Article open access publication

BRCA2 Hypomorphic Missense Variants Confer Moderate Risks of Breast Cancer

Cancer Research, American Association for Cancer Research (AACR), ISSN 0008-5472

Volume 77, 11, 2017

DOI:10.1158/0008-5472.can-16-2568, Dimensions: pub.1084230807, PMC: PMC5508554, PMID: 28283652,

Authors

Andrulis, Irene (8) (9)
Benitez, Javier (13) (14)
Bojesen, Stig E. (16) (17) (18)
Brauch, Hiltrud (11) (22) (23)
Burwinkel, Barbara (11) (28)
Fasching, Peter A. (12) (37)
Figueroa, Jonine (38) (39)
Giles, Graham G (41) (42)
Hall, Per (35)
Hartman, Mikael (31) (45)
Ito, Hidemi (46) (47)
Kosma, Veli-Matti (49) (50)
Kristensen, Vessela (20) (21) (51)
Lai, Kah Nyin (52) (53)
Mannermaa, Arto (49) (50)
Marme, Frederik (28) (59)
Matsuo, Keitaro (46) (47)
Miao, Hui (31)
Milne, Roger L. (41) (42)
Muir, Kenneth (57) (61)
Osorio, Ana (13) (14)
Pylkäs, Katri (66) (67)
Shen, Chen-Yang (73) (74)
Teo, Soo H. (52) (53)
Torres, Diana (11) (77)
Wang, Qin (19)
Winqvist, Robert (66) (67)
Wu, Anna H (44)
Zheng, Wei (75)

