UK.
¹⁰⁸ Clinical Gerontology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.
¹⁰⁹ Institute of Clinical Medicine, Pathology and Forensic Medicine, University of Eastern Finland, Kuopio, Finland.
¹¹⁰ Imaging Center, Department of Clinical Pathology, Kuopio University Hospital, Kuopio, Finland.
¹¹¹ Molecular Genetics of Breast Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany.
¹¹² Unit of Medical Genetics, Department of Medical Oncology and Hematology, Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, Milan, Italy.
¹¹³ Department of Clinical Science and Education, Södersjukhuset, Karolinska Institutet, Stockholm, Sweden.
¹¹⁴ Cancer Research Malaysia, Subang Jaya, Selangor, Malaysia.
¹¹⁵ Department of Medical Oncology, University Hospital of Heraklion, Heraklion, Greece.
¹¹⁶ Department of Gynecology and Obstetrics, University of Munich, Campus Großhadern, Munich, Germany.
¹¹⁷ MRC Clinical Trials Unit at UCL, Institute of Clinical Trials & Methodology, University College London, London, UK.
¹¹⁸ Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada.
¹¹⁹ Laboratory Medicine Program, University Health Network, Toronto, ON, Canada.
¹²⁰ Department of Obstetrics and Gynecology, Helsinki University Hospital, University of Helsinki, Helsinki, Finland.
¹²¹ Clinical Genetics Research Lab, Department of Cancer Biology and Genetics, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
¹²² Clinical Genetics Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
¹²³ The Breast Cancer Now Toby Robins Research Centre, The Institute of Cancer Research, London, UK.
¹²⁴ Centre for Cancer Research and Cell Biology, Queen's University Belfast, Belfast, Ireland, UK.
¹²⁵ Genome Diagnostics Program, IFOM - the FIRC Institute for Molecular Oncology, Milan, Italy.
¹²⁶ Department of Gynaecology and Obstetrics, University Hospital Ulm, Ulm, Germany.
¹²⁷ Clalit National Cancer Control Center, Carmel Medical Center and Technion Faculty of Medicine, Haifa, Israel.
¹²⁸ Medical Oncology Department, Hospital Universitario Puerta de Hierro, Madrid, Spain.
¹²⁹ Department of Gynaecology and Obstetrics, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nuremberg, Comprehensive Cancer Center Erlangen-EMN, Erlangen, Germany.
¹³⁰ Department of Oncology, University Hospital of Larissa, Larissa, Greece.
¹³¹ Center for Familial Breast and Ovarian Cancer, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany.
¹³² Center for Integrated Oncology (CIO), Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany.
¹³³ Center for Molecular Medicine Cologne (CMMC), Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany.
¹³⁴ National Center for Tumor Diseases, University Hospital and German Cancer Research Center, Heidelberg, Germany.
¹³⁵ Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan.
¹³⁶ School of Public Health, China Medical University, Taichung, Taiwan.
¹³⁷ Genomics Center, Centre Hospitalier Universitaire de Québec - Université Laval Research Center, Québec City, QC, Canada.
¹³⁸ Department of Clinical Pathology, The University of Melbourne, Melbourne, Victoria, Australia.
¹³⁹ Population Oncology, BC Cancer, Vancouver, BC, Canada.
¹⁴⁰ School of Population and Public Health, University of British Columbia, Vancouver, BC, Canada.
¹⁴¹ Breast Cancer Research Programme, Cancer Research Malaysia, Subang Jaya, Selangor, Malaysia.
¹⁴² Department of Surgery, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia.
¹⁴³ Department of Epidemiology, Mailman School of Public Health, Columbia University, New York, NY, USA.
¹⁴⁴ Department of Gynecology and Obstetrics, Helios Clinics Berlin-Buch, Berlin, Germany.
¹⁴⁵ Department of Health Science Research, Division of Epidemiology, Mayo Clinic, Rochester, MN, USA.
¹⁴⁶ Department of Clinical Genetics, Leiden University Medical Center, Leiden, The Netherlands.
¹⁴⁷ Department of Surgical Sciences, Uppsala University, Uppsala, Sweden.
¹⁴⁸ Department of Medicine, Institute for Human Genetics, UCSF Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA, USA.
¹⁴⁹ Center for Population Health Research, National Institute of Public Health, Cuernavaca, Morelos, Mexico.
¹⁵⁰ Division of Genetics and Epidemiology, The Institute of Cancer Research, London, UK.
¹⁵¹ Division of Breast Cancer Research, The Institute of Cancer Research, London, UK.
¹⁵² Division of Psychosocial Research and Epidemiology, The Netherlands Cancer Institute - Antoni van Leeuwenhoek hospital, Amsterdam, The Netherlands.
¹⁵³ Department of Medical Oncology, Family Cancer Clinic, Erasmus MC Cancer Institute, Rotterdam, The Netherlands. a.hollestelle@erasmusmc.nl.

