Article open access publication

Association of breast cancer risk in BRCA1 and BRCA2 mutation carriers with genetic variants showing differential allelic expression: identification of a modifier of breast cancer risk at locus 11q22.3

Breast Cancer Research and Treatment, Springer Nature, ISSN 1573-7217

Volume 161, 1, 2017

DOI:10.1007/s10549-016-4018-2, Dimensions: pub.1045330156, PMC: PMC5222911, PMID: 27796716,

Authors

Pastinen, Tomi (4) (5)
Arason, Adalgeir (10) (11)
Benitez, Javier (17) (18)
Dolcetti, Riccardo (35) (36)
Eeles, Ros (39)
EMBRACE (3)
Friedman, Eitan (48) (49)
Hays, John L (63) (64)
HEBON (65)
James, Paul (70) (71)
John, Esther M (75) (76)
Kirk, Judy (81)
Osorio, Ana (17) (18)
Rennert, Gad (103)
Snape, Katie (106)
Tan, Yen (102)
Teixeira, Manuel R. (111) (112)
Teulé, Alex (113)
Teo, Soo-Hwang (114) (115)
Tischkowitz, Marc (5) (118)
Tung, Nadine (119)
Rebbeck, Timothy (23) (124)
Nord, Silje (125)

* Corresponding author

Affiliations

Organisations

  1. (1) Genomics Center, Centre Hospitalier Universitaire de Québec Research Center and Laval University, 2705 Laurier Boulevard, G1V 4G2, Quebec, QC, Canada
  2. (2) Wellcome Sanger Institute, grid.10306.34
  3. (3) University of Cambridge, grid.5335.0
  4. (4) McGill University and Génome Québec Innovation Centre, grid.411640.6
  5. (5) McGill University, grid.14709.3b
  6. (6) Chapel Allerton Hospital, grid.413818.7
  7. (7) Helsinki University Central Hospital, grid.15485.3d
  8. (8) University of Toronto, grid.17063.33
  9. (9) Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, M5G 1X5, Toronto, ON, Canada
  10. (10) Department of Pathology hus 9, Landspitali-LSH v/Hringbraut, 101, Reykjavík, Iceland
  11. (11) University of Iceland, grid.14013.37
  12. (12) Department of Gynaecology and Obstetrics, University Hospital of Schleswig-Holstein, Christian-Albrechts University Kiel, Campus Kiel, 24105, Kiel, Germany
  13. (13) The University of Texas MD Anderson Cancer Center, grid.240145.6
  14. (14) 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
  15. (15) McMaster University, grid.25073.33
  16. (16) Centre Léon Bérard, grid.418116.b
  17. (17) Centre for Biomedical Network Research on Rare Diseases, grid.452372.5
  18. (18) Spanish National Cancer Research Centre, grid.7719.8
  19. (19) Centre Franois Baclesse, grid.476192.f
  20. (20) Maastricht University Medical Centre, grid.412966.e
  21. (21) City Of Hope National Medical Center, grid.410425.6
  22. (22) European Institute of Oncology, grid.15667.33
  23. (23) Department of Medicine, Abramson Cancer Center, Perelman School of Medicine at the University of Pennsylvania, 3400 Civic Center Boulevard, 19104, Philadelphia, PA, USA
  24. (24) Royal Devon and Exeter Hospital, grid.416118.b
  25. (25) Institute Curie, grid.418596.7
  26. (26) Huntsman Cancer Institute, grid.479969.c
  27. (27) Azienda Ospedaliera Universitaria Pisana, grid.144189.1
  28. (28) Hôpital du Saint-Sacrement, grid.416673.1
  29. (29) Columbia University, grid.21729.3f
  30. (30) Ghent University, grid.5342.0
  31. (31) Temple University Health System, grid.412530.1
  32. (32) University of Glasgow, grid.8756.c
  33. (33) Hospital Clínico San Carlos, grid.411068.a
  34. (34) Hospital Universitari Vall d'Hebron, grid.411083.f
  35. (35) Centro di Riferimento Oncologico, grid.418321.d
  36. (36) University of Queensland, grid.1003.2
  37. (37) University of Pretoria, grid.49697.35
  38. (38) Faculty of Medicine, University of Southampton, Southampton University Hospitals NHS Trust, Southampton, UK
  39. (39) Oncogenetics Team, The Institute of Cancer Research and Royal Marsden NHS Foundation Trust, SM2 5NG, Sutton, UK
  40. (40) Sahlgrenska University Hospital, grid.1649.a
  41. (41) Department of Oncology, Rigshospitalet, Copenhagen University Hospital, Blegdamsvej 9, 2100, Copenhagen, Denmark
  42. (42) Leipzig University, grid.9647.c
  43. (43) University of Manchester, grid.5379.8
  44. (44) Molecular Diagnostic Unit, Hereditary Cancer Program, IDIBELL (Bellvitge Biomedical Research Institute), Catalan Institute of Oncology, Gran Via de l’Hospitalet, 199-203, L’Hospitalet, 08908, Barcelona, Spain
  45. (45) Masaryk Memorial Cancer Institute, grid.419466.8
  46. (46) National Centre of Scientific Research Demokritos, grid.6083.d
  47. (47) Aristotle University of Thessaloniki, grid.4793.9
  48. (48) Tel Aviv University, grid.12136.37
  49. (49) Sheba Medical Center, grid.413795.d
  50. (50) University of California, Los Angeles, grid.19006.3e
  51. (51) Dana-Farber Cancer Institute, grid.65499.37
  52. (52) University of Southern California, grid.42505.36
  53. (53) Paris Descartes University, grid.10992.33
  54. (54) Rigshospitalet, grid.475435.4, Capital Region
  55. (55) University of Kansas Medical Center, grid.412016.0
  56. (56) University of Utah, grid.223827.e
