Article open access publication

Association of Type and Location of BRCA1 and BRCA2 Mutations With Risk of Breast and Ovarian Cancer

JAMA, American Medical Association (AMA), ISSN 0098-7484

Volume 313, 13, 2015

DOI:10.1001/jama.2014.5985, Dimensions: pub.1035471892, PMC: PMC4537700, PMID: 25849179,

Authors

Wan, Fei (2)
Mitchell, Gillian (20) (21)
Ross, Eric (24)
Bernard, Loris (46) (49)
Radice, Paolo (45) (51)
Pensotti, Valeria (49) (51)
Torres, Diana (55) (56)
Houdayer, Claude (87) (88)
Lasset, Christine (90) (91)
Poppe, Bruce (100)
Basil, Jack (106)
Kwong, Ava (119) (120) (121)
Olah, Edith (122)
Papp, Janos (122)
Diez, Orland (123)
Arason, Adalgeir (127) (128)
Barkardottir, Rosa B. (127) (128)
Simard, Jacques (129) (130)
Laframboise, Rachel (130) (131)
Peixoto, Ana (132)
Teixeira, Manuel R. (132) (133)
Park, Sue K (135)
Tischkowitz, Marc (5) (138)
Robson, Mark (140)
Kauff, Noah (140)
Sunde, Lone (147)
Teo, Soo-Hwang (150) (151)