Affiliations

Organisations

  1. (1) Mayo Clinic, grid.66875.3a
  2. (2) Leiden University Medical Center, grid.10419.3d
  3. (3) Genotoxic Stress and Cancer, grid.493838.d
  4. (4) University of Chicago, grid.170205.1
  5. (5) Institute Curie, grid.418596.7
  6. (6) University of Utah, grid.223827.e
  7. (7) Department of Clinical Genetics, Helsinki University Hospital, University of Helsinki, Helsinki, Finland
  8. (8) University of Toronto, grid.17063.33
  9. (9) Lunenfeld-Tanenbaum Research Institute, grid.250674.2
  10. (10) University of California, Irvine, grid.266093.8
  11. (11) German Cancer Research Center, grid.7497.d
  12. (12) Department of Gynaecology and Obstetrics, University Hospital Erlangen, Friedrich Alexander University Erlangen-Nuremberg, Comprehensive Cancer Center Erlangen-EMN, Erlangen, Germany
  13. (13) Centro de Investigación en Red de Enfermedades Raras (CIBERER), Valencia, Spain
  14. (14) Spanish National Cancer Research Centre, grid.7719.8
  15. (15) Hannover Medical School, grid.10423.34
  16. (16) Copenhagen General Population Study, Herlevand Gentofte Hospital, Copenhagen University Hospital, Herlev, Denmark
  17. (17) Department of Clinical Biochemistry, Herlev and Gentofte Hospital, Copenhagen University Hospital, Herlev, Denmark
  18. (18) University of Copenhagen, grid.5254.6, KU
  19. (19) University of Cambridge, grid.5335.0
  20. (20) K.G. Jebsen Center for Breast Cancer Research, Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway
  21. (21) Oslo University Hospital, grid.55325.34
  22. (22) Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology, grid.502798.1
  23. (23) University of Tübingen, grid.10392.39
  24. (24) International Agency For Research On Cancer, grid.17703.32
  25. (25) Antoni van Leeuwenhoek Hospital, grid.430814.a
  26. (26) Universitair Ziekenhuis Leuven, grid.410569.f
  27. (27) Ruhr University Bochum, grid.5570.7
  28. (28) Heidelberg University, grid.7700.0
  29. (29) University Cancer Center Hamburg, grid.412315.0
  30. (30) QIMR Berghofer Medical Research Institute, grid.1049.c
  31. (31) National University of Singapore, grid.4280.e
  32. (32) Seoul National University, grid.31501.36
  33. (33) Erasmus University Medical Center, grid.5645.2
  34. (34) University of Sheffield, grid.11835.3e
  35. (35) Karolinska Institute, grid.4714.6
  36. (36) London School of Hygiene & Tropical Medicine, grid.8991.9
  37. (37) University of California, Los Angeles, grid.19006.3e
  38. (38) University of Edinburgh, grid.4305.2
  39. (39) National Cancer Institute, grid.48336.3a
  40. (40) Department of Breast Surgery, Herlev and Gentofte Hospital, Copenhagen University Hospital, Herlev, Denmark
  41. (41) University of Melbourne, grid.1008.9
  42. (42) Cancer Council Victoria, grid.3263.4
  43. (43) Cancer & Environment Group, Center for Research in Epidemiology and Population Health (CESP), INSERM, University Paris-Sud, University Paris-Saclay, Villejuif, France
  44. (44) University of Southern California, grid.42505.36
  45. (45) National University Health System, grid.410759.e
  46. (46) Aichi Cancer Center, grid.410800.d
  47. (47) Nagoya University, grid.27476.30
  48. (48) Pomeranian Medical University, grid.107950.a
  49. (49) Kuopio University Hospital, grid.410705.7
  50. (50) University of Eastern Finland, grid.9668.1
  51. (51) Department of Clinical Molecular Biology, Oslo University Hospital, University of Oslo, Oslo, Norway
  52. (52) Cancer Research Initiatives Foundation, grid.427737.2
  53. (53) University Malaya Medical Centre, grid.413018.f
  54. (54) KU Leuven, grid.5596.f
  55. (55) Vesalius Research Center, Leuven, Belgium
  56. (56) University of Hawaii at Manoa, grid.410445.0
  57. (57) University of Warwick, grid.7372.1
  58. (58) Masaryk Memorial Cancer Institute, grid.419466.8
  59. (59) National Center for Tumor Diseases, University of Heidelberg, Heidelberg, Germany
  60. (60) Cyprus Institute of Neurology and Genetics, grid.417705.0
  61. (61) University of Manchester, grid.5379.8
  62. (62) City Of Hope National Medical Center, grid.410425.6
  63. (63) Department of Obstetrics and Gynecology, Helsinki University Hospital, University of Helsinki, Helsinki, Finland
  64. (64) University of Groningen, grid.4830.f
  65. (65) IFOM, The FIRC (Italian Foundation for Cancer Research) Institute of Molecular Oncology, Milan, Italy
  66. (66) Laboratory of Cancer Genetics and Tumor Biology, Northern Finland Laboratory Centre Oulu, Oulu, Finland
  67. (67) University of Oulu, grid.10858.34
  68. (68) Fondazione IRCCS Istituto Nazionale dei Tumori, grid.417893.0
  69. (69) Shaukat Khanum Memorial Cancer Hospital and Research Center, grid.415662.2
  70. (70) National Cancer Institute of Thailand, grid.419173.9
  71. (71) King's College London, grid.13097.3c
  72. (72) Institute of Cancer Research, grid.18886.3f
  73. (73) China Medical University, grid.254145.3
  74. (74) Institute of Biomedical Sciences, Academia Sinica, grid.482251.8
  75. (75) Division of Epidemiology, Department of Medicine, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, Tennessee
  76. (76) University of Oxford, grid.4991.5
  77. (77) Pontificia Universidad Javeriana, grid.41312.35
  78. (78) National Taiwan University Hospital, grid.412094.a
  79. (79) Shanghai Municipal Center For Disease Control Prevention, grid.430328.e
  80. (80) University of Sydney, grid.1013.3
  81. (81) University of Otago, grid.29980.3a
  82. (82) Molecular Diagnostics Laboratory, Institute of Radioisotopes and Radiodiagnostic Products (IRRP), Athens, Greece
  83. (83) Ghent University Hospital, grid.410566.0
  84. (84) Ospedale San Martino, grid.410345.7
  85. (85) Moffitt Cancer Center, grid.468198.a
  86. (86) University of South Florida, grid.170693.a

Description

Breast cancer risks conferred by many germline missense variants in the BRCA1 and BRCA2 genes, often referred to as variants of uncertain significance (VUS), have not been established. In this study, associations between 19 BRCA1 and 33 BRCA2 missense substitution variants and breast cancer risk were investigated through a breast cancer case-control study using genotyping data from 38 studies of predominantly European ancestry (41,890 cases and 41,607 controls) and nine studies of Asian ancestry (6,269 cases and 6,624 controls). The BRCA2 c.9104A>C, p.Tyr3035Ser (OR = 2.52; P = 0.04), and BRCA1 c.5096G>A, p.Arg1699Gln (OR = 4.29; P = 0.009) variant were associated with moderately increased risks of breast cancer among Europeans, whereas BRCA2 c.7522G>A, p.Gly2508Ser (OR = 2.68; P = 0.004), and c.8187G>T, p.Lys2729Asn (OR = 1.4; P = 0.004) were associated with moderate and low risks of breast cancer among Asians. Functional characterization of the BRCA2 variants using four quantitative assays showed reduced BRCA2 activity for p.Tyr3035Ser compared with wild-type. Overall, our results show how BRCA2 missense variants that influence protein function can confer clinically relevant, moderately increased risks of breast cancer, with potential implications for risk management guidelines in women with these specific variants. Cancer Res; 77(11); 2789-99. ©2017 AACR.

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Times Cited: 31

Field Citation Ratio (FCR): 9.71

Relative Citation ratio (RCR): 1.39

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