Article open access publication

Associations of common breast cancer susceptibility alleles with risk of breast cancer subtypes in BRCA1 and BRCA2 mutation carriers

Breast Cancer Research, Springer Nature, ISSN 1465-5411

Volume 16, 6, 2014

DOI:10.1186/s13058-014-0492-9, Dimensions: pub.1021291764, PMC: PMC4406179, PMID: 25919761,

Authors

James, Paul (14) (20)
Eeles, Ros (68)
Rhiem, Kerstin (9) (10)
Faivre, Laurence (89) (90)
Bonadona, Valérie (93) (94)
Hays, John (99)
Olah, Edith (110)
Diez, Orland (111)
Teulé, Alex (112)
Soucy, Penny (116)
Rennert, Gad (124)
Arver, Brita (132)
Borg, Ake (134)
Ehrencrona, Hans (133) (135)
HEBON (8)

* Corresponding author

Affiliations

Organisations

  1. (1) University of Cambridge, grid.5335.0
  2. (2) City Of Hope National Medical Center, grid.410425.6
  3. (3) Memorial Sloan Kettering Cancer Center, grid.51462.34
  4. (4) University Health Network, grid.231844.8
  5. (5) University of Toronto, grid.17063.33
  6. (6) Lunenfeld-Tanenbaum Research Institute, grid.250674.2
  7. (7) QIMR Berghofer Medical Research Institute, grid.1049.c
  8. (8) Antoni van Leeuwenhoek Hospital, grid.430814.a
  9. (9) University of Cologne, grid.6190.e
  10. (10) University Hospital Cologne, grid.411097.a
  11. (11) Leipzig University, grid.9647.c
  12. (12) Helsinki University Central Hospital, grid.15485.3d
  13. (13) Odense University Hospital, grid.7143.1, Southern Denmark Region
  14. (14) University of Melbourne, grid.1008.9
  15. (15) Fondazione IRCCS Istituto Nazionale dei Tumori, grid.417893.0
  16. (16) University of Southern California, grid.42505.36
  17. (17) University of Pennsylvania, grid.25879.31
  18. (18) University of California, San Francisco, grid.266102.1
  19. (19) The University of Texas MD Anderson Cancer Center, grid.240145.6
  20. (20) Peter MacCallum Cancer Centre, grid.1055.1
  21. (21) Cedars-Sinai Medical Center, grid.50956.3f
  22. (22) Cancer Prevention Institute of California, grid.280669.3
  23. (23) Columbia University, grid.21729.3f
  24. (24) Temple University Health System, grid.412530.1
  25. (25) University of Utah, grid.223827.e
  26. (26) State Research Institute Centre for Innovative Medicine, grid.493509.2
  27. (27) Vilnius University Hospital Santariskiu Klinikos, grid.426597.b
  28. (28) Latvian Biomedical Research and Study Centre, grid.419210.f
  29. (29) Beth Israel Deaconess Medical Center, grid.239395.7
  30. (30) University of Pretoria, grid.49697.35
  31. (31) Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark
  32. (32) Department of Oncology, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark
  33. (33) Department of Clinical Genetics, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark
  34. (34) Mayo Clinic, grid.66875.3a
  35. (35) Spanish National Cancer Research Centre, grid.7719.8
  36. (36) University of Valladolid, grid.5239.d
  37. (37) Covenant Health Joe Arrington Cancer Research Center, care of City of Hope Clinical Cancer Genetics Community Research Network, Duarte, CA, USA
  38. (38) Kootenai Cancer Center, care of City of Hope Clinical Cancer Genetics Community Research Network, Duarte, CA, USA
  39. (39) FIRC Institute of Molecular Oncology, grid.7678.e
  40. (40) European Institute of Oncology, grid.15667.33
  41. (41) Centro di Riferimento Oncologico, grid.418321.d
  42. (42) Ospedale San Martino, grid.410345.7
  43. (43) University of Florence, grid.8404.8
  44. (44) Ospedale di Circolo e Fondazione Macchi, grid.412972.b
  45. (45) Sapienza University of Rome, grid.7841.a
  46. (46) National Centre of Scientific Research Demokritos, grid.6083.d
  47. (47) Dana-Farber Cancer Institute, grid.65499.37
  48. (48) German Cancer Research Center, grid.7497.d
  49. (49) St Michael's Hospital, grid.416544.6
  50. (50) Royal Devon and Exeter Hospital, grid.416118.b
  51. (51) Liverpool Womens NHS Foundation Trust, grid.419317.9
  52. (52) Manchester University NHS Foundation Trust, grid.498924.a
  53. (53) University Hospital Southampton NHS Foundation Trust, grid.430506.4
  54. (54) Institute of Genetic Medicine, Centre for Life, Newcastle Upon Tyne Hospitals NHS Trust, Newcastle upon Tyne, UK
  55. (55) North West Thames Regional Genetics Service, Kennedy-Galton Centre, Harrow, UK
  56. (56) Sheffield Children's Hospital, grid.413991.7
  57. (57) Addenbrooke's Hospital, grid.120073.7
  58. (58) Yorkshire Regional Genetics Service, Leeds, UK
  59. (59) University Hospitals of Leicester NHS Trust, grid.269014.8
  60. (60) West Midlands Regional Genetics Service, Birmingham Women's Hospital Healthcare NHS Trust, Edgbaston, Birmingham, UK
  61. (61) Churchill Hospital, grid.415719.f
  62. (62) Guy's and St Thomas' NHS Foundation Trust, grid.420545.2