PMID: 32546843
PMCID: PMC7297796
DOI: 10.1038/s41598-020-65665-y

Germline HOXB13 mutations p.G84E and p.R217C do not confer an increased breast cancer risk

Jingjing Liu et al. Sci Rep. 2020.

. 2020 Jun 16;10(1):9688.

doi: 10.1038/s41598-020-65665-y.

Authors

Collaborators

Kristine K Sahlberg, Anne-Lise Børresen-Dale, 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, Tone F Bathen, Elin Borgen, Britt Fritzman, Øystein Garred, Gry Aarum Geitvik, Solveig Hofvind, Anita Langerød, Ole Christian Lingjærde, Gunhild Mari Mælandsmo, Hege G Russnes, Helle Kristine Skjerven, Therese Sørlie, Grethe I Grenaker Alnæs, Christine Clarke, Deborah Marsh, Rodney Scott, Robert Baxter, Desmond Yip, Jane Carpenter, Alison Davis, Nirmala Pathmanathan, Peter Simpson, Dinny Graham, Mythily Sachchithananthan

Affiliations

¹ Department of Medical Oncology, Family Cancer Clinic, Erasmus MC Cancer Institute, Rotterdam, The Netherlands.
² Institute of Medical and Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, China.
³ Department of Clinical Genetics, Erasmus University Medical Center, Rotterdam, The Netherlands.
⁴ Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.
⁵ Biostatistics Unit, The Cyprus Institute of Neurology & Genetics, Nicosia, Cyprus.
⁶ Cyprus School of Molecular Medicine, The Cyprus Institute of Neurology & Genetics, Nicosia, Cyprus.
⁷ Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Department of Health and Human Services, Bethesda, MD, USA.
⁸ Department of Clinical Genetics, Helsinki University Hospital, University of Helsinki, Helsinki, Finland.
⁹ Roswell Park Cancer Institute, Buffalo, NY, USA.
¹⁰ Fred A. Litwin Center for Cancer Genetics, Lunenfeld-Tanenbaum Research Institute of Mount Sinai Hospital, Toronto, ON, Canada.
¹¹ Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada.
¹² Department of Epidemiology, Genetic Epidemiology Research Institute, University of California Irvine, Irvine, CA, USA.
¹³ N.N. Alexandrov Research Institute of Oncology and Medical Radiology, Minsk, Belarus.
¹⁴ Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany.
¹⁵ Department of Gynaecology and Obstetrics, University Hospital of Schleswig-Holstein, Campus Kiel, Christian-Albrechts University Kiel, Kiel, Germany.
¹⁶ Institute of Clinical Molecular Biology, University Hospital of Schleswig-Holstein, Campus Kiel, Christian-Albrechts University Kiel, Kiel, Germany.
¹⁷ Department of Public Health Sciences, and Cancer Research Institute, Queen's University, Kingston, ON, Canada.
¹⁸ Department of Cancer Epidemiology, Clinical Sciences, Lund University, Lund, Sweden.
¹⁹ Cancer Center, Kuopio University Hospital, Kuopio, Finland.
²⁰ Institute of Clinical Medicine, Oncology, University of Eastern Finland, Kuopio, Finland.
²¹ Translational Cancer Research Area, University of Eastern Finland, Kuopio, Finland.
²² Institute of Medical Biometry and Epidemiology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
²³ Institute of Biometry and Clinical Epidemiology, Charité -Universitätsmedizin Berlin, Berlin, Germany.
²⁴ Department of Gynecology and Obstetrics, Comprehensive Cancer Center ER-EMN, University Hospital Erlangen, Friedrich-Alexander-University Erlangen-Nuremberg, Erlangen, Germany.
²⁵ Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
²⁶ Institute of Biochemistry and Genetics, Ufa Federal Research Centre of the Russian Academy of Sciences, Ufa, Russia.
²⁷ Department of Population Sciences, Beckman Research Institute of City of Hope, Duarte, CA, USA.
²⁸ Department of Radiation Oncology, Hannover Medical School, Hannover, Germany.
²⁹ Gynaecology Research Unit, Hannover Medical School, Hannover, Germany.
³⁰ Institute of Human Genetics, University of Münster, Münster, Germany.
³¹ Copenhagen General Population Study, Herlev and Gentofte Hospital, Copenhagen University Hospital, Herlev, Denmark.
³² Department of Clinical Biochemistry, Herlev and Gentofte Hospital, Copenhagen University Hospital, Herlev, Denmark.
