Article open access publication

Candidate Genetic Modifiers for Breast and Ovarian Cancer Risk in BRCA1 and BRCA2 Mutation Carriers

Cancer Epidemiology Biomarkers & Prevention, American Association for Cancer Research (AACR), ISSN 1055-9965

Volume 24, 1, 2015

DOI:10.1158/1055-9965.epi-14-0532, Dimensions: pub.1004655144, PMC: PMC4294951, PMID: 25336561,

Authors

Schmutzler, Rita K. (5) (6) (7)
Osorio, Ana (34) (35)
Benitez, Javier (34) (35)
Kennedy, M. John (60) (61)
Rhiem, Kerstin (5) (6) (7)
Houdayer, Claude (84) (86)
Coupier, Isabelle (88) (89)
Sinilnikova, Olga M (2) (87) (91)
Pujol, Pascal (89) (92)
Nevanlinna, Heli (98) (99)
Olah, Edith (108)
Diez, Orland (109) (110) (111)
Brunet, Joan (112)
Arason, Adalgeir (113) (114)
Teixeira, Manuel R. (115) (116)
Rennert, Gad (124)
Mulligan, Anna Marie (125) (126)
Andrulis, Irene L. (126) (128)
Ehrencrona, Hans (135) (136)
Borg, Åke (138)

