Article open access publication

Mutational spectrum in a worldwide study of 29,700 families with BRCA1 or BRCA2 mutations

Human Mutation, Wiley, ISSN 1098-1004

Volume 39, 5, 2018

DOI:10.1002/humu.23406, Dimensions: pub.1101040720, PMC: PMC5903938, PMID: 29446198,

Authors

Chan, TL (11)
Park, Sue Kyung (15) (16)
Torres, Diana (3) (17)
Andrulis, Irene L. (27) (28)
Benitez, Javier (36) (37)
Eeles, Ros (64)
EMBRACE (19)
Hauke, Jan (89)
HEBON (90)
John, Esther M (101) (102)
Kast, Karin (105)
Lee, Annette (112)
Lu, Karen H. (119)
Osorio, Ana (134)
Papi, Laura (135)
Peixoto, Ana (138) (139)
Ramus, Susan J (144) (145)
Robson, Mark (148)
Snape, Katie (155)
Sobol, Hagay (156)
Southey, Melissa (107) (156)
Teixeira, Manuel R. (138) (139)
Teulé, Alex (160)
Tung, Nadine (166)
Vega, Ana (172)
Walker, Lisa (176)
Zidan, Jamal (179)

Affiliations

Organisations

  1. (1) Harvard University, grid.38142.3c
  2. (2) Sheba Medical Center, grid.413795.d
  3. (3) German Cancer Research Center, grid.7497.d
  4. (4) Center for Clinical Cancer Genetics and Global Health University of Chicago Chicago USA
  5. (5) The Hong Kong Hereditary Breast Cancer Family Registry Cancer Genetics Center Hong Kong Sanatorium and Hospital Hong Kong China
  6. (6) National Institute of Oncology, grid.419617.c
  7. (7) University of Buenos Aires, grid.7345.5
  8. (8) Cancer Research Initiatives Foundation, grid.427737.2
  9. (9) Department of Clinical Genetics Odense University Hospital Odense Denmark
  10. (10) Division of Clinical Cancer Genomics City of Hope Cancer Center California USA
  11. (11) Division of Molecular Pathology Department of Pathology Hong Kong Sanatorium & Hospital Happy Valley Hong Kong
  12. (12) Department of Laboratory Medicine and Pathology and Health Sciences Research Rochester USA
  13. (13) Department of Dermatology University of Utah School of Medicine Salt Lake City USA
  14. (14) Molecular Oncology Research Center Barretos Cancer Hospital São Paulo Brazil
  15. (15) Department of Preventive Medicine Seoul National University College of Medicine Seoul Korea
  16. (16) Seoul National University, grid.31501.36
  17. (17) Pontificia Universidad Javeriana, grid.41312.35
  18. (18) Cancer Genetics Laboratory, Department of Genetics University of Pretoria South Africa
  19. (19) University of Cambridge, grid.5335.0
  20. (20) QIMR Berghofer Medical Research Institute, grid.1049.c
  21. (21) Department of Clinical Genetics Academic Medical Center Amsterdam The Netherlands
  22. (22) City Of Hope National Medical Center, grid.410425.6
  23. (23) Yorkshire Regional Genetics Service Chapel Allerton Hospital Leeds UK
  24. (24) Istituto Oncologico Veneto, grid.419546.b
  25. (25) Department of Clinical Genetics Helsinki University Hospital Helsinki Finland
  26. (26) Hereditary Cancer Clinic Prince of Wales Hospital Randwick Australia
  27. (27) Lunenfeld-Tanenbaum Research Institute, grid.250674.2
  28. (28) University of Toronto, grid.17063.33
  29. (29) Laboratory of Cell Biology, Department of Pathology, hus 9, Landspitali‐LSH v/Hringbraut, 101 Reykjavik, Iceland and BMC (Biomedical Centre), Faculty of Medicine University of Iceland Reykjavik Iceland
  30. (30) Department of Gynaecology & Oncology Medical University of Vienna Austria
  31. (31) Department of Breast Medical Oncology and Clinical Cancer Genetics Program University Of Texas MD Anderson Cancer Center Houston USA
  32. (32) Medical University of Vienna, grid.22937.3d
  33. (33) Unit of Medical Genetics, Department of Medical Oncology and Hematology Fondazione IRCCS (Istituto Di Ricovero e Cura a Carattere Scientifico) Instituto Nazionale Tumori (INT) Milan Italy
  34. (34) Department of Medical Oncology Vall d'Hebron University Hospital Barcelona Spain
  35. (35) European Institute of Oncology, grid.15667.33
  36. (36) Centre for Biomedical Network Research on Rare Diseases, grid.452372.5
  37. (37) Human Genetics Group and Genotyping Unit (CEGEN), Human Cancer Genetics Programme Spanish National Cancer Research Centre (CNIO) Madrid Spain
  38. (38) Dept of OB/GYN, Comprehensive Cancer Center Medical University of Vienna Vienna Austria
  39. (39) The Institute of Oncology Chaim Sheba Medical Center Ramat Gan Israel
  40. (40) University of California, San Francisco, grid.266102.1
  41. (41) Department of Clinical Genetics Maastricht University Medical Center Maastricht The Netherlands
  42. (42) Unité de Prévention et d'Epidémiologie Génétique Centre Léon Bérard, 28 rue Laënnec Lyon France
  43. (43) University of Pennsylvania, grid.25879.31