Affiliations

Organisations

  1. (1) Abramson Cancer Center, Perelman School of Medicine at the University of Pennsylvania, Philadelphia
  2. (2) University of Pennsylvania, grid.25879.31
  3. (3) Cancer Center of Lyon, grid.462282.8
  4. (4) QIMR Berghofer Medical Research Institute, grid.1049.c
  5. (5) University of Cambridge, grid.5335.0
  6. (6) Sheba Medical Center, grid.413795.d
  7. (7) Oncology Institute, Rivkah Ziv Medical Center Zefat, Israel
  8. (8) Uppsala University, grid.8993.b
  9. (9) Lund University, grid.4514.4
  10. (10) Linköping University, grid.5640.7
  11. (11) Sahlgrenska University Hospital, grid.1649.a
  12. (12) Karolinska University Hospital, grid.24381.3c
  13. (13) Umeå University, grid.12650.30
  14. (14) University of Chicago Medical Center, grid.412578.d
  15. (15) University of California, Los Angeles, grid.19006.3e
  16. (16) University of California, San Francisco, grid.266102.1
  17. (17) Roswell Park Cancer Institute, grid.240614.5
  18. (18) University of Southern California, grid.42505.36
  19. (19) The University of Texas MD Anderson Cancer Center, grid.240145.6
  20. (20) Peter MacCallum Cancer Centre, grid.1055.1
  21. (21) University of Melbourne, grid.1008.9
  22. (22) Cedars-Sinai Medical Center, grid.50956.3f
  23. (23) University of Kansas Medical Center, grid.412016.0
  24. (24) Temple University Health System, grid.412530.1
  25. (25) Stanford University, grid.168010.e
  26. (26) Cancer Prevention Institute of California, grid.280669.3
  27. (27) Dana-Farber Cancer Institute, grid.65499.37
  28. (28) Columbia University, grid.21729.3f
  29. (29) University of Utah, grid.223827.e
  30. (30) Vilnius University Hospital Santariskiu Klinikos, grid.426597.b
  31. (31) Latvian Biomedical Research and Study Centre, grid.419210.f
  32. (32) Beth Israel Deaconess Medical Center, grid.239395.7
  33. (33) University of Pretoria, grid.49697.35
  34. (34) City Of Hope National Medical Center, grid.410425.6
  35. (35) Departments of Oncology or Clinical Genetics, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark
  36. (36) Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark
  37. (37) Hospital de Sant Pau, grid.413396.a
  38. (38) Spanish National Cancer Research Centre, grid.7719.8
  39. (39) Hospital Clínico Universitario Lozano Blesa, grid.411050.1
  40. (40) Molecular Genetics Laboratory (Department of Genetics), Cruces University Hospital Barakaldo, Bizkaia, Spain
  41. (41) University of Valladolid, grid.5239.d
  42. (42) Clinical Cancer Genetics, City of Hope Clinical Cancer Genetics Community Research Network, Duarte, California
  43. (43) Istituti Fisioterapici Ospitalieri, grid.417520.5
  44. (44) University of Turin, grid.7605.4
  45. (45) Fondazione IRCCS Istituto Nazionale dei Tumori, grid.417893.0
  46. (46) European Institute of Oncology, grid.15667.33
  47. (47) Azienda Ospedaliera Citta' Della Salute E Della Scienza Di Torino, grid.432329.d
  48. (48) Sapienza University of Rome, grid.7841.a
  49. (49) Cogentech Cancer Genetic Test Laboratory, Milan, Italy
  50. (50) Agostino Gemelli University Polyclinic, grid.411075.6
  51. (51) FIRC Institute of Molecular Oncology, grid.7678.e
  52. (52) Centro di Riferimento Oncologico, grid.418321.d
  53. (53) Ospedale San Martino, grid.410345.7
  54. (54) Molecular Diagnostics Laboratory, IRRP, National Centre for Scientific Research “Demokritos” Aghia Paraskevi Attikis, Athens, Greece
  55. (55) Pontificia Universidad Javeriana, grid.41312.35
  56. (56) German Cancer Research Center, grid.7497.d
  57. (57) Shaukat Khanum Memorial Cancer Hospital and Research Center, grid.415662.2
  58. (58) Manchester University NHS Foundation Trust, grid.498924.a
  59. (59) National Health Service, grid.451052.7
  60. (60) Royal Hospital for Sick Children, grid.415571.3
  61. (61) Princess Anne Hospital, grid.415216.5
  62. (62) West Midlands Regional Genetics Service, Birmingham Women's Hospital Healthcare NHS Trust, Edgbaston, Birmingham, United Kingdom
  63. (63) Sheffield Children's Hospital, grid.413991.7
  64. (64) Royal Devon and Exeter Hospital, grid.416118.b
  65. (65) Clinical Genetics Department, St Georges Hospital, University of London, United Kingdom
  66. (66) Belfast City Hospital, grid.412914.b
  67. (67) Churchill Hospital, grid.415719.f
  68. (68) Western General Hospital, grid.417068.c
  69. (69) St. James's Hospital, grid.416409.e
  70. (70) Guy's Hospital, grid.239826.4
  71. (71) Yorkshire Regional Genetics Service, Leeds, United Kingdom
  72. (72) South West Regional Genetics Service, Bristol, United Kingdom
  73. (73) University Hospital Cologne, grid.411097.a
  74. (74) Leipzig University, grid.9647.c
  75. (75) Department of Gynaecology and Obstetrics, Division of Tumor Genetics, Klinikum rechts der Isar, Technical University Munich, Munich, Germany
