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

About this Publication
Title
Germline HOXB13 mutations p.G84E and p.R217C do not confer an increased breast cancer risk.
Pubmed ID
32546843 (View this publication on the PubMed website)
Digital Object Identifier
Publication
Sci Rep. 2020 Jun 16; Volume 10 (Issue 1): Pages 9688
Authors
Liu J, Prager-van der Smissen WJC, Collée JM, Bolla MK, Wang Q, Michailidou K, Dennis J, Ahearn TU, Aittomäki K, Ambrosone CB, Andrulis IL, Anton-Culver H, Antonenkova NN, Arndt V, Arnold N, Aronson KJ, Augustinsson A, Auvinen P, Becher H, Beckmann MW, ...show more Behrens S, Bermisheva M, Bernstein L, Bogdanova NV, Bogdanova-Markov N, Bojesen SE, Brauch H, Brenner H, Briceno I, Brucker SY, Brüning T, Burwinkel B, Cai Q, Cai H, Campa D, Canzian F, Castelao JE, Chang-Claude J, Chanock SJ, Choi JY, Christiaens M, Clarke CL, NBCS Collaborators, Couch FJ, Czene K, Daly MB, Devilee P, Dos-Santos-Silva I, Dwek M, Eccles DM, Eliassen AH, Fasching PA, Figueroa J, Flyger H, Fritschi L, Gago-Dominguez M, Gapstur SM, García-Closas M, García-Sáenz JA, Gaudet MM, Giles GG, Goldberg MS, Goldgar DE, Guénel P, Haiman CA, Håkansson N, Hall P, Harrington PA, Hart SN, Hartman M, Hillemanns P, Hopper JL, Hou MF, Hunter DJ, Huo D, ABCTB Investigators, Ito H, Iwasaki M, Jakimovska M, Jakubowska A, John EM, Kaaks R, Kang D, Keeman R, Khusnutdinova E, Kim SW, Kraft P, Kristensen VN, Kurian AW, Le Marchand L, Li J, Lindblom A, Lophatananon A, Luben RN, Lubiński J, Mannermaa A, Manoochehri M, Manoukian S, Margolin S, Mariapun S, Matsuo K, Maurer T, Mavroudis D, Meindl A, Menon U, Milne RL, Muir K, Mulligan AM, Neuhausen SL, Nevanlinna H, Offit K, Olopade OI, Olson JE, Olsson H, Orr N, Park SK, Peterlongo P, Peto J, Plaseska-Karanfilska D, Presneau N, Rack B, Rau-Murthy R, Rennert G, Rennert HS, Rhenius V, Romero A, Ruebner M, Saloustros E, Schmutzler RK, Schneeweiss A, Scott C, Shah M, Shen CY, Shu XO, Simard J, Sohn C, Southey MC, Spinelli JJ, Tamimi RM, Tapper WJ, Teo SH, Terry MB, Torres D, Truong T, Untch M, Vachon CM, van Asperen CJ, Wolk A, Yamaji T, Zheng W, Ziogas A, Ziv E, Torres-Mejía G, Dörk T, Swerdlow AJ, Hamann U, Schmidt MK, Dunning AM, Pharoah PDP, Easton DF, Hooning MJ, Martens JWM, Hollestelle A
Affiliations
  • Department of Medical Oncology, Family Cancer Clinic, Erasmus MC Cancer Institute, Rotterdam, The Netherlands.
  • Department of Clinical Genetics, Erasmus University Medical Center, Rotterdam, The Netherlands.
  • Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.
  • Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Department of Health and Human Services, Bethesda, MD, USA.
  • Department of Clinical Genetics, Helsinki University Hospital, University of Helsinki, Helsinki, Finland.
  • Roswell Park Cancer Institute, Buffalo, NY, USA.
  • Fred A. Litwin Center for Cancer Genetics, Lunenfeld-Tanenbaum Research Institute of Mount Sinai Hospital, Toronto, ON, Canada.
  • Department of Epidemiology, Genetic Epidemiology Research Institute, University of California Irvine, Irvine, CA, USA.
  • N.N. Alexandrov Research Institute of Oncology and Medical Radiology, Minsk, Belarus.
  • Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany.
...show more
  • Department of Gynaecology and Obstetrics, University Hospital of Schleswig-Holstein, Campus Kiel, Christian-Albrechts University Kiel, Kiel, Germany.
