Article open access publication

Refined histopathological predictors of BRCA1 and BRCA2mutation status: a large-scale analysis of breast cancer characteristics from the BCAC, CIMBA, and ENIGMA consortia

Breast Cancer Research, Springer Nature, ISSN 1465-5411

Volume 16, 6, 2014

DOI:10.1186/s13058-014-0474-y, Dimensions: pub.1029402553, PMC: PMC4352262, PMID: 25857409,

Authors

Wang, Qin (3)
Eeles, Ros (20)
Fortuzzi, Stefano (26) (27)
Pasini, Barbara (29) (30)
Borg, Åke (41)
Andrulis, Irene L (42) (43)
Osorio, Ana (53) (54)
Hall, Per (62)
Fasching, Peter A (64) (65)
Bojesen, Stig E (67) (68)
John, Esther M (75) (76)
West, Dee W (75) (76)
Torres, Diana (60) (77)
Bane, Anita L (87) (88)
Mulligan, Anna M (43) (90)
Giles, Graham G (58) (91)
Milne, Roger L (58) (91)
Baglietto, Laura (58) (91)
Scott, Rodney (93) (94)
Brauch, Hiltrud (95) (96)
Burwinkel, Barbara (60) (102)
Marme, Frederik (102) (103)
Surovy, Harald (60) (102)
Yang, Rongxi (60) (102)
Grip, Mervi (108)
Benítez, Javier (54) (111)
Mannermaa, Arto (112) (113)
Kataja, Vesa (112) (113)
Kosma, Veli-Matti (112) (113)
Hartikainen, Jaana M (112) (113)
Capra, Fabio (26) (27)
Teo, Soo H (114) (115)