³³ Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
³⁴ Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology, Stuttgart, Germany.
³⁵ iFIT-Cluster of Excellence, University of Tübingen, Tübingen, Germany.
³⁶ German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Partner Site Tübingen, Tübingen, Germany.
³⁷ Division of Preventive Oncology, German Cancer Research Center (DKFZ) and National Center for Tumor Diseases (NCT), Heidelberg, Germany.
³⁸ Institute of Human Genetics, Pontificia Universidad Javeriana, Bogota, Colombia.
³⁹ Medical Faculty, Universidad de La Sabana, Bogota, Colombia.
⁴⁰ Department of Gynecology and Obstetrics, University of Tübingen, Tübingen, Germany.
⁴¹ Institute for Prevention and Occupational Medicine of the German Social Accident Insurance, Institute of the Ruhr University Bochum (IPA), Bochum, Germany.
⁴² Molecular Epidemiology Group, C080, German Cancer Research Center (DKFZ), Heidelberg, Germany.
⁴³ Molecular Biology of Breast Cancer, University Womens Clinic Heidelberg, University of Heidelberg, Heidelberg, Germany.
⁴⁴ Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, TN, USA.
⁴⁵ Department of Biology, University of Pisa, Pisa, Italy.
⁴⁶ Genomic Epidemiology Group, German Cancer Research Center (DKFZ), Heidelberg, Germany.
⁴⁷ Oncology and Genetics Unit, Instituto de Investigacion Sanitaria Galicia Sur (IISGS), Xerencia de Xestion Integrada de Vigo-SERGAS, Vigo, Spain.
⁴⁸ Cancer Epidemiology Group, University Cancer Center Hamburg (UCCH), University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
⁴⁹ Department of Biomedical Sciences, Seoul National University Graduate School, Seoul, Korea.
⁵⁰ Cancer Research Institute, Seoul National University, Seoul, Korea.
⁵¹ Leuven Multidisciplinary Breast Center, Department of Oncology, Leuven Cancer Institute, University Hospitals Leuven, Leuven, Belgium.
⁵² Westmead Institute for Medical Research, University of Sydney, Sydney, New South Wales, Australia.
⁵³ Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA.
⁵⁴ Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
⁵⁵ Department of Clinical Genetics, Fox Chase Cancer Center, Philadelphia, PA, USA.
⁵⁶ Department of Pathology, Leiden University Medical Center, Leiden, The Netherlands.
⁵⁷ Department of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands.
⁵⁸ Department of Non-Communicable Disease Epidemiology, London School of Hygiene and Tropical Medicine, London, UK.
⁵⁹ School of Life Sciences, University of Westminster, London, UK.
⁶⁰ Faculty of Medicine, University of Southampton, Southampton, UK.
⁶¹ Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
⁶² Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
⁶³ David Geffen School of Medicine, Department of Medicine Division of Hematology and Oncology, University of California at Los Angeles, Los Angeles, CA, USA.
⁶⁴ Usher Institute of Population Health Sciences and Informatics, The University of Edinburgh, Edinburgh, UK.
⁶⁵ Cancer Research UK Edinburgh Centre, The University of Edinburgh, Edinburgh, UK.
⁶⁶ Department of Breast Surgery, Herlev and Gentofte Hospital, Copenhagen University Hospital, Herlev, Denmark.
⁶⁷ School of Public Health, Curtin University, Perth, Western Australia, Australia.
⁶⁸ Genomic Medicine Group, Galician Foundation of Genomic Medicine, Instituto de Investigación Sanitaria de Santiago de Compostela (IDIS), Complejo Hospitalario Universitario de Santiago, SERGAS, Santiago de Compostela, Spain.
⁶⁹ Moores Cancer Center, University of California San Diego, La Jolla, CA, USA.
⁷⁰ Behavioral and Epidemiology Research Group, American Cancer Society, Atlanta, GA, USA.
⁷¹ Medical Oncology Department, Hospital Clínico San Carlos, Instituto de Investigación Sanitaria San Carlos (IdISSC), Centro Investigación Biomédica en Red de Cáncer (CIBERONC), Madrid, Spain.
⁷² Cancer Epidemiology Division, Cancer Council Victoria, Melbourne, Victoria, Australia.
⁷³ Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, Victoria, Australia.
