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No evidence that protein truncating variants in BRIP1 are associated with breast cancer risk: implications for gene panel testing
  1. Douglas F Easton1,2,
  2. Fabienne Lesueur3,
  3. Brennan Decker2,4,
  4. Kyriaki Michailidou2,5,
  5. Jun Li6,
  6. Jamie Allen2,
  7. Craig Luccarini1,
  8. Karen A Pooley2,
  9. Mitul Shah1,
  10. Manjeet K Bolla2,
  11. Qin Wang2,
  12. Joe Dennis2,
  13. Jamil Ahmad7,
  14. Ella R Thompson8,9,
  15. Francesca Damiola10,
  16. Maroulio Pertesi7,
  17. Catherine Voegele7,
  18. Noura Mebirouk3,
  19. Nivonirina Robinot7,
  20. Geoffroy Durand7,
  21. Nathalie Forey7,
  22. Robert N Luben11,
  23. Shahana Ahmed1,
  24. Kristiina Aittomäki12,
  25. Hoda Anton-Culver13,
  26. Volker Arndt14,
  27. Australian Ovarian Cancer Study Group15,
  28. Caroline Baynes1,
  29. Matthias W Beckman16,
  30. Javier Benitez17,18,
  31. David Van Den Berg19,
  32. William J Blot20,21,
  33. Natalia V Bogdanova22,
  34. Stig E Bojesen23,24,25,
  35. Hermann Brenner14,26,27,
  36. Jenny Chang-Claude28,29,
  37. Kee Seng Chia30,
  38. Ji-Yeob Choi31,32,
  39. Don M Conroy1,
  40. Angela Cox33,
  41. Simon S Cross34,
  42. Kamila Czene35,
  43. Hatef Darabi35,
  44. Peter Devilee36,37,
  45. Mikael Eriksson35,
  46. Peter A Fasching16,38,
  47. Jonine Figueroa39,40,
  48. Henrik Flyger41,
  49. Florentia Fostira42,
  50. Montserrat García-Closas39,
  51. Graham G Giles43,44,
  52. Gord Glendon45,
  53. Anna González-Neira17,
  54. Pascal Guénel46,47,
  55. Christopher A Haiman19,
  56. Per Hall35,
  57. Steven N Hart48,
  58. Mikael Hartman30,49,
  59. Maartje J Hooning50,
  60. Chia-Ni Hsiung51,
  61. Hidemi Ito52,
  62. Anna Jakubowska53,
  63. Paul A James54,55,
  64. Esther M John56,57,58,
  65. Nichola Johnson59,60,
  66. Michael Jones61,
  67. Maria Kabisch62,
  68. Daehee Kang31,32,63,
  69. kConFab Investigators64,
  70. Veli-Matti Kosma65,66,67,
  71. Vessela Kristensen68,69,70,
  72. Diether Lambrechts71,72,
  73. Na Li8,73,
  74. Lifepool Investigators8,
  75. Annika Lindblom74,
  76. Jirong Long21,
  77. Artitaya Lophatananon75,
  78. Jan Lubinski53,
  79. Arto Mannermaa65,66,67,
  80. Siranoush Manoukian76,
  81. Sara Margolin77,
  82. Keitaro Matsuo78,
  83. Alfons Meindl79,
  84. Gillian Mitchell9,55,
  85. Kenneth Muir75,80,
  86. NBCS Investigators81,
  87. Ines Nevelsteen82,
  88. Ans van den Ouweland83,
  89. Paolo Peterlongo84,
  90. Sze Yee Phuah85,86,
  91. Katri Pylkäs87,88,
  92. Simone M Rowley8,
  93. Suleeporn Sangrajrang89,
  94. Rita K Schmutzler90,91,92,
  95. Chen-Yang Shen93,94,
  96. Xiao-Ou Shu95,
  97. Melissa C Southey54,
  98. Harald Surowy96,97,
  99. Anthony Swerdlow60,61,
  100. Soo H Teo85,86,
  101. Rob A E M Tollenaar98,
  102. Ian Tomlinson99,
  103. Diana Torres62,100,
  104. Thérèse Truong46,47,
  105. Celine Vachon48,
  106. Senno Verhoef101,
  107. Michelle Wong-Brown102,
  108. Wei Zheng21,
  109. Ying Zheng103,
  110. Heli Nevanlinna104,
  111. Rodney J Scott102,105,
  112. Irene L Andrulis45,106,
  113. Anna H Wu19,
  114. John L Hopper107,
  115. Fergus J Couch108,
  116. Robert Winqvist87,88,
  117. Barbara Burwinkel96,97,
  118. Elinor J Sawyer109,
  119. Marjanka K Schmidt101,
  120. Anja Rudolph28,
  121. Thilo Dörk110,
  122. Hiltrud Brauch26,111,112,
  123. Ute Hamann62,
  124. Susan L Neuhausen113,
  125. Roger L Milne43,44,
  126. Olivia Fletcher59,60,
  127. Paul D P Pharoah1,2,
  128. Ian G Campbell8,9,54,
  129. Alison M Dunning1,
  130. Florence Le Calvez-Kelm7,
  131. David E Goldgar114,115,
  132. Sean V Tavtigian116,
  133. Georgia Chenevix-Trench6
  1. 1Department of Oncology, Centre for Cancer Genetic Epidemiology, University of Cambridge, Cambridge, UK
  2. 2Department of Public Health and Primary Care, Centre for Cancer Genetic Epidemiology, University of Cambridge, Cambridge, UK