  44. (44) Department of Clinical Genetics Royal Devon & Exeter Hospital Exeter UK
  45. (45) Service de Génétique Institut Curie, 26 rue d'Ulm Paris France
  46. (46) Department of Medicine Huntsman Cancer Institute Salt Lake City USA
  47. (47) Molecular Oncology Laboratory Hospital Clinico San Carlos Instituto de Investigación Sanitaria San Carlos (IdISSC) Centro Investigación Biomédica en Red de Cáncer (CIBERONC) Madrid Spain
  48. (48) Institute of Human Genetics University Hospital of Schleswig‐Holstein Kiel Germany
  49. (49) Section of Molecular Genetics, Dept. of Laboratory Medicine University Hospital of Pisa Pisa Italy
  50. (50) Research Division Peter MacCallum Cancer Centre Melbourne Australia
  51. (51) CRCHU de Quebec‐oncologie, Centre des maladies du sein Deschênes‐Fabia Hôpital du Saint‐Sacrement Sainte‐Foy Canada
  52. (52) Columbia University, grid.21729.3f
  53. (53) Ghent University, grid.5342.0
  54. (54) Department of Clinical Genetics, Family Cancer Clinic Erasmus University Medical Center Rotterdam The Netherlands
  55. (55) Sheffield Clinical Genetics Service Sheffield Children's Hospital Sheffield UK
  56. (56) University of Glasgow, grid.8756.c
  57. (57) Unité d'oncogénétique ICO‐Centre René Gauducheau Saint Herblain France
  58. (58) Oncogenetics Group, Vall d'Hebron Institute of Oncology (VHIO), Clinical and Molecular Genetics Area Vall d'Hebron University Hospital Barcelona Spain
  59. (59) Department of Population Sciences Beckman Research Institute of City of Hope Duarte USA
  60. (60) Ludwig Maximilian University of Munich, grid.5252.0
  61. (61) Cáncer Hereditario, Instituto de Biología y Genética Molecular, IBGM Universidad de Valladolid Valladolid Spain
  62. (62) University of Münster, grid.5949.1
  63. (63) Nottingham Clinical Genetics Service Nottingham University Hospitals NHS Trust Nottingham UK
  64. (64) National Health Service, grid.451052.7
  65. (65) Skåne University Hospital, grid.411843.b
  66. (66) Department of Oncology, Rigshospitalet Copenhagen University Hospital Copenhagen Denmark
  67. (67) Institute for Medical Informatics, Statistics and Epidemiology University of Leipzig Leipzig Germany
  68. (68) Department of Gynaecology and Obstetrics, Division of Tumor Genetics, Klinikum rechts der Isar Technical University Munich Germany
  69. (69) Genomic Medicine, Manchester Academic Health Sciences Centre, Division of Evolution and Genomic Sciences University of Manchester, Central Manchester University Hospitals NHS Foundation Trust Manchester UK
  70. (70) Centre de Lutte Contre le Cancer Georges François Leclerc, France and Genomic and Immunotherapy Medical Institute Dijon University Hospital Dijon France
  71. (71) Molecular Diagnostic Unit, Hereditary Cancer Program, ICO‐IDIBELL (Catalan Institute of Oncology‐Bellvitge Biomedical Research Institute) Barcelona Spain
  72. (72) Laboratoire de Génétique Chromosomique Hôtel Dieu Centre Hospitalier Chambéry France
  73. (73) Department of Cancer Epidemiology and Genetics Masaryk Memorial Cancer Institute Brno Czech Republic
  74. (74) Columbus University, grid.441420.7
  75. (75) Oncogenetics Department Barretos Cancer Hospital Barretos Brazil
  76. (76) UCLA Schools of Medicine and Public Health, Division of Cancer Prevention & Control Research Jonsson Comprehensive Cancer Center Los Angeles USA
  77. (77) Dana-Farber Cancer Institute, grid.65499.37
  78. (78) University of Würzburg, grid.8379.5
  79. (79) Department of Tumour Biology Institut Curie Paris France
  80. (80) Institute Curie, grid.418596.7
  81. (81) Department of Clinical Genetics Copenhagen Denmark
  82. (82) Service Régional Oncogénétique Poitou‐Charentes Centre Hospitalier Niort France
  83. (83) Department of Molecular Medicine University La Sapienza, and Istituto Pasteur ‐ Fondazione Cenci‐Bolognetti Rome Italy
  84. (84) Bâtiment Cheney D Centre Léon Bérard Lyon France
  85. (85) Ontario Cancer Genetics Network: Lunenfeld‐Tanenbaum Research Institute Mount Sinai Hospital Toronto Canada
  86. (86) Department of Pathology and Laboratory Medicine University of Kansas Medical Center Kansas City USA
  87. (87) Clinical Genetics Branch, DCEG, NCI NIH Bethesda USA
  88. (88) Pomeranian Medical University, grid.107950.a
  89. (89) Center for Familial Breast and Ovarian Cancer, Center for Integrated Oncology (CIO), Medical Faculty University Hospital Cologne Cologne Germany
  90. (90) The Hereditary Breast and Ovarian Cancer Research Group Netherlands (HEBON) Netherlands Cancer Institute Amsterdam The Netherlands
  91. (91) Institute of Genetic Medicine Centre for Life Newcastle Upon Tyne Hospitals NHS Trust Newcastle upon Tyne UK