⁷⁴ Precision Medicine, School of Clinical Sciences at Monash Health, Monash University, Clayton, Victoria, Australia.
⁷⁵ Department of Medicine, McGill University, Montréal, QC, Canada.
⁷⁶ Division of Clinical Epidemiology, Royal Victoria Hospital, McGill University, Montréal, QC, Canada.
⁷⁷ Department of Dermatology, Huntsman Cancer Institute, University of Utah School of Medicine, Salt Lake City, UT, USA.
⁷⁸ Cancer & Environment Group, Center for Research in Epidemiology and Population Health (CESP), INSERM, University Paris-Sud, University Paris-Saclay, Villejuif, France.
⁷⁹ Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
⁸⁰ Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.
⁸¹ Department of Oncology, Södersjukhuset, Stockholm, Sweden.
⁸² Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Cambridge, UK.
⁸³ Department of Health Sciences Research, Mayo Clinic, Rochester, MN, USA.
⁸⁴ Saw Swee Hock School of Public Health, National University of Singapore and National University Health System, Singapore, Singapore.
⁸⁵ Department of Surgery, National University Health System, Singapore, Singapore.
⁸⁶ Department of Surgery, Kaohsiung Municipal Hsiao-Kang Hospital, Kaohsiung, Taiwan.
⁸⁷ Program in Genetic Epidemiology and Statistical Genetics, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
⁸⁸ Nuffield Department of Population Health, University of Oxford, Oxford, UK.
⁸⁹ Center for Clinical Cancer Genetics, The University of Chicago, Chicago, IL, USA.
⁹⁰ Division of Cancer Epidemiology and Prevention, Aichi Cancer Center Research Institute, Nagoya, Japan.
⁹¹ Division of Cancer Epidemiology, Nagoya University Graduate School of Medicine, Nagoya, Japan.
⁹² Division of Epidemiology, Center for Public Health Sciences, National Cancer Center, Tokyo, Japan.
⁹³ Research Centre for Genetic Engineering and Biotechnology 'Georgi D. Efremov', MASA, Skopje, Republic of North Macedonia.
⁹⁴ Department of Genetics and Pathology, Pomeranian Medical University, Szczecin, Poland.
⁹⁵ Independent Laboratory of Molecular Biology and Genetic Diagnostics, Pomeranian Medical University, Szczecin, Poland.
⁹⁶ Department of Medicine, Division of Oncology, Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA, USA.
⁹⁷ Department of Preventive Medicine, Seoul National University College of Medicine, Seoul, Korea.
⁹⁸ Division of Molecular Pathology, The Netherlands Cancer Institute - Antoni van Leeuwenhoek Hospital, Amsterdam, The Netherlands.
⁹⁹ Saint Petersburg State University, Saint-Petersburg, Russia.
¹⁰⁰ Department of Surgery, Daerim Saint Mary's Hospital, Seoul, Korea.
¹⁰¹ Department of Medical Genetics, Oslo University Hospital and University of Oslo, Oslo, Norway.
¹⁰² Department of Health Research and Policy, Stanford University School of Medicine, Stanford, CA, USA.
¹⁰³ Epidemiology Program, University of Hawaii Cancer Center, Honolulu, HI, USA.
¹⁰⁴ Human Genetics Division, Genome Institute of Singapore, Singapore, Singapore.
¹⁰⁵ Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.
¹⁰⁶ Department of Clinical Genetics, Karolinska University Hospital, Stockholm, Sweden.
¹⁰⁷ Division of Population Health, Health Services Research and Primary Care, School of Health Sciences, Faculty of Biology, Medicine and Health, The University of Manchester, Manchester, UK.
¹⁰⁸ Clinical Gerontology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.
¹⁰⁹ Institute of Clinical Medicine, Pathology and Forensic Medicine, University of Eastern Finland, Kuopio, Finland.
¹¹⁰ Imaging Center, Department of Clinical Pathology, Kuopio University Hospital, Kuopio, Finland.
¹¹¹ Molecular Genetics of Breast Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany.
¹¹² Unit of Medical Genetics, Department of Medical Oncology and Hematology, Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, Milan, Italy.
¹¹³ Department of Clinical Science and Education, Södersjukhuset, Karolinska Institutet, Stockholm, Sweden.