  63. (63) Great Ormond Street Hospital for Children NHS Foundation Trust, grid.424537.3
  64. (64) St. James's Hospital, grid.416409.e
  65. (65) University Hospital of Wales, grid.241103.5
  66. (66) Western General Hospital, grid.417068.c
  67. (67) Queen's University Belfast, grid.4777.3
  68. (68) Royal Marsden NHS Foundation Trust, grid.5072.0
  69. (69) Royal Hospital for Sick Children, grid.415571.3
  70. (70) University College London, grid.83440.3b
  71. (71) University of Kansas Medical Center, grid.412016.0
  72. (72) Department of Gynaecology and Obstetrics, Division of Tumor Genetics, Klinikum rechts der Isar, Technical University of Munich, Munich, Germany
  73. (73) Ludwig Maximilian University of Munich, grid.5252.0
  74. (74) University Hospital Schleswig-Holstein, grid.412468.d
  75. (75) Institute of Human Genetics, University Hospital of Schleswig-Holstein, University Kiel, Kiel, Germany
  76. (76) Heinrich Heine University Düsseldorf, grid.411327.2
  77. (77) Heidelberg University, grid.7700.0
  78. (78) Hannover Medical School, grid.10423.34
  79. (79) University of Bonn, grid.10388.32
  80. (80) University Hospital Carl Gustav Carus, grid.412282.f
  81. (81) Charité, grid.6363.0
  82. (82) University Hospital Ulm, grid.410712.1
  83. (83) University of Würzburg, grid.8379.5
  84. (84) Institute Curie, grid.418596.7
  85. (85) Paris Descartes University, grid.10992.33
  86. (86) Hôpital René Huguenin, grid.418205.a
  87. (87) Service de Génétique Clinique Chromosomique et Moléculaire, Centre Hospitalier Universitaire de St Etienne, St Etienne, France
  88. (88) University of Lyon System, grid.25697.3f
  89. (89) Centre Georges François Leclerc, grid.418037.9
  90. (90) Centre de Génétique, CHU Dijon, Université de Bourgogne, Dijon, France
  91. (91) University of Bordeaux, grid.412041.2
  92. (92) Unité Mixte de Génétique Constitutionnelle des Cancers Fréquents, Hospices Civils de Lyon, Centre Léon Bérard, Lyon, France
  93. (93) Centre Léon Bérard, grid.418116.b
  94. (94) Claude Bernard University Lyon 1, grid.7849.2
  95. (95) Georgetown University Medical Center, grid.411667.3
  96. (96) Ghent University, grid.5342.0
  97. (97) Roswell Park Cancer Institute, grid.240614.5
  98. (98) Prince of Wales Hospital, grid.415193.b
  99. (99) The Ohio State University, grid.261331.4
  100. (100) NorthShore University HealthSystem, grid.240372.0
  101. (101) Instituto de Investigación Sanitaria del Hospital Clínico San Carlos, grid.414780.e
  102. (102) Academic Medical Center, grid.5650.6
  103. (103) VU University Medical Center, grid.16872.3a
  104. (104) University of Groningen, grid.4830.f
  105. (105) Leiden University Medical Center, grid.10419.3d
  106. (106) Maastricht University Medical Centre, grid.412966.e
  107. (107) Radboud University Nijmegen Medical Centre, grid.10417.33
  108. (108) Erasmus University Medical Center, grid.5645.2
  109. (109) University Medical Center Utrecht, grid.7692.a
  110. (110) National Institute of Oncology, grid.419617.c
  111. (111) Hospital Universitari Vall d'Hebron, grid.411083.f
  112. (112) Catalan Institute of Oncology, grid.418701.b
  113. (113) Pomeranian Medical University, grid.107950.a
  114. (114) University of Iceland, grid.14013.37
  115. (115) Hôpitaux Universitaires de Strasbourg, grid.412220.7
  116. (116) Centre Hospitalier Universitaire de Québec, grid.411081.d
  117. (117) Istituti di Ricovero e Cura a Carattere Scientifico, grid.414603.4
  118. (118) Portuguese Oncology Institute, grid.418711.a
  119. (119) Mayo Clinic, grid.417468.8
  120. (120) National Human Genome Research Institute, grid.280128.1
  121. (121) Medical University of Vienna, grid.22937.3d
  122. (122) Moffitt Cancer Center, grid.468198.a
  123. (123) National Cancer Institute, grid.48336.3a
  124. (124) Technion – Israel Institute of Technology, grid.6451.6
  125. (125) Institute of Oncology NN Petrov, grid.465337.0
  126. (126) Mount Sinai Hospital, grid.416166.2
  127. (127) Vejle Sygehus, grid.417271.6, Southern Denmark Region
  128. (128) Aalborg Hospital, grid.27530.33, North Denmark Region
  129. (129) Aarhus University Hospital, grid.154185.c, Central Denmark Region
  130. (130) Azienda Ospedaliera Universitaria Pisana, grid.144189.1
  131. (131) Sheba Medical Center, grid.413795.d
  132. (132) Karolinska University Hospital, grid.24381.3c
  133. (133) Skåne University Hospital, grid.411843.b
  134. (134) Lund University, grid.4514.4
  135. (135) University of Chicago Medical Center, grid.412578.d
  136. (136) 5841 South Maryland Avenue, 2115, Chicago, MC, IL, USA
  137. (137) GEMO Study: National Cancer Genetics Network, UNICANCER Genetic Group, Paris, France