* Corresponding author

Affiliations

Organisations

  1. (1) QIMR Berghofer Medical Research Institute, grid.1049.c
  2. (2) Mayo Clinic, grid.66875.3a
  3. (3) University of Cambridge, grid.5335.0
  4. (4) University Hospital Cologne, grid.411097.a
  5. (5) Leipzig University, grid.9647.c
  6. (6) Technical University of Munich, grid.6936.a
  7. (7) Ludwig Maximilian University of Munich, grid.5252.0
  8. (8) Department of Gynaecology and Obstetrics, University Hospital of Schleswig-Holstein, Campus Kiel, Christian Albrechts University Kiel, Kiel, Germany
  9. (9) Institute of Human Genetics, University Hospital of Schleswig-Holstein, Campus Kiel, Christian-Albrechts University Kiel, Kiel, Germany
  10. (10) University Hospital Schleswig-Holstein, grid.412468.d
  11. (11) Department of Gynaecology and Obstetrics, University Hospital Düsseldorf, Heinrich Heine University Düsseldorf, Düsseldorf, Germany
  12. (12) Institute of Human Genetics, University Hospital Heidelberg, Im Neuenheimer Feld 366, 69120, Heidelberg, Germany
  13. (13) University Hospital Ulm, grid.410712.1
  14. (14) Hannover Medical School, grid.10423.34
  15. (15) University of Münster, grid.5949.1
  16. (16) Department of Gynecology and Obstetrics, University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany
  17. (17) Institute of Human Genetics, Campus Virchov Klinikum, Charite Berlin, Germany
  18. (18) Manchester University NHS Foundation Trust, grid.498924.a
  19. (19) Guy's and St Thomas' NHS Foundation Trust, grid.420545.2
  20. (20) Oncogenetics Team, The Institute of Cancer Research and Royal Marsden NHS Foundation Trust, Sutton, UK
  21. (21) Chapel Allerton Hospital, grid.413818.7
  22. (22) Southern General Hospital, grid.413030.5
  23. (23) West Midlands Regional Genetics Service, Birmingham Women's Hospital Healthcare NHS Trust, Edgbaston, Birmingham, UK
  24. (24) Fondazione IRCCS Istituto Nazionale dei Tumori, grid.417893.0
  25. (25) European Institute of Oncology, grid.15667.33
  26. (26) FIRC Institute of Molecular Oncology, grid.7678.e
  27. (27) Cogentech Cancer Genetic Test Laboratory, Via Adamello, 16, 20139, Milan, Italy
  28. (28) Division of Experimental Oncology 1, CRO Aviano National Cancer Institute, Via Franco Gallini 2, 33081, Aviano, PN, Italy
  29. (29) AOU Città della Salute e della Scienza, corso Bramante 88, 10126, Turin, Italy
  30. (30) University of Turin, grid.7605.4
  31. (31) University of Florence, grid.8404.8
  32. (32) Ospedale San Martino, grid.410345.7
  33. (33) University of Sydney, grid.1013.3
  34. (34) University of Pennsylvania, grid.25879.31
  35. (35) Memorial Sloan Kettering Cancer Center, grid.51462.34
  36. (36) Pomeranian Medical University, grid.107950.a
  37. (37) Mayo Clinic, grid.417468.8
  38. (38) Odense University Hospital, grid.7143.1, Southern Denmark Region
  39. (39) Aarhus University Hospital, grid.154185.c, Central Denmark Region
  40. (40) Department of Clinical Genetics, Karolinska University Hospital L5:03, S-171 76, Stockholm, Sweden
  41. (41) Skåne University Hospital, grid.411843.b
  42. (42) Lunenfeld-Tanenbaum Research Institute, grid.250674.2
  43. (43) University of Toronto, grid.17063.33
  44. (44) Case Western Reserve University, grid.67105.35
  45. (45) Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital, Blegdamsvej 9, DK-2100, Copenhagen, Denmark
  46. (46) Hospital Clínico San Carlos, grid.411068.a
  47. (47) City Of Hope National Medical Center, grid.410425.6
  48. (48) The Ohio State University, grid.261331.4
  49. (49) Department of Obstetrics and Gynecology, University of Helsinki and Helsinki University Central Hospital, Haartmaninkatu 8, FI-00029, Helsinki, HUS, Finland
  50. (50) Istituto Oncologico Veneto, grid.419546.b
  51. (51) Dana-Farber Cancer Institute, grid.65499.37
  52. (52) University of Kansas Medical Center, grid.412016.0
  53. (53) Centre for Biomedical Network Research on Rare Diseases, grid.452372.5
  54. (54) Spanish National Cancer Research Centre, grid.7719.8
  55. (55) University of Utah, grid.223827.e
  56. (56) Columbia University, grid.21729.3f
  57. (57) Cedars-Sinai Medical Center, grid.50956.3f
  58. (58) University of Melbourne, grid.1008.9
  59. (59) Department of Basic Sciences, Shaukat Khanum Memorial Cancer Hospital and Research Centre (SKMCH & RC) 7A, Block R3, Johar, Pakistan
  60. (60) German Cancer Research Center, grid.7497.d
  61. (61) 331 Brookline Avenue, 02215, Boston, MA, USA
  62. (62) Karolinska Institute, grid.4714.6
  63. (63) Antoni van Leeuwenhoek Hospital, grid.430814.a
  64. (64) Department of Gynecology and Obstetrics, University Breast Center Franconia, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nuremberg, Comprehensive Cancer Center Erlangen-EMN, Universitätsstrasse 21-23, 91054, Erlangen, Germany
  65. (65) University of California, Los Angeles, grid.19006.3e
  66. (66) Institute of Human Genetics, University Hospital Erlangen, Friedrich Alexander University Erlangen-Nuremberg, Schlossplatz 4, 91054, Erlangen, Germany
  67. (67) University of Copenhagen, grid.5254.6, KU
  68. (68) Herlev Hospital, grid.411900.d, Capital Region
  69. (69) University Medical Center Hamburg-Eppendorf, grid.13648.38
  70. (70) Department of Clinical Genetics, University of Helsinki and Helsinki University Central Hospital, Haartmaninkatu 8, FI-00029, Helsinki, HUS, Finland
  71. (71) Helsinki University Central Hospital, grid.15485.3d
  72. (72) Department of Oncology, University of Helsinki and Helsinki University Central Hospital, Haartmaninkatu 8, FI-00029, HelsinkiHUS, Finland
  73. (73) National Cancer Institute, grid.48336.3a
  74. (74) Maria Skłodowska-Curie Memorial Cancer Center and Institute of Oncology, grid.418165.f
  75. (75) Stanford University, grid.168010.e
  76. (76) Cancer Prevention Institute of California, grid.280669.3
  77. (77) Pontificia Universidad Javeriana, grid.41312.35
  78. (78) Frauenklinik der Stadtklinik Baden-Baden, Balger Straße 50, 76532, Baden-Baden, Germany
  79. (79) Charité, grid.6363.0
  80. (80) Leiden University Medical Center, grid.10419.3d
  81. (81) Erasmus University Medical Center, grid.5645.2
  82. (82) University of Southampton, grid.5491.9
  83. (83) Queen Mary University of London, grid.4868.2
  84. (84) London School of Hygiene & Tropical Medicine, grid.8991.9
  85. (85) Institute of Cancer Research, grid.18886.3f
  86. (86) University of Westminster, grid.12896.34
  87. (87) Juravinski Hospital, grid.414019.9
  88. (88) McMaster University, grid.25073.33
  89. (89) Ontario Cancer Genetics Network, Lunenfeld-Tanenbaum Research Institute of Mount Sinai Hospital, 600 University Avenue, M5G 1X5, Toronto, ON, Canada
  90. (90) University Health Network, grid.231844.8
  91. (91) Cancer Council Victoria, grid.3263.4
  92. (92) The Alfred Hospital, grid.1623.6
  93. (93) John Hunter Hospital, grid.414724.0
  94. (94) University of Newcastle Australia, grid.266842.c
  95. (95) Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology, grid.502798.1
  96. (96) University of Tübingen, grid.10392.39
  97. (97) Institute for Prevention and Occupational Medicine of the German Social Accident Insurance (IPA), Bürkle-de-la-Camp-Platz 1, 44789, Bochum, Germany
  98. (98) Evangelische Kliniken Bonn gGmbH, Johanniter Krankenhaus, Johanniterstraße 3, 53113, Bonn, Germany
  99. (99) University of Sheffield, grid.11835.3e
  100. (100) University of Southern California, grid.42505.36
  101. (101) University of Hawaii at Manoa, grid.410445.0
  102. (102) Heidelberg University, grid.7700.0
  103. (103) National Center for Tumor Diseases, University of Heidelberg, Im Neuenheimer Feld 280, 69120, Heidelberg, Germany
  104. (104) University of California, Irvine, grid.266093.8
  105. (105) Krebsregister Saarland, grid.482902.5
  106. (106) University of Oulu, grid.10858.34
  107. (107) Department of Oncology, Oulu University Hospital, University of Oulu, Kajaanintie 50, FI-90220, Oulu, Finland
  108. (108) Department of Surgery, Oulu University Hospital, University of Oulu, Kajaanintie 50, FI-90220, Oulu, Finland
  109. (109) Hospital Monte Naranco, grid.414858.4
  110. (110) Hospital Universitario La Paz, grid.81821.32
  111. (111) Centro de Investigación en Red de Enfermedades Raras (CIBERER), Valencia, Spain
  112. (112) Kuopio University Hospital, grid.410705.7
  113. (113) University of Eastern Finland, grid.9668.1
  114. (114) Cancer Research Initiatives Foundation, Sime Darby Medical Centre, 1 Jalan SS 12/1a, Ss 12, Subang Jaya, Selangor, Malaysia
  115. (115) University of Malaya, grid.10347.31

