Article open access publication

Inheritance of deleterious mutations at both BRCA1 and BRCA2 in an international sample of 32,295 women

Breast Cancer Research, Springer Nature, ISSN 1465-5411

Volume 18, 1, 2016

DOI:10.1186/s13058-016-0768-3, Dimensions: pub.1037742468, PMC: PMC5106833, PMID: 27836010,

Authors

Wan, Fei (3)
Benitez, Javier (11) (12)
Borg, Ake (15)
EMBRACE (26)
Friedman, Eitan (13) (29)
Godwin, Andrew K (2) (32)
HEBON (38)
Kwong, Ava (46) (47)
Laitman, Yael (13) (29)
Mitchell, Gillian (45) (51)
Teo, Soo-Hwang (71) (72)
Zidan, Jamal (81) (82)
Ramus, Susan J (4) (84)

* Corresponding author

Affiliations

Organisations

  1. (1) Department Epidemiology, Dana Farber Cancer Institute and Harvard T.H. Chan School of Public Health, 1101 Dana Building, 450 Brookline Avenue, Boston, MA, USA
  2. (2) University of Pennsylvania, grid.25879.31
  3. (3) Group Health Cooperative, grid.280243.f
  4. (4) University of Southern California, grid.42505.36
  5. (5) Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, M5G 1X5, Toronto, Ontario, Canada
  6. (6) University of Toronto, grid.17063.33
  7. (7) National Centre of Scientific Research Demokritos, grid.6083.d
  8. (8) Department of Gynaecology and Obstetrics, University Hospital of Schleswig-Holstein, Campus Kiel, Christian-Albrechts University, Kiel, Germany
  9. (9) The University of Texas MD Anderson Cancer Center, grid.240145.6
  10. (10) QIMR Berghofer Medical Research Institute, grid.1049.c
  11. (11) Centre for Biomedical Network Research on Rare Diseases, grid.452372.5
  12. (12) Spanish National Cancer Research Centre, grid.7719.8
  13. (13) Sheba Medical Center, grid.413795.d
  14. (14) Centre Franois Baclesse, grid.476192.f
  15. (15) Skåne University Hospital, grid.411843.b
  16. (16) Huntsman Cancer Institute, grid.479969.c
  17. (17) Hospital Clínico San Carlos, grid.411068.a
  18. (18) Royal Prince Alfred Hospital, grid.413249.9
  19. (19) Hôpital du Saint-Sacrement, grid.416673.1
  20. (20) Ghent University, grid.5342.0
  21. (21) Mayo Clinic, grid.66875.3a
  22. (22) Pomeranian Medical University, grid.107950.a
  23. (23) Temple University Health System, grid.412530.1
  24. (24) Hospital Universitari Vall d'Hebron, grid.411083.f
  25. (25) Department of Medicine, Abramson Cancer Center, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA
  26. (26) University of Cambridge, grid.5335.0
  27. (27) University of Manchester, grid.5379.8
  28. (28) Masaryk Memorial Cancer Institute, grid.419466.8
  29. (29) Tel Aviv University, grid.12136.37
  30. (30) University of California, Los Angeles, grid.19006.3e
  31. (31) Mount Sinai Hospital, grid.416166.2
  32. (32) University of Kansas Medical Center, grid.412016.0
  33. (33) National Institute of Arthritis and Musculoskeletal and Skin Diseases, grid.420086.8
  34. (34) University Hospital Cologne, grid.411097.a
  35. (35) Mayo Clinic, grid.417468.8
  36. (36) German Cancer Research Center, grid.7497.d
  37. (37) Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital, Blegdamsvej 9, Copenhagen, DK-2100, Denmark
  38. (38) Antoni van Leeuwenhoek Hospital, grid.430814.a
  39. (39) Institute of Oncology NN Petrov, grid.465337.0
  40. (40) Georgetown University, grid.213910.8
  41. (41) State Research Institute Centre for Innovative Medicine, grid.493509.2
  42. (42) Vilnius University Hospital Santariskiu Klinikos, grid.426597.b
  43. (43) Cancer Prevention Institute of California, grid.280669.3
  44. (44) Cedars-Sinai Medical Center, grid.50956.3f
  45. (45) Peter MacCallum Cancer Centre, grid.1055.1
  46. (46) Hong Kong Sanatorium and Hospital, grid.414329.9
  47. (47) University of Hong Kong, grid.194645.b
  48. (48) Centre Léon Bérard, grid.418116.b
  49. (49) Institut d'Investigació Biomédica de Bellvitge, grid.418284.3
  50. (50) Unit of Medical Genetics, Department of Preventive and Predictive Medicine, Fondazione IRCCS (Istituto Di Ricovero e Cura a Carattere Scientifico) Istituto Nazionale Tumori (INT), Via Giacomo Venezian 1, 20133, Milan, Italy
  51. (51) University of Melbourne, grid.1008.9
  52. (52) Immunology and Molecular Oncology Unit, Veneto Institute of Oncology IOC - IRCCS, Via Gattamelata 64, Padua, Italy
  53. (53) City Of Hope National Medical Center, grid.410425.6
  54. (54) Helsinki University Central Hospital, grid.15485.3d
  55. (55) Department of Gynaecology and Obstetrics, University Hospital Düsseldorf, Heinrich Heine University Düsseldorf, Düsseldorf, Germany
  56. (56) 513 Parnassus Ave., HSE 901E, 94143-0794, San Francisco, CA, USA
  57. (57) Memorial Sloan Kettering Cancer Center, grid.51462.34
  58. (58) National Institute of Oncology, grid.419617.c
  59. (59) 5841 South Maryland Avenue, MC 2115, Chicago, IL, USA
  60. (60) Seoul National University, grid.31501.36
  61. (61) Roswell Park Cancer Institute, grid.240614.5
  62. (62) Unit of Molecular Bases of Genetic Risk and Genetic Testing, Department of Preventive and Predicted Medicine, Fondazione IRCCS (Istituto Di Ricovero e Cura a Carattere Scientifico) Istituto Nazionale Tumori (INT), c/o Amaedeolab, via GA Amadeo 42, 20133, Milan, Italy
  63. (63) Medical University of Vienna, grid.22937.3d
  64. (64) Department of Epidemiology, Netherlands Cancer Institute, P.O. Box 90203, 1000, Amsterdam, BE, The Netherlands
  65. (65) Department of Medical Oncology, Family Cancer Clinic Erasmus University Medical Center Cancer institute, P.O. Box 5201, 3008, Rotterdam, AE, The Netherlands
  66. (66) Genomics Center, Centre Hospitalier Universitaire de Québec Research Center and Laval University, 2705 Laurier Boulevard, Quebec City, Quebec, Canada
  67. (67) Institute Curie, grid.418596.7
  68. (68) National Human Genome Research Institute, grid.280128.1
  69. (69) Azienda Ospedaliera Universitaria Pisana, grid.144189.1
  70. (70) Portuguese Oncology Institute, grid.418711.a
  71. (71) Cancer Research Initiatives Foundation, Sime Darby Medical Centre, 1 Jalan SS12/1A, 47500, Subang Jaya, Malaysia
  72. (72) University of Malaya, grid.10347.31
  73. (73) Columbia University, grid.21729.3f
  74. (74) Odense University Hospital, grid.7143.1, Southern Denmark Region
  75. (75) Latvian Biomedical Research and Study Centre, grid.419210.f
  76. (76) McGill University, grid.14709.3b
  77. (77) The Ohio State University, grid.261331.4
  78. (78) Beth Israel Deaconess Medical Center, grid.239395.7
  79. (79) University of Pretoria, grid.49697.35
  80. (80) University Hospital Ulm, grid.410712.1
  81. (81) Bar-Ilan University, grid.22098.31
  82. (82) Rebecca Sieff Hospital, grid.415739.d
  83. (83) 4301 West Markham Street, Slot 793, 72205, Little Rock, AR, USA
  84. (84) Garvan Institute of Medical Research, grid.415306.5