  57. (57) National Cancer Institute, grid.48336.3a
  58. (58) Pomeranian Medical University, grid.107950.a
  59. (59) University Hospital Cologne, grid.411097.a
  60. (60) German Cancer Research Center, grid.7497.d
  61. (61) Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital, Blegdamsvej 9, 2100, Copenhagen, Denmark
  62. (62) Mayo Clinic, grid.66875.3a
  63. (63) Comprehensive Cancer Center Arthur C. James Cancer Hospital and Richard J. Solove Research Institute Biomedical Research Tower, Room 588, 460 West 12th Avenue, 43210, Columbus, OH, USA
  64. (64) The Ohio State University, grid.261331.4
  65. (65) Antoni van Leeuwenhoek Hospital, grid.430814.a
  66. (66) NorthShore University HealthSystem, grid.240372.0
  67. (67) Institute of Oncology NN Petrov, grid.465337.0
  68. (68) Georgetown University, grid.213910.8
  69. (69) Guy's and St Thomas' NHS Foundation Trust, grid.420545.2
  70. (70) Peter MacCallum Cancer Centre, grid.1055.1
  71. (71) University of Melbourne, grid.1008.9
  72. (72) State Research Institute Centre for Innovative Medicine, grid.493509.2
  73. (73) Vilnius University Hospital Santariskiu Klinikos, grid.426597.b
  74. (74) Aarhus University Hospital, grid.154185.c, Central Denmark Region
  75. (75) Cancer Prevention Institute of California, grid.280669.3
  76. (76) Stanford University, grid.168010.e
  77. (77) Memorial Sloan Kettering Cancer Center, grid.51462.34
  78. (78) University of Ulm, grid.6582.9
  79. (79) Cedars-Sinai Medical Center, grid.50956.3f
  80. (80) Radboud University Nijmegen Medical Centre, grid.10417.33
  81. (81) Westmead Hospital, grid.413252.3
  82. (82) Erasmus University Medical Center, grid.5645.2
  83. (83) PSL Research University, grid.440907.e
  84. (84) Karolinska University Hospital, grid.24381.3c
  85. (85) Skåne University Hospital, grid.411843.b
  86. (86) University of Lyon System, grid.25697.3f
  87. (87) VU University Medical Center, grid.16872.3a
  88. (88) Roswell Park Cancer Institute, grid.240614.5
  89. (89) Immunology and Molecular Oncology Unit, Veneto Institute of Oncology IOV-IRCCS, Via Gattamelata 64, 35128, Padua, Italy
  90. (90) St. Michael's Hospital, grid.415502.7
  91. (91) University of California, San Francisco, grid.266102.1
  92. (92) National Institute of Oncology, grid.419617.c
  93. (93) Department of Medicine, University of Chicago, 5841 South Maryland Avenue, MC 2115, Chicago, IL, USA
  94. (94) West Midlands Regional Genetics Service, Birmingham Women's Hospital Healthcare NHS Trust, Edgbaston, Birmingham, UK
  95. (95) Department of Genetics, University Medical Center Groningen, University of Groningen, 9700 RB, Groningen, The Netherlands
  96. (96) University of Florence, grid.8404.8
  97. (97) Seoul National University, grid.31501.36
  98. (98) Aalborg Hospital, grid.27530.33, North Denmark Region
  99. (99) IFOM, The FIRC (Italian Foundation for Cancer Research) Institute of Molecular Oncology, c/o IFOM-IEO Campus, Via Adamello 16, 20139, Milan, Italy
  100. (100) Moffitt Cancer Center, grid.468198.a
  101. (101) 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
  102. (102) Medical University of Vienna, grid.22937.3d
  103. (103) 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., 34362, Haifa, Israel
  104. (104) Johns Hopkins University, grid.21107.35
  105. (105) Institut Bergonié, grid.476460.7
  106. (106) University College London, grid.83440.3b
  107. (107) Laboratoire de génétique médicale Nancy Université, Centre Hospitalier Régional et Universitaire, Rue du Morvan cedex 1, 54511, Vandoeuvre-les-Nancy, France
  108. (108) Slagelse Hospital, grid.452905.f, Zealand Region
  109. (109) QIMR Berghofer Medical Research Institute, grid.1049.c
  110. (110) University Hospital Heidelberg, grid.5253.1
  111. (111) Portuguese Oncology Institute, grid.418711.a
  112. (112) University of Porto, grid.5808.5
  113. (113) Genetic Counseling Unit, Hereditary Cancer Program, IDIBELL (Bellvitge Biomedical Research Institute), Catalan Institute of Oncology, Gran Via de l’Hospitalet, 199-203, L’Hospitalet, 08908, Barcelona, Spain
  114. (114) Cancer Research Initiatives Foundation, Sime Darby Medical Centre, 1 Jalan SS12/1A, 47500, Subang Jaya, Malaysia
  115. (115) University of Malaya, grid.10347.31
  116. (116) Odense University Hospital, grid.7143.1, Southern Denmark Region
  117. (117) Latvian Biomedical Research and Study Centre, grid.419210.f
  118. (118) Addenbrooke's Hospital, grid.120073.7
  119. (119) Beth Israel Deaconess Medical Center, grid.239395.7
  120. (120) University Medical Center Utrecht, grid.7692.a
  121. (121) Academic Medical Center, grid.5650.6
  122. (122) Charité, grid.6363.0
  123. (123) Leiden University Medical Center, grid.10419.3d
  124. (124) University of Pennsylvania, grid.25879.31
  125. (125) Oslo University Hospital, grid.55325.34