  3. 3Genetic Epidemiology of Cancer team, Inserm, U900, Institut Curie, Mines ParisTech, Paris, France
  4. 4Cancer Genetics and Comparative Genomics Section, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland, USA
  5. 5Department of Electron Microscopy/Molecular Pathology, The Cyprus Institute of Neurology and Genetics, Nicosia, Cyprus
  6. 6Department of Genetics, QIMR Berghofer Medical Research Institute, Brisbane, Australia
  7. 7Genetic Cancer Susceptibility Group, International Agency for Research on Cancer, Lyon, France
  8. 8Research Division, Peter MacCallum Cancer Centre, East Melbourne, Australia
  9. 9Sir Peter MacCallum Department of Oncology, The University of Melbourne, Melbourne, Australia
  10. 10Genetic of Breast Cancer Team, Cancer Research Center of Lyon, Centre Léon Bérard, Lyon, France
  11. 11Clinical Gerontology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK
  12. 12Department of Clinical Genetics, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
  13. 13Department of Epidemiology, University of California Irvine, Irvine, California, USA
  14. 14Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany
  15. 15Peter MacCallum Cancer Centre, The University of Melbourne, Melbourne, Australia
  16. 16Department of Gynaecology and Obstetrics, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nuremberg, Comprehensive Cancer Center Erlangen-EMN, Erlangen, Germany
  17. 17Human Cancer Genetics Program, Spanish National Cancer Research Centre, Madrid, Spain
  18. 18Centro de Investigación en Red de Enfermedades Raras (CIBERER), Valencia, Spain
  19. 19Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California, USA
  20. 20International Epidemiology Institute, Rockville, Maryland, USA
  21. 21Division of Epidemiology, Department of Medicine, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, Tennessee, USA
  22. 22Department of Radiation Oncology, Hannover Medical School, Hannover, Germany
  23. 23Copenhagen General Population Study, Herlev and Gentofte Hospital, Copenhagen University Hospital, Herlev, Denmark
  24. 24Department of Clinical Biochemistry, Herlev and Gentofte Hospital, Copenhagen University Hospital, Herlev, Denmark
  25. 25Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
  26. 26German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany
  27. 27Division of Preventive Oncology, German Cancer Research Center (DKFZ) and National Center for Tumor Diseases (NCT), Heidelberg, Germany
  28. 28Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany
  29. 29University Cancer Center Hamburg (UCCH), University Medical Center Hamburg-Eppendorf, Hamburg, Germany
  30. 30Saw Swee Hock School of Public Health, National University of Singapore and National University Health System, Singapore, Singapore
  31. 31Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea
  32. 32Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, Korea
  33. 33Sheffield Cancer Research, Department of Oncology, University of Sheffield, Sheffield, UK
  34. 34Academic Unit of Pathology, Department of Neuroscience, University of Sheffield, Sheffield, UK
  35. 35Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden
  36. 36Department of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands
  37. 37Department of Pathology, Leiden University Medical Center, Leiden, The Netherlands
  38. 38David Geffen School of Medicine, Department of Medicine Division of Hematology and Oncology, University of California, Los Angeles, California, USA
  39. 39Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland, USA
  40. 40Usher Institute of Population Health Sciences and Informatics, The University of Edinburgh Medical School, Edinburgh, UK
  41. 41Department of Breast Surgery, Herlev and Gentofte Hospital, Copenhagen University Hospital, Herlev, Denmark