Description

BACKGROUND: Most BRCA1 or BRCA2 mutation carriers have inherited a single (heterozygous) mutation. Transheterozygotes (TH) who have inherited deleterious mutations in both BRCA1 and BRCA2 are rare, and the consequences of transheterozygosity are poorly understood. METHODS: From 32,295 female BRCA1/2 mutation carriers, we identified 93 TH (0.3 %). "Cases" were defined as TH, and "controls" were single mutations at BRCA1 (SH1) or BRCA2 (SH2). Matched SH1 "controls" carried a BRCA1 mutation found in the TH "case". Matched SH2 "controls" carried a BRCA2 mutation found in the TH "case". After matching the TH carriers with SH1 or SH2, 91 TH were matched to 9316 SH1, and 89 TH were matched to 3370 SH2. RESULTS: The majority of TH (45.2 %) involved the three common Jewish mutations. TH were more likely than SH1 and SH2 women to have been ever diagnosed with breast cancer (BC; p = 0.002). TH were more likely to be diagnosed with ovarian cancer (OC) than SH2 (p = 0.017), but not SH1. Age at BC diagnosis was the same in TH vs. SH1 (p = 0.231), but was on average 4.5 years younger in TH than in SH2 (p < 0.001). BC in TH was more likely to be estrogen receptor (ER) positive (p = 0.010) or progesterone receptor (PR) positive (p = 0.013) than in SH1, but less likely to be ER positive (p < 0.001) or PR positive (p = 0.012) than SH2. Among 15 tumors from TH patients, there was no clear pattern of loss of heterozygosity (LOH) for BRCA1 or BRCA2 in either BC or OC. CONCLUSIONS: Our observations suggest that clinical TH phenotypes resemble SH1. However, TH breast tumor marker characteristics are phenotypically intermediate to SH1 and SH2.

Funders

Research Categories

Main Subject Area

Fields of Research

Links & Metrics

NORA University Profiles

University of Southern Denmark

Dimensions Citation Indicators

Times Cited: 17

Field Citation Ratio (FCR): 4.43

Relative Citation ratio (RCR): 1.2

Open Access Info

Pure Gold