¹¹⁴ Cancer Research Malaysia, Subang Jaya, Selangor, Malaysia.
¹¹⁵ Department of Medical Oncology, University Hospital of Heraklion, Heraklion, Greece.
¹¹⁶ Department of Gynecology and Obstetrics, University of Munich, Campus Großhadern, Munich, Germany.
¹¹⁷ MRC Clinical Trials Unit at UCL, Institute of Clinical Trials & Methodology, University College London, London, UK.
¹¹⁸ Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada.
¹¹⁹ Laboratory Medicine Program, University Health Network, Toronto, ON, Canada.
¹²⁰ Department of Obstetrics and Gynecology, Helsinki University Hospital, University of Helsinki, Helsinki, Finland.
¹²¹ Clinical Genetics Research Lab, Department of Cancer Biology and Genetics, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
¹²² Clinical Genetics Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
¹²³ The Breast Cancer Now Toby Robins Research Centre, The Institute of Cancer Research, London, UK.
¹²⁴ Centre for Cancer Research and Cell Biology, Queen's University Belfast, Belfast, Ireland, UK.
¹²⁵ Genome Diagnostics Program, IFOM - the FIRC Institute for Molecular Oncology, Milan, Italy.
¹²⁶ Department of Gynaecology and Obstetrics, University Hospital Ulm, Ulm, Germany.
¹²⁷ Clalit National Cancer Control Center, Carmel Medical Center and Technion Faculty of Medicine, Haifa, Israel.
¹²⁸ Medical Oncology Department, Hospital Universitario Puerta de Hierro, Madrid, Spain.
¹²⁹ Department of Gynaecology and Obstetrics, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nuremberg, Comprehensive Cancer Center Erlangen-EMN, Erlangen, Germany.
¹³⁰ Department of Oncology, University Hospital of Larissa, Larissa, Greece.
¹³¹ Center for Familial Breast and Ovarian Cancer, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany.
¹³² Center for Integrated Oncology (CIO), Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany.
¹³³ Center for Molecular Medicine Cologne (CMMC), Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany.
¹³⁴ National Center for Tumor Diseases, University Hospital and German Cancer Research Center, Heidelberg, Germany.
¹³⁵ Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan.
¹³⁶ School of Public Health, China Medical University, Taichung, Taiwan.
¹³⁷ Genomics Center, Centre Hospitalier Universitaire de Québec - Université Laval Research Center, Québec City, QC, Canada.
¹³⁸ Department of Clinical Pathology, The University of Melbourne, Melbourne, Victoria, Australia.
¹³⁹ Population Oncology, BC Cancer, Vancouver, BC, Canada.
¹⁴⁰ School of Population and Public Health, University of British Columbia, Vancouver, BC, Canada.
¹⁴¹ Breast Cancer Research Programme, Cancer Research Malaysia, Subang Jaya, Selangor, Malaysia.
¹⁴² Department of Surgery, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia.
¹⁴³ Department of Epidemiology, Mailman School of Public Health, Columbia University, New York, NY, USA.
¹⁴⁴ Department of Gynecology and Obstetrics, Helios Clinics Berlin-Buch, Berlin, Germany.
¹⁴⁵ Department of Health Science Research, Division of Epidemiology, Mayo Clinic, Rochester, MN, USA.
¹⁴⁶ Department of Clinical Genetics, Leiden University Medical Center, Leiden, The Netherlands.
¹⁴⁷ Department of Surgical Sciences, Uppsala University, Uppsala, Sweden.
¹⁴⁸ Department of Medicine, Institute for Human Genetics, UCSF Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA, USA.
¹⁴⁹ Center for Population Health Research, National Institute of Public Health, Cuernavaca, Morelos, Mexico.
¹⁵⁰ Division of Genetics and Epidemiology, The Institute of Cancer Research, London, UK.
¹⁵¹ Division of Breast Cancer Research, The Institute of Cancer Research, London, UK.
¹⁵² Division of Psychosocial Research and Epidemiology, The Netherlands Cancer Institute - Antoni van Leeuwenhoek hospital, Amsterdam, The Netherlands.
¹⁵³ Department of Medical Oncology, Family Cancer Clinic, Erasmus MC Cancer Institute, Rotterdam, The Netherlands. a.hollestelle@erasmusmc.nl.