Description

INTRODUCTION: More than 70 common alleles are known to be involved in breast cancer (BC) susceptibility, and several exhibit significant heterogeneity in their associations with different BC subtypes. Although there are differences in the association patterns between BRCA1 and BRCA2 mutation carriers and the general population for several loci, no study has comprehensively evaluated the associations of all known BC susceptibility alleles with risk of BC subtypes in BRCA1 and BRCA2 carriers. METHODS: We used data from 15,252 BRCA1 and 8,211 BRCA2 carriers to analyze the associations between approximately 200,000 genetic variants on the iCOGS array and risk of BC subtypes defined by estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2) and triple-negative- (TN) status; morphologic subtypes; histological grade; and nodal involvement. RESULTS: The estimated BC hazard ratios (HRs) for the 74 known BC alleles in BRCA1 carriers exhibited moderate correlations with the corresponding odds ratios from the general population. However, their associations with ER-positive BC in BRCA1 carriers were more consistent with the ER-positive associations in the general population (intraclass correlation (ICC) = 0.61, 95% confidence interval (CI): 0.45 to 0.74), and the same was true when considering ER-negative associations in both groups (ICC = 0.59, 95% CI: 0.42 to 0.72). Similarly, there was strong correlation between the ER-positive associations for BRCA1 and BRCA2 carriers (ICC = 0.67, 95% CI: 0.52 to 0.78), whereas ER-positive associations in any one of the groups were generally inconsistent with ER-negative associations in any of the others. After stratifying by ER status in mutation carriers, additional significant associations were observed. Several previously unreported variants exhibited associations at P <10(-6) in the analyses by PR status, HER2 status, TN phenotype, morphologic subtypes, histological grade and nodal involvement. CONCLUSIONS: Differences in associations of common BC susceptibility alleles between BRCA1 and BRCA2 carriers and the general population are explained to a large extent by differences in the prevalence of ER-positive and ER-negative tumors. Estimates of the risks associated with these variants based on population-based studies are likely to be applicable to mutation carriers after taking ER status into account, which has implications for risk prediction.

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Times Cited: 36

Field Citation Ratio (FCR): 7.46

Relative Citation ratio (RCR): 1.56

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