Article open access publication

Fine-Scale Mapping at 9p22.2 Identifies Candidate Causal Variants That Modify Ovarian Cancer Risk in BRCA1 and BRCA2 Mutation Carriers

PLoS ONE, Public Library of Science (PLoS), ISSN 1932-6203

Volume 11, 7, 2016

DOI:10.1371/journal.pone.0158801, Dimensions: pub.1047404737, PMC: PMC4963094, PMID: 27463617,

Authors

Eeles, Ros (31)
Kwong, Ava (61)
Tea, Muy-Kheng (10) (83)
Kirk, Judy (98)

* Corresponding author

Affiliations

Organisations

  1. (1) University of Cambridge, grid.5335.0
  2. (2) QIMR Berghofer Medical Research Institute, grid.1049.c
  3. (3) Chapel Allerton Hospital, grid.413818.7
  4. (4) Department of Pathology, University Hospital (Landspitali) and University of Iceland School of Medicine, Hringbraut, 101 Reykjavik, Iceland
  5. (5) Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario M5G 1X5, Canada
  6. (6) The University of Texas MD Anderson Cancer Center, grid.240145.6
  7. (7) Centre Léon Bérard, grid.418116.b
  8. (8) Institute Curie, grid.418596.7
  9. (9) Spanish National Cancer Research Centre, grid.7719.8
  10. (10) Medical University of Vienna, grid.22937.3d
  11. (11) Vejle Sygehus, grid.417271.6, Southern Denmark Region
  12. (12) European Institute of Oncology, grid.15667.33
  13. (13) Royal Devon and Exeter Hospital, grid.416118.b
  14. (14) Hospital Clínico San Carlos, grid.411068.a
  15. (15) Section of Genetic Oncology, Dept. of Laboratory Medicine, University and University Hospital of Pisa, Pisa Italy
  16. (16) Peter MacCallum Cancer Centre, grid.1055.1
  17. (17) 1600 Divisadero Street, C415, San Francisco, CA 94143–1714, United States of America
  18. (18) Ghent University, grid.5342.0
  19. (19) The Ohio State University, grid.261331.4
  20. (20) Sheffield Children's Hospital, grid.413991.7
  21. (21) Temple University Health System, grid.412530.1
  22. (22) University of Glasgow, grid.8756.c
  23. (23) Institut de Cancérologie de l'Ouest, grid.418191.4
  24. (24) Hospital Universitari Vall d'Hebron, grid.411083.f
  25. (25) Department of Medicine, Abramson Cancer Center, Perelman School of Medicine at the University of Pennsylvania, 3400 Civic Center Boulevard, Philadelphia, PA 19104, United States of America
  26. (26) Genomics Center, Centre Hospitalier Universitaire de Québec Research Center and Laval University, 2705 Laurier Boulevard, Quebec City (Quebec), Canada
  27. (27) Pomeranian Medical University, grid.107950.a
  28. (28) University of Münster, grid.5949.1
  29. (29) University Hospital Southampton NHS Foundation Trust, grid.430506.4
  30. (30) Umeå University, grid.12650.30
  31. (31) Oncogenetics Team, The Institute of Cancer Research and Royal Marsden NHS Foundation Trust, Sutton, United Kingdom
  32. (32) Department of Oncology, Rigshospitalet, Copenhagen University Hospital, Blegdamsvej 9, DK-2100 Copenhagen, Denmark
  33. (33) University of Manchester, grid.5379.8
  34. (34) Molecular Diagnostic Unit, Hereditary Cancer Program, IDIBELL (Bellvitge Biomedical Research Institute), Catalan Institute of Oncology, Gran Via de l'Hospitalet, 199–203, 08908 L'Hospitalet, Barcelona, Spain
  35. (35) National Centre of Scientific Research Demokritos, grid.6083.d
  36. (36) McGill University, grid.14709.3b
  37. (37) Sheba Medical Center, grid.413795.d
  38. (38) Memorial Sloan Kettering Cancer Center, grid.51462.34
  39. (39) University of California, Los Angeles, grid.19006.3e
  40. (40) Dana-Farber Cancer Institute, grid.65499.37
  41. (41) University of Würzburg, grid.8379.5
  42. (42) Department of Clinical Genetics, Rigshospitalet 4062, Blegdamsvej 9, København Ø, Denmark
  43. (43) Hospices Civils de Lyon, grid.413852.9
  44. (44) University of Kansas Medical Center, grid.412016.0
  45. (45) University of Utah, grid.223827.e
  46. (46) City Of Hope National Medical Center, grid.410425.6
  47. (47) Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital, Blegdamsvej 9, DK-2100 Copenhagen, Denmark
  48. (48) University College London, grid.83440.3b
  49. (49) Antoni van Leeuwenhoek Hospital, grid.430814.a
  50. (50) NorthShore University HealthSystem, grid.240372.0
  51. (51) Institute of Oncology NN Petrov, grid.465337.0
  52. (52) Georgetown University, grid.213910.8
  53. (53) Guy's and St Thomas' NHS Foundation Trust, grid.420545.2
  54. (54) Catalan Institute of Oncology, grid.418701.b
