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No evidence that protein truncating variants in BRIP1 are associated with breast cancer risk: implications for gene panel testing

Easton DF 1 , Lesueur F 2 , Decker B 3 , Michailidou K 4 , Li J 5 , Allen J 6 Show all authors , Luccarini C 7 , Pooley KA 6 , Shah M 7 , Bolla MK 6 , Wang Q 6 , Dennis J 6 , Ahmad J 8 , Thompson ER 9 , Damiola F 10 , Pertesi M 8 , Voegele C 8 , Mebirouk N 2 , Robinot N 8 , Durand G 8 , Forey N 8 , Luben RN 11 , Ahmed S 7 , Aittomäki K 12 , Anton-Culver H 13 , Arndt V 14 , Australian Ovarian Cancer Study Group , Baynes C 7 , Beckman MW 15 , Benitez J 16 , Van Den Berg D 17 , Blot WJ 18 , Bogdanova NV 19 , Bojesen SE 20 , Brenner H 21 , Chang-Claude J 22 , Chia KS 23 , Choi JY 24 , Conroy DM 7 , Cox A 25 , Cross SS 26 , Czene K 27 , Darabi H 27 , Devilee P 28 , Eriksson M 27 , Fasching PA 29 , Figueroa J 30 , Flyger H 31 , Fostira F 32 , García-Closas M 33 , Giles GG 34 , Glendon G 35 , González-Neira A 36 , Guénel P 37 , Haiman CA 17 , Hall P 27 , Hart SN 38 , Hartman M 39 , Hooning MJ 40 , Hsiung CN 41 , Ito H 42 , Jakubowska A 43 , James PA 44 , John EM 45 , Johnson N 46 , Jones M 47 , Kabisch M 48 , Kang D 49 , kConFab Investigators , Kosma VM 50 , Kristensen V 51 , Lambrechts D 52 , Li N 53 , Lifepool Investigators , Lindblom A 54 , Long J 55 , Lophatananon A 56 , Lubinski J 43 , Mannermaa A 50 , Manoukian S 57 , Margolin S 58 , Matsuo K 59 , Meindl A 60 , Mitchell G 61 , Muir K 62 , NBCS Investigators , Nevelsteen I 63 , van den Ouweland A 64 , Peterlongo P 65 , Phuah SY 66 , Pylkäs K 67 , Rowley SM 68 , Sangrajrang S 69 , Schmutzler RK 70 , Shen CY 71 , Shu XO 72 , Southey MC 73 , Surowy H 74 , Swerdlow A 75 , Teo SH 66 , Tollenaar RA 76 , Tomlinson I 77 , Torres D 78 , Truong T 37 , Vachon C 38 , Verhoef S 79 , Wong-Brown M 80 , Zheng W 55 , Zheng Y 81 , Nevanlinna H 82 , Scott RJ 83 , Andrulis IL 84 , Wu AH 17 , Hopper JL 85 , Couch FJ 86 , Winqvist R 67 , Burwinkel B 74 , Sawyer EJ 87 , Schmidt MK 79 , Rudolph A 88 , Dörk T 89 , Brauch H 90 , Hamann U 48 , Neuhausen SL 91 , Milne RL 34 , Fletcher O 46 , Pharoah PD 1 , Campbell IG 92 , Dunning AM 7 , Le Calvez-Kelm F 8 , Goldgar DE 93 , Tavtigian SV 94 , Chenevix-Trench G 5

