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.
Highlights
Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK. 5Biostatistics Unit, The Cyprus Institute of Neurology & Genetics, Nicosia, Cyprus. 6Cyprus School of Molecular Medicine, The Cyprus Institute of Neurology & Genetics, Nicosia, Cyprus. 7Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Department of Health and Human Services, Bethesda, MD, USA. 8Department of Clinical Genetics, Helsinki University Hospital, University of Helsinki, Helsinki, Finland. 9Roswell Park Cancer Institute, Buffalo, NY, USA. 10Fred A
In Asian and African Breast Cancer Association Consortium (BCAC) studies, the p.G84E mutation was not detected, while the carrier allele frequency (CAF) was highest in Northern European countries (i.e. Sweden, Denmark and the Netherlands in controls) (Supplementary Table S1)
The p.P190L and p.R217C mutations were present in the African ancestry BCAC studies, but not p.G84E and p.R268Q
Summary
Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK. 5Biostatistics Unit, The Cyprus Institute of Neurology & Genetics, Nicosia, Cyprus. 6Cyprus School of Molecular Medicine, The Cyprus Institute of Neurology & Genetics, Nicosia, Cyprus. 7Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Department of Health and Human Services, Bethesda, MD, USA. 8Department of Clinical Genetics, Helsinki University Hospital, University of Helsinki, Helsinki, Finland. 9Roswell Park Cancer Institute, Buffalo, NY, USA. 10Fred A. Litwin Center for Cancer Genetics, LunenfeldTanenbaum Research Institute of Mount Sinai Hospital, Toronto, ON, Canada. 11Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada. 12Department of Epidemiology, Genetic Epidemiology Research Institute, University of California Irvine, Irvine, CA, USA. 13N.N. Alexandrov Research Institute of Oncology and Medical Radiology, Minsk, Belarus. 14Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany. 15Department of Gynaecology and Obstetrics, University Hospital of Schleswig-Holstein, Campus Kiel, Christian-Albrechts University Kiel, Kiel, Germany. 16Institute of Clinical Molecular Biology, University Hospital of Schleswig-Holstein, Campus Kiel, Christian-Albrechts University Kiel, Kiel, Germany. 17Department of Public Health Sciences, and Cancer Research Institute, Queen’s University, Kingston, ON, Canada. 18Department of Cancer Epidemiology, Clinical Sciences, Lund University, Lund, Sweden. 19Cancer Center, Kuopio University Hospital, Kuopio, Finland. 20Institute of Clinical Medicine, Oncology, University of Eastern Finland, Kuopio, Finland. 21Translational Cancer Research Area, University of Eastern Finland, Kuopio, Finland. 22Institute of Medical Biometry and Epidemiology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany. 23Institute of Biometry and Clinical Epidemiology, Charité –Universitätsmedizin Berlin, Berlin, Germany. 24Department of Gynecology and Obstetrics, Comprehensive Cancer Center ER-EMN, University Hospital Erlangen, FriedrichAlexander-University Erlangen-Nuremberg, Erlangen, Germany. 25Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany. 26Institute of Biochemistry and Genetics, Ufa Federal Research Centre of the Russian Academy of Sciences, Ufa, Russia. 27Department of Population Sciences, Beckman Research Institute of City of Hope, Duarte, CA, USA. 28Department of Radiation Oncology, Hannover Medical School, Hannover, Germany. 29Gynaecology Research Unit, Hannover Medical School, Hannover, Germany. 30Institute of Human Genetics, University of Münster, Münster, Germany. 31Copenhagen General Population Study, Herlev and Gentofte Hospital, Copenhagen University Hospital, Herlev, Denmark. 32Department of Clinical Biochemistry, Herlev and Gentofte Hospital, Copenhagen University Hospital, Herlev, Denmark. 33Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark. 34Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology, Stuttgart, Germany. 35iFIT-Cluster of Excellence, University of Tübingen, Tübingen, Germany. 36German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Partner Site Tübingen, Tübingen, Germany. 37Division of Preventive Oncology, German Cancer Research Center (DKFZ) and National Center for Tumor Diseases (NCT), Heidelberg, Germany. 38Institute of Human Genetics, Pontificia Universidad Javeriana, Bogota, Colombia. 39Medical Faculty, Universidad de La Sabana, Bogota, Colombia. 40Department of Gynecology and Obstetrics, University of Tübingen, Tübingen, Germany. 41Institute for Prevention and Occupational Medicine of the German Social Accident Insurance, Institute of the Ruhr University Bochum (IPA), Bochum, Germany. 42Molecular Epidemiology Group, C080, German Cancer Research Center (DKFZ), Heidelberg, Germany. 43Molecular Biology of Breast Cancer, University Womens Clinic Heidelberg, University of Heidelberg, Heidelberg, Germany. 44Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, TN, USA. 45Department of Biology, University of Pisa, Pisa, Italy. 46Genomic Epidemiology Group, German Cancer Research Center (DKFZ), Heidelberg, Germany. 47Oncology and Genetics Unit, Instituto de Investigacion Sanitaria Galicia Sur (IISGS), Xerencia de Xestion Integrada de Vigo-SERGAS, Vigo, Spain. 48Cancer Epidemiology Group, University Cancer Center Hamburg (UCCH), University Medical Center Hamburg-Eppendorf, Hamburg, Germany. 49Department of Biomedical Sciences, Seoul National University Graduate School, Seoul, Korea. 