  55. (55) Vilnius University Hospital Santariskiu Clinics, Hematology, oncology and transfusion medicine center, Dept. of Molecular and Regenerative Medicine, Santariskiu st., State Research Institute Centre for Innovative medicine, Zygymantu st. 9, Vilnius, Lithuania
  56. (56) Aarhus University Hospital, grid.154185.c, Central Denmark Region
  57. (57) Cancer Prevention Institute of California, grid.280669.3
  58. (58) Cedars-Sinai Medical Center, grid.50956.3f
  59. (59) Department of Gynaecology and Obstetrics, University Hospital Carl Gustav Carus, Technical University Dresden, Dresden, Germany
  60. (60) Helsinki University Central Hospital, grid.15485.3d
  61. (61) The Hong Kong Hereditary Breast Cancer Family Registry, Cancer Genetics Center, Hong Kong Sanatorium and Hospital, Hong Kong China
  62. (62) Genetic Epidemiology of Cancer team, Inserm U900, Institut Curie, Mines ParisTech, 26 rue d'Ulm, 75248 Paris cedex 05, France
  63. (63) Karolinska University Hospital, grid.24381.3c
  64. (64) National Institute of Arthritis and Musculoskeletal and Skin Diseases, grid.420086.8
  65. (65) Unit of Medical Genetics, Department of Preventive and Predictive Medicine, Fondazione IRCCS (Istituto Di Ricovero e Cura a Carattere Scientifico) Istituto Nazionale Tumori (INT), Via Giacomo Venezian 1, 20133 Milan, Italy
  66. (66) Department of Gynaecology and Obstetrics, Division of Tumor Genetics, Klinikum rechts der Isar, Technical University Munich, Munich, Germany
  67. (67) Radboud University Nijmegen Medical Centre, grid.10417.33
  68. (68) Istituto Oncologico Veneto, grid.419546.b
  69. (69) Department of Gynaecology and Obstetrics, University Hospital Düsseldorf, Heinrich Heine University Düsseldorf, Düsseldorf, Germany
  70. (70) National Institute of Oncology, grid.419617.c
  71. (71) University of Chicago, grid.170205.1
  72. (72) West Midlands Regional Genetics Service, Birmingham Women's Hospital Healthcare NHS Trust, Edgbaston, Birmingham, United Kingdom
  73. (73) Seoul National University, grid.31501.36
  74. (74) Uppsala University, grid.8993.b
  75. (75) Aalborg Hospital, grid.27530.33, North Denmark Region
  76. (76) IFOM, The FIRC (Italian Foundation for Cancer Research) Institute of Molecular Oncology, c/o IFOM-IEO campus, via Adamello 16, 20139 Milan, Italy
  77. (77) Moffitt Cancer Center, grid.468198.a
  78. (78) Roswell Park Cancer Institute, grid.240614.5
  79. (79) Translational Research Laboratory, IDIBELL (Bellvitge Biomedical Research Institute), Catalan Institute of Oncology, Barcelona, Spain
  80. (80) Unit of Molecular Bases of Genetic Risk and Genetic Testing, Department of Preventive and Predicted Medicine, Fondazione IRCCS (Istituto Di Ricovero e Cura a Carattere Scientifico) Istituto Nazionale Tumori (INT), c/o Amaedeolab, via GA Amadeo 42, 20133 Milan, Italy
  81. (81) Clalit National Israeli Cancer Control Center and Department of Community Medicine and Epidemiology, Carmel Medical Center and B. Rappaport Faculty of Medicine, 7 Michal St., Haifa 34362, Israel
  82. (82) University Hospital Cologne, grid.411097.a
  83. (83) Dept of OB/GYN, Medical University of Vienna, Vienna, Austria, and Waehringer Guertel 18–20, A 1090 Vienna, Austria
  84. (84) University of Melbourne, grid.1008.9
  85. (85) Hannover Medical School, grid.10423.34
  86. (86) University Hospital Heidelberg, grid.5253.1
  87. (87) National Human Genome Research Institute, grid.280128.1
  88. (88) Portuguese Oncology Institute, grid.418711.a
  89. (89) Cancer Research Initiatives Foundation, Sime Darby Medical Centre, 1 Jalan SS12/1A, Subang Jaya, 47500 Malaysia
  90. (90) Columbia University, grid.21729.3f
  91. (91) Odense University Hospital, grid.7143.1, Southern Denmark Region
  92. (92) UO Anatomia Patologica, Ospedale di Circolo-Università dell'Insubria, Via O.Rossi 9, 21100 Varese, Italy
  93. (93) Latvian Biomedical Research and Study Centre, grid.419210.f
  94. (94) University of Pretoria, grid.49697.35
  95. (95) 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, largo Rosanna Benzi 10, 16132 Genoa, Italy
  96. (96) Charité, grid.6363.0
  97. (97) Molecular Diagnostics Laboratory, (INRASTES) Institute of Nuclear and Radiological Sciences and Technology, National Centre for Scientific Research "Demokritos" Patriarchou Gregoriou & Neapoleos str., Aghia Paraskevi, Attiki, Athens, Greece
  98. (98) Westmead Hospital, grid.413252.3
  99. (99) German Cancer Research Center, grid.7497.d
  100. (100) Mayo Clinic, grid.417468.8
  101. (101) University of Southern California, grid.42505.36
  102. (102) Mayo Clinic, grid.66875.3a