Description

INTRODUCTION: The distribution of histopathological features of invasive breast tumors in BRCA1 or BRCA2 germline mutation carriers differs from that of individuals with no known mutation. Histopathological features thus have utility for mutation prediction, including statistical modeling to assess pathogenicity of BRCA1 or BRCA2 variants of uncertain clinical significance. We analyzed large pathology datasets accrued by the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA) and the Breast Cancer Association Consortium (BCAC) to reassess histopathological predictors of BRCA1 and BRCA2 mutation status, and provide robust likelihood ratio (LR) estimates for statistical modeling. METHODS: Selection criteria for study/center inclusion were estrogen receptor (ER) status or grade data available for invasive breast cancer diagnosed younger than 70 years. The dataset included 4,477 BRCA1 mutation carriers, 2,565 BRCA2 mutation carriers, and 47,565 BCAC breast cancer cases. Country-stratified estimates of the likelihood of mutation status by histopathological markers were derived using a Mantel-Haenszel approach. RESULTS: ER-positive phenotype negatively predicted BRCA1 mutation status, irrespective of grade (LRs from 0.08 to 0.90). ER-negative grade 3 histopathology was more predictive of positive BRCA1 mutation status in women 50 years or older (LR = 4.13 (3.70 to 4.62)) versus younger than 50 years (LR = 3.16 (2.96 to 3.37)). For BRCA2, ER-positive grade 3 phenotype modestly predicted positive mutation status irrespective of age (LR = 1.7-fold), whereas ER-negative grade 3 features modestly predicted positive mutation status at 50 years or older (LR = 1.54 (1.27 to 1.88)). Triple-negative tumor status was highly predictive of BRCA1 mutation status for women younger than 50 years (LR = 3.73 (3.43 to 4.05)) and 50 years or older (LR = 4.41 (3.86 to 5.04)), and modestly predictive of positive BRCA2 mutation status in women 50 years or older (LR = 1.79 (1.42 to 2.24)). CONCLUSIONS: These results refine likelihood-ratio estimates for predicting BRCA1 and BRCA2 mutation status by using commonly measured histopathological features. Age at diagnosis is an important variable for most analyses, and grade is more informative than ER status for BRCA2 mutation carrier prediction. The estimates will improve BRCA1 and BRCA2 variant classification and inform patient mutation testing and clinical management.

Funders

Research Categories

Main Subject Area

Fields of Research

Links & Metrics

NORA University Profiles

University of Copenhagen

Aarhus University

Dimensions Citation Indicators

Times Cited: 55

Field Citation Ratio (FCR): 11.43

Relative Citation ratio (RCR): 1.95

Open Access Info

Pure Gold