50Cancer Research Institute, Seoul National University, Seoul, Korea. 51Leuven Multidisciplinary Breast Center, Department of Oncology, Leuven Cancer Institute, University Hospitals Leuven, Leuven, Belgium. 52Westmead Institute for Medical Research, University of Sydney, Sydney, New South Wales, Australia. 63Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA. 64Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden. 65Department of Clinical Genetics, Fox Chase Cancer Center, Philadelphia, PA, USA. 66Department of Pathology, Leiden University Medical Center, Leiden, The Netherlands. 67Department of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands. 68Department of NonCommunicable Disease Epidemiology, London School of Hygiene and Tropical Medicine, London, UK. 69School of Life Sciences, University of Westminster, London, UK. 70Faculty of Medicine, University of Southampton, Southampton, UK. 71Channing Division of Network Medicine, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA, USA. 72Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA. 73David Geffen School of Medicine, Department of Medicine Division of Hematology and Oncology, University of California at Los Angeles, Los Angeles, CA, USA. 74Usher Institute of Population Health Sciences and Informatics, The University of Edinburgh, Edinburgh, UK. 75Cancer Research UK Edinburgh Centre, The University of Edinburgh, Edinburgh, UK. 76Department of Breast Surgery, Herlev and Gentofte Hospital, Copenhagen University Hospital, Herlev, Denmark. 77School of Public Health, Curtin University, Perth, Western Australia, Australia. 78Genomic 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. 79Moores Cancer Center, University of California San Diego, La Jolla, CA, USA. 80Behavioral and Epidemiology Research Group, American Cancer Society, Atlanta, GA, USA. 81Medical Oncology Department, Hospital Clínico San Carlos, Instituto de Investigación Sanitaria San Carlos (IdISSC), Centro Investigación Biomédica en Red de Cáncer (CIBERONC), Madrid, Spain. 82Cancer Epidemiology Division, Cancer Council Victoria, Melbourne, Victoria, Australia. 83Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, Victoria, Australia. 84Precision Medicine, School of Clinical Sciences at Monash Health, Monash University, Clayton, Victoria, Australia. 85Department of Medicine, McGill University, Montréal, QC, Canada. 86Division of Clinical Epidemiology, Royal Victoria Hospital, McGill University, Montréal, QC, Canada. 87Department of Dermatology, Huntsman Cancer Institute, University of Utah School of Medicine, Salt Lake City, UT, USA. 88Cancer & Environment Group, Center for Research in Epidemiology and Population Health (CESP), INSERM, University Paris-Sud, University Paris-Saclay, Villejuif, France. 89Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA. 90Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden. 91Department of Oncology, Södersjukhuset, Stockholm, Sweden. 92Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Cambridge, UK. 93Department of Health Sciences Research, Mayo Clinic, Rochester, MN, USA. 94Saw Swee Hock School of Public Health, National University of Singapore and National University Health System, Singapore, Singapore. 95Department of Surgery, National University Health System, Singapore, Singapore. 96Department of Surgery, Kaohsiung Municipal Hsiao-Kang Hospital, Kaohsiung, Taiwan. 97Program in Genetic Epidemiology and Statistical Genetics, Harvard T.H. Chan School of Public Health, Boston, MA, USA. 98Nuffield Department of Population Health, University of Oxford, Oxford, UK. 99Center for Clinical Cancer Genetics, The University of Chicago, Chicago, IL, USA. 100Division of Cancer Epidemiology and Prevention, Aichi Cancer Center Research Institute, Nagoya, Japan. 101Division of Cancer Epidemiology, Nagoya University Graduate School of Medicine, Nagoya, Japan. 102Division of Epidemiology, Center for Public Health Sciences, National Cancer Center, Tokyo, Japan. 103Research Centre for Genetic Engineering and Biotechnology ‘Georgi D. Efremov’, MASA, Skopje, Republic of North Macedonia. 104Department of Genetics and Pathology, Pomeranian Medical University, Szczecin, Poland. 105Independent Laboratory of Molecular Biology and Genetic Diagnostics, Pomeranian Medical University, Szczecin, Poland. 106Department of Medicine, Division of Oncology, Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA, USA. 107Department of Preventive Medicine, Seoul National University College of Medicine, Seoul, Korea. 108Division of Molecular Pathology, The Netherlands Cancer Institute - Antoni van Leeuwenhoek Hospital, Amsterdam, The Netherlands. 109Saint Petersburg State University, Saint-Petersburg, Russia. 110Department of Surgery, Daerim Saint Mary’s Hospital, Seoul, Korea. 111Department of Medical Genetics, Oslo University Hospital and University of Oslo, Oslo, Norway. 112Department of Health Research and Policy, Stanford University School of Medicine, Stanford, CA, USA. 113Epidemiology Program, University of Hawaii Cancer Center, Honolulu, HI, USA. 114Human Genetics Division, Genome Institute of Singapore, Singapore, Singapore. 115Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden. 116Department of Clinical Genetics, Karolinska University Hospital, Stockholm, Sweden. 117Division of Population Health, Health
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