  92. (92) Institute of Human Genetics University Leipzig Leipzig Germany
  93. (93) Family Cancer Clinic Netherlands Cancer Institute Amsterdam The Netherlands
  94. (94) Department of Gynaecology and Obstetrics University Hospital Düsseldorf, Heinrich‐Heine University Düsseldorf Germany
  95. (95) Institute of Oncology NN Petrov, grid.465337.0
  96. (96) Georgetown University, grid.213910.8
  97. (97) Genetic Counseling Unit, Hereditary Cancer Program, IDIBGI (Institut d'Investigació Biomèdica de Girona) Catalan Institute of Oncology Girona Spain
  98. (98) Parkville Familial Cancer Centre Peter MacCallum Cancer Centre Melbourne Australia
  99. (99) Hematology, oncology and transfusion medicine center, Dept. of Molecular and Regenerative Medicine Vilnius University Hospital Santariskiu Clinics Vilnius Lithuania
  100. (100) Department of Clinical Genetics Aarhus University Hospital Aarhus N Denmark
  101. (101) Department of Epidemiology, Cancer Prevention Institute of California Fremont USA
  102. (102) Department of Health Research and Policy (Epidemiology) and Stanford Cancer Institute Stanford University School of Medicine Stanford USA
  103. (103) Clinical Genetics Research Laboratory, Dept. of Medicine Memorial Sloan‐Kettering Cancer Center New York USA
  104. (104) Women's Cancer Program at the Samuel Oschin Comprehensive Cancer Institute Cedars‐Sinai Medical Center Los Angeles USA
  105. (105) Department of Gynecology and Obstetrics Medical Faculty and University Hospital Carl Gustav Carus Dresden Germany
  106. (106) Peter MacCallum Cancer Centre, grid.1055.1
  107. (107) University of Melbourne, grid.1008.9
  108. (108) Department of Surgery Daerim St. Mary's Hospital Seoul Korea
  109. (109) Molecular Diagnostics Laboratory, INRASTES (Institute of Nuclear and Radiological Sciences and Technology) National Centre for Scientific Research “Demokritos” Athens Greece
  110. (110) The Gyneco‐Oncology Department Chaim Sheba Medical Center Ramat Gan Israel
  111. (111) Servicio de Genética‐CIBERER U705 Hospital de la Santa Creu i Sant Pau Barcelona Spain
  112. (112) Feinstein Institute for Medical Research, grid.250903.d
  113. (113) Soonchunhyang University, grid.412674.2
  114. (114) Inserm U900, Institut Curie PSL Research University Paris France
  115. (115) Department of Oncology Radiumhemmet and Institution of Oncology and Patology Karolinska University Hospital and Karolinska Institutet Solna Sweden
  116. (116) Department of Health Sciences Research Mayo Clinic Scottsdale USA
  117. (117) Oncogénétique Institut Bergonié Bordeaux France
  118. (118) Clinical Genetics Branch, DCEG, NCI, NIH Bethesda USA
  119. (119) Department of Gynecological Oncology and Clinical Cancer Genetics Program University Of Texas MD Anderson Cancer Center Houston USA
  120. (120) Centre Antoine Lacassagne, grid.417812.9
  121. (121) Laboratorio de Genética Molecular, Servicio de Genética Hospital Universitario Cruces, BioCruces Health Research Institute Barakaldo Spain
  122. (122) Department of Clinical Genetics VU University Medical Center Amsterdam The Netherlands
  123. (123) Department of Human Genetics Radboud University Medical Center Nijmegen The Netherlands
  124. (124) Vilnius University, grid.6441.7
  125. (125) NRG Oncology Statistics and Data Management Center Roswell Park Cancer Institute Buffalo USA
  126. (126) Department of Cancer Prevention and Control Roswell Park Cancer Institute Buffalo USA
  127. (127) Department of Obstetrics and Gynecology University of Helsinki and Helsinki University Hospital HUS Finland
  128. (128) Cancer Genetics Service Division of Medical Oncology National Cancer Centre Singapore Bukit Merah Singapore
  129. (129) University of Tübingen, grid.10392.39
  130. (130) Rigshospitalet, grid.475435.4, Capital Region
  131. (131) Clinical Genetics Research Laboratory Dept. of Medicine Cancer Biology and Genetics Memorial Sloan‐Kettering Cancer Center New York USA
  132. (132) Department of Clinical Genetics Sahlgrenska University Hospital Gothenburg Sweden
  133. (133) West Midlands Regional Genetics Service Birmingham Women's Hospital Healthcare NHS Trust Edgbaston UK
  134. (134) Spanish National Cancer Research Centre, grid.7719.8
  135. (135) University of Florence, grid.8404.8
  136. (136) University of Turin, grid.7605.4
  137. (137) Section of Molecular Diagnostics Department of Biochemistry Aalborg University Hospital Aalborg Denmark
  138. (138) Department of Genetics Portuguese Oncology Institute of Porto (IPO Porto) Porto Portugal