  76. (76) University Hospital Schleswig-Holstein, grid.412468.d
  77. (77) Institute of Human Genetics, University Medical Center Schleswig-Holstein, Campus Kiel, Germany
  78. (78) Department of Gynaecology and Obstetrics, University Hospital Düsseldorf, Heinrich Heine University Düsseldorf, Düsseldorf, Germany
  79. (79) University Hospital Heidelberg, grid.5253.1
  80. (80) University Hospital Ulm, grid.410712.1
  81. (81) Hannover Medical School, grid.10423.34
  82. (82) Department of Gynaecology and Obstetrics, University Hospital Carl Gustav Carus, Technical University Dresden, Dresden, Germany
  83. (83) TU Dresden, grid.4488.0
  84. (84) Charité, grid.6363.0
  85. (85) University of Würzburg, grid.8379.5
  86. (86) University of Regensburg, grid.7727.5
  87. (87) Paris Descartes University, grid.10992.33
  88. (88) Institute Curie, grid.418596.7
  89. (89) Unité Mixte de Génétique Constitutionnelle des Cancers Fréquents, Hospices Civils de Lyon–Centre Léon Bérard, Lyon, France
  90. (90) Centre Léon Bérard, grid.418116.b
  91. (91) Claude Bernard University Lyon 1, grid.7849.2
  92. (92) Aix-Marseille University, grid.5399.6
  93. (93) Centre Oscar Lambret, grid.452351.4
  94. (94) Unité d’Oncogénétique, CLCC Paul Strauss, Strasbourg, France
  95. (95) Centre Hospitalier Universitaire de Besançon, grid.411158.8
  96. (96) Bretonneau Hospital, grid.411777.3
  97. (97) Oncogénétique Clinique, Hôpital René Huguenin/Institut Curie, Saint-Cloud, France
  98. (98) Laboratoire d’Oncogénétique, Hôpital René Huguenin/Institut Curie, Saint-Cloud, France
  99. (99) Georgetown University Medical Center, grid.411667.3
  100. (100) Ghent University, grid.5342.0
  101. (101) GOG Statistical and Data Center, Buffalo, New York
  102. (102) Evanston Hospital, grid.410470.6
  103. (103) Tufts University, grid.429997.8
  104. (104) University of North Carolina System, grid.410711.2
  105. (105) New York University, grid.137628.9
  106. (106) Good Samaritan Hospital, grid.413160.1
  107. (107) Yale University, grid.47100.32
  108. (108) Hospital Clínico San Carlos, grid.411068.a
  109. (109) Helsinki University Central Hospital, grid.15485.3d
  110. (110) University of Groningen, grid.4830.f
  111. (111) Antoni van Leeuwenhoek Hospital, grid.430814.a
  112. (112) Erasmus University Medical Center, grid.5645.2
  113. (113) VU University Medical Center, grid.16872.3a
  114. (114) Leiden University Medical Center, grid.10419.3d
  115. (115) Maastricht University Medical Centre, grid.412966.e
  116. (116) Radboud University Nijmegen Medical Centre, grid.10417.33
  117. (117) University Medical Center Utrecht, grid.7692.a
  118. (118) Academic Medical Center, grid.5650.6
  119. (119) Hong Kong Hereditary Breast Cancer Family Registry, Hong Kong
  120. (120) Hong Kong Sanatorium and Hospital, grid.414329.9
  121. (121) University of Hong Kong, grid.194645.b
  122. (122) National Institute of Oncology, grid.419617.c
  123. (123) Hospital Universitari Vall d'Hebron, grid.411083.f
  124. (124) Catalan Institute of Oncology, grid.418701.b
  125. (125) Pomeranian Medical University, grid.107950.a
  126. (126) Medical University of Warsaw, grid.13339.3b
  127. (127) National University Hospital of Iceland, grid.410540.4
  128. (128) University of Iceland, grid.14013.37
  129. (129) Laval University, grid.23856.3a
  130. (130) Centre Hospitalier Universitaire de Québec, grid.411081.d
  131. (131) Istituto Oncologico Veneto, grid.419546.b
  132. (132) Portuguese Oncology Institute, grid.418711.a
  133. (133) University of Porto, grid.5808.5
  134. (134) Soonchunhyang University Hospital, grid.412678.e
  135. (135) Seoul National University, grid.31501.36
  136. (136) Seoul St. Mary's Hospital, grid.414966.8
  137. (137) Mayo Clinic, grid.66875.3a
  138. (138) McGill University, grid.14709.3b
  139. (139) Department of Cancer Epidemiology and Genetics, Masaryk Memorial Cancer Institute and MF MU, Brno, Czech Republic
  140. (140) Memorial Sloan Kettering Cancer Center, grid.51462.34
  141. (141) Medical University of Vienna, grid.22937.3d
  142. (142) National Cancer Institute, grid.48336.3a
  143. (143) Institute of Oncology NN Petrov, grid.465337.0
  144. (144) The Ohio State University, grid.261331.4
  145. (145) Vejle Sygehus, grid.417271.6, Southern Denmark Region
  146. (146) Aalborg Hospital, grid.27530.33, North Denmark Region
  147. (147) Aarhus University Hospital, grid.154185.c, Central Denmark Region
  148. (148) Odense University Hospital, grid.7143.1, Southern Denmark Region
  149. (149) Azienda Ospedaliera Universitaria Pisana, grid.144189.1
  150. (150) Cancer Research Initiatives Foundation, Sime Darby Medical Centre, Subang Jaya, Malaysia
  151. (151) University of Malaya, grid.10347.31
  152. (152) NorthShore University HealthSystem, grid.240372.0
  153. (153) Lunenfeld-Tanenbaum Research Institute, grid.250674.2