Description

PURPOSE: Cis-acting regulatory SNPs resulting in differential allelic expression (DAE) may, in part, explain the underlying phenotypic variation associated with many complex diseases. To investigate whether common variants associated with DAE were involved in breast cancer susceptibility among BRCA1 and BRCA2 mutation carriers, a list of 175 genes was developed based of their involvement in cancer-related pathways. METHODS: Using data from a genome-wide map of SNPs associated with allelic expression, we assessed the association of ~320 SNPs located in the vicinity of these genes with breast and ovarian cancer risks in 15,252 BRCA1 and 8211 BRCA2 mutation carriers ascertained from 54 studies participating in the Consortium of Investigators of Modifiers of BRCA1/2. RESULTS: We identified a region on 11q22.3 that is significantly associated with breast cancer risk in BRCA1 mutation carriers (most significant SNP rs228595 p = 7 × 10-6). This association was absent in BRCA2 carriers (p = 0.57). The 11q22.3 region notably encompasses genes such as ACAT1, NPAT, and ATM. Expression quantitative trait loci associations were observed in both normal breast and tumors across this region, namely for ACAT1, ATM, and other genes. In silico analysis revealed some overlap between top risk-associated SNPs and relevant biological features in mammary cell data, which suggests potential functional significance. CONCLUSION: We identified 11q22.3 as a new modifier locus in BRCA1 carriers. Replication in larger studies using estrogen receptor (ER)-negative or triple-negative (i.e., ER-, progesterone receptor-, and HER2-negative) cases could therefore be helpful to confirm the association of this locus with breast cancer risk.

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