  139. (139) University of Porto, grid.5808.5
  140. (140) IFOM The FIRC (Italian Foundation for Cancer Research) Institute of Molecular Oncology Milan Italy
  141. (141) Service de Génétique Clinique Chromosomique et Moléculaire Hôpital Nord St Etienne France
  142. (142) Unité d'Oncogénétique CHU Arnaud de Villeneuve Montpellier France
  143. (143) Unit of Molecular Bases of Genetic Risk and Genetic Testing Department of Research Fondazione IRCCS (Istituto Di Ricovero e Cura a Carattere Scientifico), Istituto Nazionale Tumori (INT) Milan Italy
  144. (144) The Kinghorn Cancer Centre, grid.410697.d
  145. (145) UNSW Sydney, grid.1005.4
  146. (146) Department of Clinical Genetics Karolinska University Hospital Stockholm Sweden
  147. (147) Department of Basic Sciences Shaukat Khanum Memorial Cancer Hospital and Research Centre Lahore Pakistan
  148. (148) Clinical Genetics Services Dept. of Medicine Memorial Sloan‐Kettering Cancer Center New York USA
  149. (149) Division of Gynecologic Oncology North Shore University Health System University of Chicago Evanston USA
  150. (150) All Wales Medical Genetics Services University Hospital of Wales Cardiff UK
  151. (151) Department of Gynecology Vilnius University Hospital Santariskiu Clinics Centre of Woman's Health and pathology Vilnius Lithuania
  152. (152) Clinical Cancer Genetics Program Division of Human Genetics Department of Internal Medicine The Comprehensive Cancer Center The Ohio State University Columbus USA
  153. (153) Department of Internal Medicine Division of Oncology University of Kansas Medical Center Westwood USA
  154. (154) Genomics Center Centre Hospitalier Universitaire de Québec Research Center and Laval University Quebec City Canada
  155. (155) Medical Genetics Unit University of London St George's UK
  156. (156) Département Oncologie Génétique Prévention et Dépistage Institut Paoli‐Calmettes Marseille Medical School‐AM University Marseille France
  157. (157) Institute of Cell and Molecular Pathology Hannover Medical School Hannover Germany
  158. (158) University Hospital Heidelberg, grid.5253.1
  159. (159) National Human Genome Research Institute, grid.280128.1
  160. (160) Genetic Counseling Unit Hereditary Cancer Program IDIBELL (Bellvitge Biomedical Research Institute) Catalan Institute of Oncology, CIBERONC Gran Via de l'Hospitalet Barcelona Spain
  161. (161) Mayo Clinic, grid.66875.3a
  162. (162) Department of Medicine Magee‐Womens Hospital University of Pittsburgh School of Medicine Pittsburgh USA
  163. (163) Program in Cancer Genetics Departments of Human Genetics and Oncology McGill University Montreal Canada
  164. (164) Division of Human Genetics Departments of Internal Medicine and Cancer Biology and Genetics Comprehensive Cancer Center The Ohio State University Columbus USA
  165. (165) Parkville Familial Cancer Centre Royal Melbourne Hospital Melbourne Australia
  166. (166) Department of Medical Oncology Beth Israel Deaconess Medical Center Massachusetts USA
  167. (167) Leiden University Medical Center, grid.10419.3d
  168. (168) Department of Genetics University Medical Center Groningen University Groningen The Netherlands
  169. (169) University Medical Center Utrecht, grid.7692.a
  170. (170) Unit of Hereditary Cancer Department of Epidemiology, Prevention and Special Functions IRCCS (Istituto Di Ricovero e Cura a Carattere Scientifico) AOU San Martino ‐ IST Istituto Nazionale per la Ricerca sul Cancro Genoa Italy
  171. (171) Institute of Human Genetics Campus Virchov Klinikum Berlin Germany
  172. (172) Fundación Pública Galega de Medicina Xenómica-SERGAS, Grupo de Medicina Xenómica-USC, CIBERER, IDIS, Santiago de Compostela Spain
  173. (173) Centro de Cancer de Mama del Hospital Zambrano Hellion Tecnologico de Monterrey San Pedro Garza Garcia Mexico
  174. (174) Departamento de Investigacion y de Tumores Mamarios del Instituto Nacional de Cancerologia Mexico City Mexico
  175. (175) Karolinska University Hospital, grid.24381.3c
  176. (176) Oxford Regional Genetics Service Churchill Hospital Oxford UK
  177. (177) Department of Gynaecology and Obstetrics University Hospital Ulm Germany
  178. (178) University of Regensburg, grid.7727.5
  179. (179) Institute of Oncology Rivka Ziv Medical Center Zefat Israel
  180. (180) Magee-Womens Hospital, grid.411487.f
  181. (181) Center for Medical Genetics North Shore University Health System Evanston USA
  182. (182) Medical Director, Center for Medical Genetics, NorthShore University HealthSystem, Clinical Assistant Professor of Medicine University of Chicago Pritzker School of Medicine Evanston USA