Affiliations 

  • 1 Department of Oncology, Centre for Cancer Genetic Epidemiology, University of Cambridge, Cambridge, UK Department of Public Health and Primary Care, Centre for Cancer Genetic Epidemiology, University of Cambridge, Cambridge, UK
  • 2 Genetic Epidemiology of Cancer team, Inserm, U900, Institut Curie, Mines ParisTech, Paris, France
  • 3 Department of Public Health and Primary Care, Centre for Cancer Genetic Epidemiology, University of Cambridge, Cambridge, UK Cancer Genetics and Comparative Genomics Section, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland, USA
  • 4 Department of Public Health and Primary Care, Centre for Cancer Genetic Epidemiology, University of Cambridge, Cambridge, UK Department of Electron Microscopy/Molecular Pathology, The Cyprus Institute of Neurology and Genetics, Nicosia, Cyprus
  • 5 Department of Genetics, QIMR Berghofer Medical Research Institute, Brisbane, Australia
  • 6 Department of Public Health and Primary Care, Centre for Cancer Genetic Epidemiology, University of Cambridge, Cambridge, UK
  • 7 Department of Oncology, Centre for Cancer Genetic Epidemiology, University of Cambridge, Cambridge, UK
  • 8 Genetic Cancer Susceptibility Group, International Agency for Research on Cancer, Lyon, France
  • 9 Research Division, Peter MacCallum Cancer Centre, East Melbourne, Australia Sir Peter MacCallum Department of Oncology, The University of Melbourne, Melbourne, Australia
  • 10 Genetic of Breast Cancer Team, Cancer Research Center of Lyon, Centre Léon Bérard, Lyon, France
  • 11 Clinical Gerontology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK
  • 12 Department of Clinical Genetics, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
  • 13 Department of Epidemiology, University of California Irvine, Irvine, California, USA
  • 14 Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany
  • 15 Department of Gynaecology and Obstetrics, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nuremberg, Comprehensive Cancer Center Erlangen-EMN, Erlangen, Germany
  • 16 Human Cancer Genetics Program, Spanish National Cancer Research Centre, Madrid, Spain Centro de Investigación en Red de Enfermedades Raras (CIBERER), Valencia, Spain
  • 17 Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California, USA
  • 18 International Epidemiology Institute, Rockville, Maryland, USA Division of Epidemiology, Department of Medicine, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, Tennessee, USA
  • 19 Department of Radiation Oncology, Hannover Medical School, Hannover, Germany
  • 20 Copenhagen General Population Study, Herlev and Gentofte Hospital, Copenhagen University Hospital, Herlev, Denmark Department of Clinical Biochemistry, Herlev and Gentofte Hospital, Copenhagen University Hospital, Herlev, Denmark Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
  • 21 Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany Division of Preventive Oncology, German Cancer Research Center (DKFZ) and National Center for Tumor Diseases (NCT), Heidelberg, Germany
  • 22 Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany University Cancer Center Hamburg (UCCH), University Medical Center Hamburg-Eppendorf, Hamburg, Germany
  • 23 Saw Swee Hock School of Public Health, National University of Singapore and National University Health System, Singapore, Singapore
  • 24 Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, Korea
  • 25 Sheffield Cancer Research, Department of Oncology, University of Sheffield, Sheffield, UK
  • 26 Academic Unit of Pathology, Department of Neuroscience, University of Sheffield, Sheffield, UK
  • 27 Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden
  • 28 Department of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands Department of Pathology, Leiden University Medical Center, Leiden, The Netherlands
  • 29 Department of Gynaecology and Obstetrics, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nuremberg, Comprehensive Cancer Center Erlangen-EMN, Erlangen, Germany David Geffen School of Medicine, Department of Medicine Division of Hematology and Oncology, University of California, Los Angeles, California, USA
  • 30 Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland, USA Usher Institute of Population Health Sciences and Informatics, The University of Edinburgh Medical School, Edinburgh, UK
  • 31 Department of Breast Surgery, Herlev and Gentofte Hospital, Copenhagen University Hospital, Herlev, Denmark
  • 32 Molecular Diagnostics Laboratory, INRASTES, National Centre for Scientific Research "Demokritos", Athens, Greece
  • 33 Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland, USA
  • 34 Cancer Epidemiology Centre, Cancer Council Victoria, Melbourne, Victoria, Australia Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, Victoria, Australia
  • 35 Lunenfeld-Tanenbaum Research Institute of Mount Sinai Hospital, Toronto, Ontario, Canada
  • 36 Human Cancer Genetics Program, Spanish National Cancer Research Centre, Madrid, Spain
  • 37 University Paris-Sud, UMRS 1018, Villejuif, France Inserm, CESP Center for research in Epidemiology and Population Health, U1018, Cancer & Environment Group, Villejuif, France
  • 38 Department of Health Sciences Research, Mayo Clinic, Rochester, Minnesota, USA
  • 39 Saw Swee Hock School of Public Health, National University of Singapore and National University Health System, Singapore, Singapore Department of Surgery, National University Health System, Singapore, Singapore
  • 40 Department of Medical Oncology, Family Cancer Clinic, Erasmus University Medical Center, Rotterdam, The Netherlands
  • 41 Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan
  • 42 Division of Epidemiology and Prevention, Aichi Cancer Center Research Institute, Nagoya, Aichi, Japan
  • 43 Department of Genetics and Pathology, Pomeranian Medical University, Szczecin, Poland
  • 44 Department of Pathology, The University of Melbourne, Melbourne, Victoria, Australia Familial Cancer Centre, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia
  • 45 Department of Epidemiology, Cancer Prevention Institute of California, Fremont, California, USA Department of Health Research and Policy-Epidemiology, Stanford University School of Medicine, Stanford, California, USA Stanford Cancer Institute, Stanford University School of Medicine, Stanford, California, USA
  • 46 Breakthrough Breast Cancer Research Centre, The Institute of Cancer Research, London, UK Division of Breast Cancer Research, The Institute of Cancer Research, London, UK
  • 47 Division of Genetics and Epidemiology, The Institute of Cancer Research, London, UK