  42. 42Molecular Diagnostics Laboratory, INRASTES, National Centre for Scientific Research “Demokritos”, Athens, Greece
  43. 43Cancer Epidemiology Centre, Cancer Council Victoria, Melbourne, Victoria, Australia
  44. 44Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, Victoria, Australia
  45. 45Lunenfeld-Tanenbaum Research Institute of Mount Sinai Hospital, Toronto, Ontario, Canada
  46. 46University Paris-Sud, UMRS 1018, Villejuif, France
  47. 47Inserm, CESP Center for research in Epidemiology and Population Health, U1018, Cancer & Environment Group, Villejuif, France
  48. 48Department of Health Sciences Research, Mayo Clinic, Rochester, Minnesota, USA
  49. 49Department of Surgery, National University Health System, Singapore, Singapore
  50. 50Department of Medical Oncology, Family Cancer Clinic, Erasmus University Medical Center, Rotterdam, The Netherlands
  51. 51Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan
  52. 52Division of Epidemiology and Prevention, Aichi Cancer Center Research Institute, Nagoya, Aichi, Japan
  53. 53Department of Genetics and Pathology, Pomeranian Medical University, Szczecin, Poland
  54. 54Department of Pathology, The University of Melbourne, Melbourne, Victoria, Australia
  55. 55Familial Cancer Centre, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia
  56. 56Department of Epidemiology, Cancer Prevention Institute of California, Fremont, California, USA
  57. 57Department of Health Research and Policy—Epidemiology, Stanford University School of Medicine, Stanford, California, USA
  58. 58Stanford Cancer Institute, Stanford University School of Medicine, Stanford, California, USA
  59. 59Breakthrough Breast Cancer Research Centre, The Institute of Cancer Research, London, UK
  60. 60Division of Breast Cancer Research, The Institute of Cancer Research, London, UK
  61. 61Division of Genetics and Epidemiology, The Institute of Cancer Research, London, UK
  62. 62Molecular Genetics of Breast Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany
  63. 63Department of Preventive Medicine, Seoul National University College of Medicine, Seoul National University, Seoul, Korea
  64. 64kConFab: Kathleen Cuningham Consortium for Research into Familial Breast Cancer, Peter MacCallum Cancer Center, Melbourne, Victoria, Australia
  65. 65Institute of Clinical Medicine, Pathology and Forensic Medicine, University of Eastern Finland, Kuopio, Finland
  66. 66Imaging Center, Department of Clinical Pathology, Kuopio University Hospital, Kuopio, Finland
  67. 67Cancer Center of Eastern Finland, University of Eastern Finland, Kuopio, Finland
  68. 68Department of Genetics, Institute for Cancer Research, Oslo University Hospital, Radiumhospitalet, Oslo, Norway
  69. 69Faculty of Medicine, K.G. Jebsen Center for Breast Cancer Research, Institute of Clinical Medicine, University of Oslo, Oslo, Norway
  70. 70Department of Clinical Molecular Biology (EpiGen), University of Oslo (UiO), Oslo, Norway
  71. 71Vesalius Research Center, VIB, Leuven, Belgium
  72. 72Laboratory for Translational Genetics, Department of Oncology, University of Leuven, Leuven, Belgium
  73. 73Cancer Biology Research Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
  74. 74Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden
  75. 75Division of Health Sciences, Warwick Medical school, Warwick University, Coventry, UK
  76. 76Unit 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
  77. 77Department of Oncology—Pathology, Karolinska Institutet, Stockholm, Sweden
  78. 78Division of Molecular Medicine, Aichi Cancer Center Research Institute, Nagoya, Japan
  79. 79Division of Gynaecology and Obstetrics, Technische Universität München, Munich, Germany
  80. 80Institute of Population Health, University of Manchester, Manchester, UK