  • Department of Public Health Sciences, and Cancer Research Institute, Queen's University, Kingston, ON, Canada.
  • Department of Cancer Epidemiology, Clinical Sciences, Lund University, Lund, Sweden.
  • Cancer Center, Kuopio University Hospital, Kuopio, Finland.
  • Institute of Medical Biometry and Epidemiology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
  • Department of Gynecology and Obstetrics, Comprehensive Cancer Center ER-EMN, University Hospital Erlangen, Friedrich-Alexander-University Erlangen-Nuremberg, Erlangen, Germany.
  • Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
  • Institute of Biochemistry and Genetics, Ufa Federal Research Centre of the Russian Academy of Sciences, Ufa, Russia.
  • Department of Population Sciences, Beckman Research Institute of City of Hope, Duarte, CA, USA.
  • Institute of Human Genetics, University of Münster, Münster, Germany.
  • Copenhagen General Population Study, Herlev and Gentofte Hospital, Copenhagen University Hospital, Herlev, Denmark.
  • Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology, Stuttgart, Germany.
  • Institute of Human Genetics, Pontificia Universidad Javeriana, Bogota, Colombia.
  • Department of Gynecology and Obstetrics, University of Tübingen, Tübingen, Germany.
  • Institute for Prevention and Occupational Medicine of the German Social Accident Insurance, Institute of the Ruhr University Bochum (IPA), Bochum, Germany.
  • Molecular Epidemiology Group, C080, German Cancer Research Center (DKFZ), Heidelberg, Germany.
  • Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, TN, USA.
  • Genomic Epidemiology Group, German Cancer Research Center (DKFZ), Heidelberg, Germany.
  • Oncology and Genetics Unit, Instituto de Investigacion Sanitaria Galicia Sur (IISGS), Xerencia de Xestion Integrada de Vigo-SERGAS, Vigo, Spain.
  • Department of Biomedical Sciences, Seoul National University Graduate School, Seoul, Korea.
  • Leuven Multidisciplinary Breast Center, Department of Oncology, Leuven Cancer Institute, University Hospitals Leuven, Leuven, Belgium.
  • Westmead Institute for Medical Research, University of Sydney, Sydney, New South Wales, Australia.
  • Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA.
  • Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
  • Department of Clinical Genetics, Fox Chase Cancer Center, Philadelphia, PA, USA.
  • Department of Pathology, Leiden University Medical Center, Leiden, The Netherlands.
  • Department of Non-Communicable Disease Epidemiology, London School of Hygiene and Tropical Medicine, London, UK.
  • School of Life Sciences, University of Westminster, London, UK.
  • Faculty of Medicine, University of Southampton, Southampton, UK.
  • Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
  • Department of Breast Surgery, Herlev and Gentofte Hospital, Copenhagen University Hospital, Herlev, Denmark.
  • School of Public Health, Curtin University, Perth, Western Australia, Australia.
  • 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.
  • Behavioral and Epidemiology Research Group, American Cancer Society, Atlanta, GA, USA.
  • Medical Oncology Department, Hospital Clínico San Carlos, Instituto de Investigación Sanitaria San Carlos (IdISSC), Centro Investigación Biomédica en Red de Cáncer (CIBERONC), Madrid, Spain.
  • Cancer Epidemiology Division, Cancer Council Victoria, Melbourne, Victoria, Australia.
  • Department of Medicine, McGill University, Montréal, QC, Canada.
  • Department of Dermatology, Huntsman Cancer Institute, University of Utah School of Medicine, Salt Lake City, UT, USA.
  • Cancer & Environment Group, Center for Research in Epidemiology and Population Health (CESP), INSERM, University Paris-Sud, University Paris-Saclay, Villejuif, France.
  • Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
  • Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.
  • Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Cambridge, UK.
  • Department of Health Sciences Research, Mayo Clinic, Rochester, MN, USA.
  • Saw Swee Hock School of Public Health, National University of Singapore and National University Health System, Singapore, Singapore.
  • Gynaecology Research Unit, Hannover Medical School, Hannover, Germany.
  • Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, Victoria, Australia.
  • Department of Surgery, Kaohsiung Municipal Hsiao-Kang Hospital, Kaohsiung, Taiwan.
  • Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
  • Center for Clinical Cancer Genetics, The University of Chicago, Chicago, IL, USA.
  • Division of Cancer Epidemiology and Prevention, Aichi Cancer Center Research Institute, Nagoya, Japan.