Description

The prevalence and spectrum of germline mutations in BRCA1 and BRCA2 have been reported in single populations, with the majority of reports focused on White in Europe and North America. The Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA) has assembled data on 18,435 families with BRCA1 mutations and 11,351 families with BRCA2 mutations ascertained from 69 centers in 49 countries on six continents. This study comprehensively describes the characteristics of the 1,650 unique BRCA1 and 1,731 unique BRCA2 deleterious (disease-associated) mutations identified in the CIMBA database. We observed substantial variation in mutation type and frequency by geographical region and race/ethnicity. In addition to known founder mutations, mutations of relatively high frequency were identified in specific racial/ethnic or geographic groups that may reflect founder mutations and which could be used in targeted (panel) first pass genotyping for specific populations. Knowledge of the population-specific mutational spectrum in BRCA1 and BRCA2 could inform efficient strategies for genetic testing and may justify a more broad-based oncogenetic testing in some populations.

Funders

Research Categories

Main Subject Area

Fields of Research

Links & Metrics

NORA University Profiles

Aalborg University

Danish Open Access Indicator

2018: Realized

Research area: Medicine

Danish Bibliometrics Indicator

2018: Level 2

Research area: Medicine

Dimensions Citation Indicators

Times Cited: 77

Field Citation Ratio (FCR): 24.31

Relative Citation ratio (RCR): 8.46

Open Access Info

Green, Published