Description

IMPORTANCE: Limited information about the relationship between specific mutations in BRCA1 or BRCA2 (BRCA1/2) and cancer risk exists. OBJECTIVE: To identify mutation-specific cancer risks for carriers of BRCA1/2. DESIGN, SETTING, AND PARTICIPANTS: Observational study of women who were ascertained between 1937 and 2011 (median, 1999) and found to carry disease-associated BRCA1 or BRCA2 mutations. The international sample comprised 19,581 carriers of BRCA1 mutations and 11,900 carriers of BRCA2 mutations from 55 centers in 33 countries on 6 continents. We estimated hazard ratios for breast and ovarian cancer based on mutation type, function, and nucleotide position. We also estimated RHR, the ratio of breast vs ovarian cancer hazard ratios. A value of RHR greater than 1 indicated elevated breast cancer risk; a value of RHR less than 1 indicated elevated ovarian cancer risk. EXPOSURES: Mutations of BRCA1 or BRCA2. MAIN OUTCOMES AND MEASURES: Breast and ovarian cancer risks. RESULTS: Among BRCA1 mutation carriers, 9052 women (46%) were diagnosed with breast cancer, 2317 (12%) with ovarian cancer, 1041 (5%) with breast and ovarian cancer, and 7171 (37%) without cancer. Among BRCA2 mutation carriers, 6180 women (52%) were diagnosed with breast cancer, 682 (6%) with ovarian cancer, 272 (2%) with breast and ovarian cancer, and 4766 (40%) without cancer. In BRCA1, we identified 3 breast cancer cluster regions (BCCRs) located at c.179 to c.505 (BCCR1; RHR = 1.46; 95% CI, 1.22-1.74; P = 2 × 10(-6)), c.4328 to c.4945 (BCCR2; RHR = 1.34; 95% CI, 1.01-1.78; P = .04), and c. 5261 to c.5563 (BCCR2', RHR = 1.38; 95% CI, 1.22-1.55; P = 6 × 10(-9)). We also identified an ovarian cancer cluster region (OCCR) from c.1380 to c.4062 (approximately exon 11) with RHR = 0.62 (95% CI, 0.56-0.70; P = 9 × 10(-17)). In BRCA2, we observed multiple BCCRs spanning c.1 to c.596 (BCCR1; RHR = 1.71; 95% CI, 1.06-2.78; P = .03), c.772 to c.1806 (BCCR1'; RHR = 1.63; 95% CI, 1.10-2.40; P = .01), and c.7394 to c.8904 (BCCR2; RHR = 2.31; 95% CI, 1.69-3.16; P = .00002). We also identified 3 OCCRs: the first (OCCR1) spanned c.3249 to c.5681 that was adjacent to c.5946delT (6174delT; RHR = 0.51; 95% CI, 0.44-0.60; P = 6 × 10(-17)). The second OCCR spanned c.6645 to c.7471 (OCCR2; RHR = 0.57; 95% CI, 0.41-0.80; P = .001). Mutations conferring nonsense-mediated decay were associated with differential breast or ovarian cancer risks and an earlier age of breast cancer diagnosis for both BRCA1 and BRCA2 mutation carriers. CONCLUSIONS AND RELEVANCE: Breast and ovarian cancer risks varied by type and location of BRCA1/2 mutations. With appropriate validation, these data may have implications for risk assessment and cancer prevention decision making for carriers of BRCA1 and BRCA2 mutations.

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Times Cited: 212

Field Citation Ratio (FCR): 46.72

Relative Citation ratio (RCR): 8.78

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