PMID: 32546843
PMCID: PMC7297796
DOI: 10.1038/s41598-020-65665-y

Abstract

In breast cancer, high levels of homeobox protein Hox-B13 (HOXB13) have been associated with disease progression of ER-positive breast cancer patients and resistance to tamoxifen treatment. Since HOXB13 p.G84E is a prostate cancer risk allele, we evaluated the association between HOXB13 germline mutations and breast cancer risk in a previous study consisting of 3,270 familial non-BRCA1/2 breast cancer cases and 2,327 controls from the Netherlands. Although both recurrent HOXB13 mutations p.G84E and p.R217C were not associated with breast cancer risk, the risk estimation for p.R217C was not very precise. To provide more conclusive evidence regarding the role of HOXB13 in breast cancer susceptibility, we here evaluated the association between HOXB13 mutations and increased breast cancer risk within 81 studies of the international Breast Cancer Association Consortium containing 68,521 invasive breast cancer patients and 54,865 controls. Both HOXB13 p.G84E and p.R217C did not associate with the development of breast cancer in European women, neither in the overall analysis (OR = 1.035, 95% CI = 0.859-1.246, P = 0.718 and OR = 0.798, 95% CI = 0.482-1.322, P = 0.381 respectively), nor in specific high-risk subgroups or breast cancer subtypes. Thus, although involved in breast cancer progression, HOXB13 is not a material breast cancer susceptibility gene.

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Conflict of interest statement

Matthias W. Beckmann conducts research funded by Amgen, Novartis and Pfizer. Peter A. Fasching conducts research funded by Amgen, Novartis and Pfizer. He received Honoraria from Roche, Novartis and Pfizer. Allison W. Kurian received research funding to her institution from Myriad Genetics for an unrelated project (funding dates 2017–2019). Usha Menon has stocks in Abcodia awarded to her by UCL. Paolo Peterlongo is a member of the Editorial Board of Scientific Reports. All other authors declare no conflict of interest.

References

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Germline HOXB13 mutations p.G84E and p.R217C do not confer an increased breast cancer risk

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Germline HOXB13 mutations p.G84E and p.R217C do not confer an increased breast cancer risk

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