  • 48 Molecular Genetics of Breast Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany
  • 49 Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, Korea Department of Preventive Medicine, Seoul National University College of Medicine, Seoul National University, Seoul, Korea
  • 50 Institute of Clinical Medicine, Pathology and Forensic Medicine, University of Eastern Finland, Kuopio, Finland Imaging Center, Department of Clinical Pathology, Kuopio University Hospital, Kuopio, Finland Cancer Center of Eastern Finland, University of Eastern Finland, Kuopio, Finland
  • 51 Department of Genetics, Institute for Cancer Research, Oslo University Hospital, Radiumhospitalet, Oslo, Norway Faculty of Medicine, K.G. Jebsen Center for Breast Cancer Research, Institute of Clinical Medicine, University of Oslo, Oslo, Norway Department of Clinical Molecular Biology (EpiGen), University of Oslo (UiO), Oslo, Norway
  • 52 Vesalius Research Center, VIB, Leuven, Belgium Laboratory for Translational Genetics, Department of Oncology, University of Leuven, Leuven, Belgium
  • 53 Research Division, Peter MacCallum Cancer Centre, East Melbourne, Australia Cancer Biology Research Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
  • 54 Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden
  • 55 Division of Epidemiology, Department of Medicine, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, Tennessee, USA
  • 56 Division of Health Sciences, Warwick Medical school, Warwick University, Coventry, UK
  • 57 Unit of Medical Genetics, Department of Preventive and Predictive Medicine, Fondazione IRCCS (Istituto di Ricovero e Cura a Carattere Scientifico) Istituto Nazionale Tumori (INT), Milan, Italy
  • 58 Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden
  • 59 Division of Molecular Medicine, Aichi Cancer Center Research Institute, Nagoya, Japan
  • 60 Division of Gynaecology and Obstetrics, Technische Universität München, Munich, Germany
  • 61 Sir Peter MacCallum Department of Oncology, The University of Melbourne, Melbourne, Australia Familial Cancer Centre, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia
  • 62 Division of Health Sciences, Warwick Medical school, Warwick University, Coventry, UK Institute of Population Health, University of Manchester, Manchester, UK
  • 63 University Hospital Gashuisberg, Leuven, Belgium
  • 64 Department of Clinical Genetics, Erasmus University Medical Center, Rotterdam, The Netherlands
  • 65 IFOM, The FIRC (Italian Foundation for Cancer Research) Institute of Molecular Oncology, Milan, Italy
  • 66 Breast Cancer Research Unit, University Malaya Cancer Research Institute, University Malaya Medical Centre (UMMC), Kuala Lumpur, Malaysia Cancer Research Initiatives Foundation, Sime Darby Medical Centre, Subang Jaya, Malaysia
  • 67 Laboratory of Cancer Genetics and Tumor Biology, Northern Finland Laboratory Centre NordLab, Oulu, Finland Laboratory of Cancer Genetics and Tumor Biology, Cancer Research and Translational Medicine, Biocenter Oulu, University of Oulu, Oulu, Finland
  • 68 Research Division, Peter MacCallum Cancer Centre, East Melbourne, Australia
  • 69 National Cancer Institute, Bangkok, Thailand
  • 70 Center for Integrated Oncology (CIO), Medical Faculty, University Hospital Cologne, Germany Medical Faculty, Center for Hereditary Breast and Ovarian Cancer, University Hospital Cologne, Germany Center for Molecular Medicine Cologne (CMMC), University of Cologne, Germany
  • 71 School of Public Health, China Medical University, Taichung, Taiwan Taiwan Biobank, Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan
  • 72 Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, Tennessee, USA
  • 73 Department of Pathology, The University of Melbourne, Melbourne, Victoria, Australia
  • 74 Molecular Epidemiology Group, German Cancer Research Center (DKFZ), Heidelberg, Germany Department of Obstetrics and Gynecology, University of Heidelberg, Heidelberg, Germany
  • 75 Division of Breast Cancer Research, The Institute of Cancer Research, London, UK Division of Genetics and Epidemiology, The Institute of Cancer Research, London, UK
  • 76 Department of Surgery, Leiden University Medical Center, Leiden, The Netherlands
  • 77 Wellcome Trust Centre for Human Genetics and Oxford Biomedical Research Centre, University of Oxford, Oxford, UK
  • 78 Molecular Genetics of Breast Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany Institute of Human Genetics, Pontificia Universidad Javeriana, Bogota, Colombia
  • 79 Netherlands Cancer Institute, Antoni van Leeuwenhoek hospital, Amsterdam, The Netherlands
  • 80 Division of Genetics, Hunter Area Pathology Service, John Hunter Hospital, Newcastle, New South Wales, Australia
  • 81 Shanghai Municipal Center for Disease Control and Prevention, Shanghai, China
  • 82 Department of Obstetrics and Gynecology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
  • 83 Division of Genetics, Hunter Area Pathology Service, John Hunter Hospital, Newcastle, New South Wales, Australia Division of Molecular Medicine, Pathology North, John Hunter Hospital, Newcastle, New South Wales, Australia
  • 84 Lunenfeld-Tanenbaum Research Institute of Mount Sinai Hospital, Toronto, Ontario, Canada Department of Molecular Genetics, University of Toronto, Ontario, Canada
  • 85 Centre for Epidemiology and Biostatistics, University of Melbourne, Melbourne, Victoria, Australia
  • 86 Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota, USA
  • 87 Research Oncology, Division of Cancer Studies, King's College London, Guy's Hospital, London, UK
  • 88 Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany
  • 89 Gynaecology Research Unit, Hannover Medical School, Hannover, Germany
  • 90 German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology, Stuttgart, Germany University of Tübingen, Tübingen, Germany
  • 91 Department of Population Sciences, Beckman Research Institute of City of Hope, Duarte, California, USA
  • 92 Research Division, Peter MacCallum Cancer Centre, East Melbourne, Australia Sir Peter MacCallum Department of Oncology, The University of Melbourne, Melbourne, Australia Department of Pathology, The University of Melbourne, Melbourne, Victoria, Australia
  • 93 Department of Dermatology, University of Utah School of Medicine, Salt Lake City, Utah, USA Cancer Control and Population Sciences, Huntsman Cancer Institute, Salt Lake City, Utah, USA
  • 94 Department of Oncological Sciences, Huntsman Cancer Institute, University of Utah School of Medicine, Salt Lake City, Utah, USA
J Med Genet, 2016 May;53(5):298-309.
PMID: 26921362 DOI: 10.1136/jmedgenet-2015-103529