Affiliations

Organisations

  1. (1) Fondazione IRCCS Istituto Nazionale dei Tumori, grid.417893.0
  2. (2) FIRC Institute of Molecular Oncology, grid.7678.e
  3. (3) German Cancer Research Center, grid.7497.d
  4. (4) Roswell Park Cancer Institute, grid.240614.5
  5. (5) Center for Hereditary Breast and Ovarian Cancer, Medical Faculty, University Hospital Cologne, Germany
  6. (6) Center for Integrated Oncology (CIO), Medical Faculty, University Hospital Cologne, Germany
  7. (7) University of Cologne, grid.6190.e
  8. (8) Centre Hospitalier Universitaire de Québec, grid.411081.d
  9. (9) Oncogenetics Team, The Institute of Cancer Research and Royal Marsden NHS Foundation Trust, Surrey, United Kingdom
  10. (10) University of Cambridge, grid.5335.0
  11. (11) Antoni van Leeuwenhoek Hospital, grid.430814.a
  12. (12) QIMR Berghofer Medical Research Institute, grid.1049.c
  13. (13) University of Otago, grid.29980.3a
  14. (14) University of Algarve, grid.7157.4
  15. (15) Istituto Oncologico Veneto, grid.419546.b
  16. (16) Pomeranian Medical University, grid.107950.a
  17. (17) Maastricht University Medical Centre, grid.412966.e
  18. (18) University of Chicago Medical Center, grid.412578.d
  19. (19) University of California, San Francisco, grid.266102.1
  20. (20) Department of Medicine, Abramson Cancer Center, Perelman School of Medicine at the University of Pennsylvania, Philadephia, Pennsylvania
  21. (21) Department of Epidemiology and Biostatistics, Abramson Cancer Center, Perelman School of Medicine at the University of Pennsylvania, Philadephia, Pennsylvania
  22. (22) The University of Texas MD Anderson Cancer Center, grid.240145.6
  23. (23) Cedars-Sinai Medical Center, grid.50956.3f
  24. (24) Columbia University, grid.21729.3f
  25. (25) Case Western Reserve University, grid.67105.35
  26. (26) University of Melbourne, grid.1008.9
  27. (27) University of Utah, grid.223827.e
  28. (28) Vilnius University Hospital Santariskiu Clinics, Hematology, Oncology, and Transfusion Medicine Center, Dept. of Molecular and Regenerative Medicine; State Research Institute Centre for Innovative Medicine, Vilnius, Lithuania
  29. (29) University of Pretoria, grid.49697.35
  30. (30) City Of Hope National Medical Center, grid.410425.6
  31. (31) Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark
  32. (32) Department of Clinical Genetics, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark
  33. (33) Department of Oncology, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark
  34. (34) Centre for Biomedical Network Research on Rare Diseases, grid.452372.5
  35. (35) Spanish National Cancer Research Centre, grid.7719.8
  36. (36) Molecular Genetics Laboratory, Department of Biochemistry, Cruces Hospital Barakaldo, 48903-Barakaldo-Bizkaia, Spain
  37. (37) Saint Alphonsus Regional Medical Center, care of City of Hope Clinical Cancer Genetics Community Research Network, Duarte, California
  38. (38) European Institute of Oncology, grid.15667.33
  39. (39) Cogentech Cancer Genetic Test Laboratory, Milan, Italy
  40. (40) Division of Experimental Oncology 1, CRO Aviano National Cancer Institute, Aviano (PN), Italy
  41. (41) Sapienza University of Rome, grid.7841.a
  42. (42) University of Florence, grid.8404.8
  43. (43) Istituti Fisioterapici Ospitalieri, grid.417520.5
  44. (44) UO Anatomia Patologica Ospedale di Circolo e Fondazione Macchi, Polo Universitario Varese, Italy
  45. (45) National Centre of Scientific Research Demokritos, grid.6083.d
  46. (46) Dana-Farber Cancer Institute, grid.65499.37
  47. (47) St Michael's Hospital, grid.416544.6
  48. (48) Royal Devon and Exeter Hospital, grid.416118.b
  49. (49) Liverpool Womens NHS Foundation Trust, grid.419317.9
  50. (50) Manchester University NHS Foundation Trust, grid.498924.a
  51. (51) University of Southampton, Faculty of Medicine, Southampton University Hospitals NHS Trust, Southampton, United Kingdom
  52. (52) North West Thames Regional Genetics Service, Kennedy-Galton Centre, Harrow, United Kingdom
  53. (53) Sheffield Children's Hospital, grid.413991.7
  54. (54) Addenbrooke's Hospital, grid.120073.7
  55. (55) Yorkshire Regional Genetics Service, Leeds, United Kingdom
  56. (56) University Hospitals of Leicester NHS Trust, grid.269014.8
  57. (57) Churchill Hospital, grid.415719.f
  58. (58) Guy's and St Thomas' NHS Foundation Trust, grid.420545.2
  59. (59) Great Ormond Street Hospital for Children NHS Foundation Trust, grid.424537.3
  60. (60) St. James's Hospital, grid.416409.e
  61. (61) Trinity College Dublin, grid.8217.c
  62. (62) University Hospital of Wales, grid.241103.5
  63. (63) Western General Hospital, grid.417068.c
  64. (64) Queen's University Belfast, grid.4777.3
  65. (65) Southern General Hospital, grid.413030.5
  66. (66) Medical Genetics Unit, St. George's, University of London, London, United Kingdom
  67. (67) West Midlands Regional Genetics Service, Birmingham Women's Hospital Healthcare NHS Trust, Edgbaston, Birmingham, United Kingdom
  68. (68) University of Kansas Medical Center, grid.412016.0
  69. (69) Ghent University, grid.5342.0
  70. (70) Department of Gynaecology and Obstetrics, Division of Tumor Genetics, Klinikum rechts der Isar, Technical University Munich, Germany
  71. (71) University of Würzburg, grid.8379.5
  72. (72) Heidelberg University, grid.7700.0
  73. (73) Leipzig University, grid.9647.c
  74. (74) Heinrich Heine University Düsseldorf, grid.411327.2
  75. (75) Hannover Medical School, grid.10423.34