  • Division of Epidemiology, Center for Public Health Sciences, National Cancer Center, Tokyo, Japan.
  • Research Centre for Genetic Engineering and Biotechnology 'Georgi D. Efremov', MASA, Skopje, Republic of North Macedonia.
  • Department of Genetics and Pathology, Pomeranian Medical University, Szczecin, Poland.
  • Department of Medicine, Division of Oncology, Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA, USA.
  • Division of Molecular Pathology, The Netherlands Cancer Institute - Antoni van Leeuwenhoek Hospital, Amsterdam, The Netherlands.
  • Department of Surgery, Daerim Saint Mary's Hospital, Seoul, Korea.
  • Department of Medical Genetics, Oslo University Hospital and University of Oslo, Oslo, Norway.
  • Epidemiology Program, University of Hawaii Cancer Center, Honolulu, HI, USA.
  • Human Genetics Division, Genome Institute of Singapore, Singapore, Singapore.
  • Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.
  • 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.
  • Clinical Gerontology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.
  • Translational Cancer Research Area, University of Eastern Finland, Kuopio, Finland.
  • Molecular Genetics of Breast Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany.
  • Unit of Medical Genetics, Department of Medical Oncology and Hematology, Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, Milan, Italy.
  • Department of Oncology, Södersjukhuset, Stockholm, Sweden.
  • Cancer Research Malaysia, Subang Jaya, Selangor, Malaysia.
  • Cancer Epidemiology Group, University Cancer Center Hamburg (UCCH), University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
  • Department of Medical Oncology, University Hospital of Heraklion, Heraklion, Greece.
  • Department of Gynecology and Obstetrics, University of Munich, Campus Großhadern, Munich, Germany.
  • MRC Clinical Trials Unit at UCL, Institute of Clinical Trials & Methodology, University College London, London, UK.
  • Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada.
  • Department of Obstetrics and Gynecology, Helsinki University Hospital, University of Helsinki, Helsinki, Finland.
  • Clinical Genetics Research Lab, Department of Cancer Biology and Genetics, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
  • The Breast Cancer Now Toby Robins Research Centre, The Institute of Cancer Research, London, UK.
  • Genome Diagnostics Program, IFOM - the FIRC Institute for Molecular Oncology, Milan, Italy.
  • Department of Gynaecology and Obstetrics, University Hospital Ulm, Ulm, Germany.
  • Clinical Genetics Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
  • Clalit National Cancer Control Center, Carmel Medical Center and Technion Faculty of Medicine, Haifa, Israel.
  • Medical Oncology Department, Hospital Universitario Puerta de Hierro, Madrid, Spain.
  • Department of Gynaecology and Obstetrics, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nuremberg, Comprehensive Cancer Center Erlangen-EMN, Erlangen, Germany.
  • Department of Oncology, University Hospital of Larissa, Larissa, Greece.
  • Center for Familial Breast and Ovarian Cancer, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany.
  • Molecular Biology of Breast Cancer, University Womens Clinic Heidelberg, University of Heidelberg, Heidelberg, Germany.
  • Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan.
  • Genomics Center, Centre Hospitalier Universitaire de Québec - Université Laval Research Center, Québec City, QC, Canada.
  • National Center for Tumor Diseases, University Hospital and German Cancer Research Center, Heidelberg, Germany.
  • Population Oncology, BC Cancer, Vancouver, BC, Canada.
  • Breast Cancer Research Programme, Cancer Research Malaysia, Subang Jaya, Selangor, Malaysia.
  • Department of Epidemiology, Mailman School of Public Health, Columbia University, New York, NY, USA.
  • Department of Gynecology and Obstetrics, Helios Clinics Berlin-Buch, Berlin, Germany.
  • Department of Health Science Research, Division of Epidemiology, Mayo Clinic, Rochester, MN, USA.
  • Department of Clinical Genetics, Leiden University Medical Center, Leiden, The Netherlands.
  • Department of Medicine, Institute for Human Genetics, UCSF Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA, USA.
  • Center for Population Health Research, National Institute of Public Health, Cuernavaca, Morelos, Mexico.
  • Division of Genetics and Epidemiology, The Institute of Cancer Research, London, UK.
  • Department of Medical Oncology, Family Cancer Clinic, Erasmus MC Cancer Institute, Rotterdam, The Netherlands. a.hollestelle@erasmusmc.nl.
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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