Abstract

BACKGROUND: BRCA1 interacting protein C-terminal helicase 1 (BRIP1) is one of the Fanconi Anaemia Complementation (FANC) group family of DNA repair proteins. Biallelic mutations in BRIP1 are responsible for FANC group J, and previous studies have also suggested that rare protein truncating variants in BRIP1 are associated with an increased risk of breast cancer. These studies have led to inclusion of BRIP1 on targeted sequencing panels for breast cancer risk prediction.

METHODS: We evaluated a truncating variant, p.Arg798Ter (rs137852986), and 10 missense variants of BRIP1, in 48 144 cases and 43 607 controls of European origin, drawn from 41 studies participating in the Breast Cancer Association Consortium (BCAC). Additionally, we sequenced the coding regions of BRIP1 in 13 213 cases and 5242 controls from the UK, 1313 cases and 1123 controls from three population-based studies as part of the Breast Cancer Family Registry, and 1853 familial cases and 2001 controls from Australia.

RESULTS: The rare truncating allele of rs137852986 was observed in 23 cases and 18 controls in Europeans in BCAC (OR 1.09, 95% CI 0.58 to 2.03, p=0.79). Truncating variants were found in the sequencing studies in 34 cases (0.21%) and 19 controls (0.23%) (combined OR 0.90, 95% CI 0.48 to 1.70, p=0.75).

CONCLUSIONS: These results suggest that truncating variants in BRIP1, and in particular p.Arg798Ter, are not associated with a substantial increase in breast cancer risk. Such observations have important implications for the reporting of results from breast cancer screening panels.

* Title and MeSH Headings from MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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