  76. (76) Institute of Human Genetics, University Hospital of Schleswig-Holstein/University Kiel, Kiel, Germany
  77. (77) Department of Gynecology and Obstetrics, University Hospital Carl Gustav Carus, Technische Universität Dresden, Germany
  78. (78) Ludwig Maximilian University of Munich, grid.5252.0
  79. (79) Department of Gynecology and Obstetrics, University Hospital of Schleswig-Holstein/University Kiel, Kiel, Germany
  80. (80) Institute of Human Genetics, Charite Berlin, Germany
  81. (81) University Hospital Ulm, grid.410712.1
  82. (82) French Institute of Health and Medical Research, grid.7429.8
  83. (83) Institut Gustave Roussy, grid.14925.3b
  84. (84) Institute Curie, grid.418596.7
  85. (85) Institut de Cancérologie de l'Ouest, grid.418191.4
  86. (86) Paris Descartes University, grid.10992.33
  87. (87) Cancer Center of Lyon, grid.462282.8
  88. (88) Unité d'Oncogénétique, CRLCC Val d'Aurelle, Montpellier, France
  89. (89) Hôpital Arnaud De Villeneuve, grid.413745.0
  90. (90) Hôpital Universitaire Dupuytren, grid.412212.6
  91. (91) Centre Léon Bérard, grid.418116.b
  92. (92) INSERM 896, CRCM Val d'Aurelle, Montpellier, France
  93. (93) GEMO study: National Cancer Genetics Network “UNICANCER Genetic Group,” France
  94. (94) Australia New Zealand Gynaecological Oncology Group, grid.492287.2
  95. (95) NorthShore University HealthSystem, grid.240372.0
  96. (96) The Ohio State University, grid.261331.4
  97. (97) Hospital Clínico San Carlos, grid.411068.a
  98. (98) University of Helsinki, grid.7737.4
  99. (99) Helsinki University Central Hospital, grid.15485.3d
  100. (100) Academic Medical Center, grid.5650.6
  101. (101) VU University Medical Center, grid.16872.3a
  102. (102) University of Groningen, grid.4830.f
  103. (103) Leiden University Medical Center, grid.10419.3d
  104. (104) Radboud University Nijmegen Medical Centre, grid.10417.33
  105. (105) University Medical Center Utrecht, grid.7692.a
  106. (106) Department of Obstetrics and Gynecology, Division of Gynecologic Oncology, Erasmus University MC Cancer Institute, Rotterdam, the Netherlands
  107. (107) Erasmus University Medical Center, grid.5645.2
  108. (108) National Institute of Oncology, grid.419617.c
  109. (109) Autonomous University of Barcelona, grid.7080.f
  110. (110) Hospital Universitari Vall d'Hebron, grid.411083.f
  111. (111) Vall d'Hebron Research Institute, grid.430994.3
  112. (112) Catalan Institute of Oncology, grid.418701.b
  113. (113) University of Iceland, grid.14013.37
  114. (114) National University Hospital of Iceland, grid.410540.4
  115. (115) Portuguese Oncology Institute, grid.418711.a
  116. (116) University of Porto, grid.5808.5
  117. (117) Mayo Clinic, grid.66875.3a
  118. (118) Mayo Clinic, grid.417468.8
  119. (119) National Human Genome Research Institute, NIH, Bethesda, Maryland
  120. (120) Memorial Sloan Kettering Cancer Center, grid.51462.34
  121. (121) Medical University of Vienna, grid.22937.3d
  122. (122) Moffitt Cancer Center, grid.468198.a
  123. (123) Clinical Genetics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, Rockville, Maryland
  124. (124) Clalit National Cancer Control Center, Haifa, Israel
  125. (125) University Health Network, grid.231844.8
  126. (126) University of Toronto, grid.17063.33
  127. (127) Mount Sinai Hospital, grid.416166.2
  128. (128) Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada
  129. (129) Vejle Sygehus, grid.417271.6, Southern Denmark Region
  130. (130) Aalborg Hospital, grid.27530.33, North Denmark Region
  131. (131) Odense University Hospital, grid.7143.1, Southern Denmark Region
  132. (132) Aarhus University Hospital, grid.154185.c, Central Denmark Region
  133. (133) Sheba Medical Center, grid.413795.d
  134. (134) Karolinska University Hospital, grid.24381.3c
  135. (135) Skåne University Hospital, grid.411843.b
  136. (136) Uppsala University, grid.8993.b
  137. (137) Linköping University, grid.5640.7
  138. (138) Lund University, grid.4514.4
  139. (139) ConFab: Kathleen Cuningham Consortium for Research into Familial Breast Cancer—Peter MacCallum Cancer Center, Melbourne, Australia

Description

BACKGROUND: BRCA1 and BRCA2 mutation carriers are at substantially increased risk for developing breast and ovarian cancer. The incomplete penetrance coupled with the variable age at diagnosis in carriers of the same mutation suggests the existence of genetic and nongenetic modifying factors. In this study, we evaluated the putative role of variants in many candidate modifier genes. METHODS: Genotyping data from 15,252 BRCA1 and 8,211 BRCA2 mutation carriers, for known variants (n = 3,248) located within or around 445 candidate genes, were available through the iCOGS custom-designed array. Breast and ovarian cancer association analysis was performed within a retrospective cohort approach. RESULTS: The observed P values of association ranged between 0.005 and 1.000. None of the variants was significantly associated with breast or ovarian cancer risk in either BRCA1 or BRCA2 mutation carriers, after multiple testing adjustments. CONCLUSION: There is little evidence that any of the evaluated candidate variants act as modifiers of breast and/or ovarian cancer risk in BRCA1 or BRCA2 mutation carriers. IMPACT: Genome-wide association studies have been more successful at identifying genetic modifiers of BRCA1/2 penetrance than candidate gene studies.

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Times Cited: 16

Field Citation Ratio (FCR): 3.53

Relative Citation ratio (RCR): 0.64

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