Description

Population-based genome wide association studies have identified a locus at 9p22.2 associated with ovarian cancer risk, which also modifies ovarian cancer risk in BRCA1 and BRCA2 mutation carriers. We conducted fine-scale mapping at 9p22.2 to identify potential causal variants in BRCA1 and BRCA2 mutation carriers. Genotype data were available for 15,252 (2,462 ovarian cancer cases) BRCA1 and 8,211 (631 ovarian cancer cases) BRCA2 mutation carriers. Following genotype imputation, ovarian cancer associations were assessed for 4,873 and 5,020 SNPs in BRCA1 and BRCA 2 mutation carriers respectively, within a retrospective cohort analytical framework. In BRCA1 mutation carriers one set of eight correlated candidate causal variants for ovarian cancer risk modification was identified (top SNP rs10124837, HR: 0.73, 95%CI: 0.68 to 0.79, p-value 2× 10-16). These variants were located up to 20 kb upstream of BNC2. In BRCA2 mutation carriers one region, up to 45 kb upstream of BNC2, and containing 100 correlated SNPs was identified as candidate causal (top SNP rs62543585, HR: 0.69, 95%CI: 0.59 to 0.80, p-value 1.0 × 10-6). The candidate causal in BRCA1 mutation carriers did not include the strongest associated variant at this locus in the general population. In sum, we identified a set of candidate causal variants in a region that encompasses the BNC2 transcription start site. The ovarian cancer association at 9p22.2 may be mediated by different variants in BRCA1 mutation carriers and in the general population. Thus, potentially different mechanisms may underlie ovarian cancer risk for mutation carriers and the general population.

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Times Cited: 7

Field Citation Ratio (FCR): 1.82

Relative Citation ratio (RCR): 0.18

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