  81. 81Norwegian Breast Cancer Study, Department of Genetics, Institute for Cancer Research, Oslo University Hospital Radiumhospitalet, Oslo, Norway
  82. 82University Hospital Gashuisberg, Leuven, Belgium
  83. 83Department of Clinical Genetics, Erasmus University Medical Center, Rotterdam, The Netherlands
  84. 84IFOM, The FIRC (Italian Foundation for Cancer Research) Institute of Molecular Oncology, Milan, Italy
  85. 85Breast Cancer Research Unit, University Malaya Cancer Research Institute, University Malaya Medical Centre (UMMC), Kuala Lumpur, Malaysia
  86. 86Cancer Research Initiatives Foundation, Sime Darby Medical Centre, Subang Jaya, Malaysia
  87. 87Laboratory of Cancer Genetics and Tumor Biology, Northern Finland Laboratory Centre NordLab, Oulu, Finland
  88. 88Laboratory of Cancer Genetics and Tumor Biology, Cancer Research and Translational Medicine, Biocenter Oulu, University of Oulu, Oulu, Finland
  89. 89National Cancer Institute, Bangkok, Thailand
  90. 90Center for Integrated Oncology (CIO), Medical Faculty, University Hospital Cologne, Germany
  91. 91Medical Faculty, Center for Hereditary Breast and Ovarian Cancer, University Hospital Cologne, Germany
  92. 92Center for Molecular Medicine Cologne (CMMC), University of Cologne, Germany
  93. 93School of Public Health, China Medical University, Taichung, Taiwan
  94. 94Taiwan Biobank, Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan
  95. 95Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, Tennessee, USA
  96. 96Molecular Epidemiology Group, German Cancer Research Center (DKFZ), Heidelberg, Germany
  97. 97Department of Obstetrics and Gynecology, University of Heidelberg, Heidelberg, Germany
  98. 98Department of Surgery, Leiden University Medical Center, Leiden, The Netherlands
  99. 99Wellcome Trust Centre for Human Genetics and Oxford Biomedical Research Centre, University of Oxford, Oxford, UK
  100. 100Institute of Human Genetics, Pontificia Universidad Javeriana, Bogota, Colombia
  101. 101Netherlands Cancer Institute, Antoni van Leeuwenhoek hospital, Amsterdam, The Netherlands
  102. 102Division of Genetics, Hunter Area Pathology Service, John Hunter Hospital, Newcastle, New South Wales, Australia
  103. 103Shanghai Municipal Center for Disease Control and Prevention, Shanghai, China
  104. 104Department of Obstetrics and Gynecology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
  105. 105Division of Molecular Medicine, Pathology North, John Hunter Hospital, Newcastle, New South Wales, Australia
  106. 106Department of Molecular Genetics, University of Toronto, Ontario, Canada
  107. 107Centre for Epidemiology and Biostatistics, University of Melbourne, Melbourne, Victoria, Australia
  108. 108Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota, USA
  109. 109Research Oncology, Division of Cancer Studies, King's College London, Guy's Hospital, London, UK
  110. 110Gynaecology Research Unit, Hannover Medical School, Hannover, Germany
  111. 111Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology, Stuttgart, Germany
  112. 112University of Tübingen, Tübingen, Germany
  113. 113Department of Population Sciences, Beckman Research Institute of City of Hope, Duarte, California, USA
  114. 114Department of Dermatology, University of Utah School of Medicine, Salt Lake City, Utah, USA
  115. 115Cancer Control and Population Sciences, Huntsman Cancer Institute, Salt Lake City, Utah, USA
  116. 116Department of Oncological Sciences, Huntsman Cancer Institute, University of Utah School of Medicine, Salt Lake City, Utah, USA
  1. Correspondence to Dr G Chenevix-Trench, Department of Genetics and Computational Biology, QIMR Berghofer, c/o Locked Bag 2000, RBH Post Office, Herston, QLD 4029, Australia; georgiaT{at}qimr.edu.au

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.

  • Cancer: breast

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