Article open access publication

Fine-mapping identifies two additional breast cancer susceptibility loci at 9q31.2

Human Molecular Genetics, Oxford University Press (OUP), ISSN 1460-2083

Volume 24, 10, 2015

DOI:10.1093/hmg/ddv035, Dimensions: pub.1022615011, PMC: PMC4406292, PMID: 25652398,

Authors

Orr, Nick (1) (2)
Dryden, Nicola (1) (2)
Maguire, Sarah (1) (2)
Novo, Daniela (1) (2)
Perrakis, Eleni (1) (2)
Warren, Helen (12) (13)
Burwinkel, Barbara (17) (18)
Marme, Frederik (17) (19)
Guénel, Pascal (20) (21)
Truong, Thérèse (20) (21)
Sanchez, Marie (20) (21)
Bojesen, Stig E. (22) (23)
Nielsen, Sune F. (22) (23)
Benitez, Javier (25) (26)
Brenner, Hermann (18) (32)
Brauch, Hiltrud (18) (35) (36)
Ko, Yon-Dschun (18) (34) (35) (36) (37) (38) (39) (40)
Bogdanova, Natalia (44) (45)
Mannermaa, Arto (48) (49)
Kataja, Vesa (50) (51) (52)
Kosma, Veli-Matti (48) (49)
Beesley, Jonathan (53) (54)
Moisse, Matthieu (55) (56)
Pensotti, Valeria (60) (62)
Giles, Graham G (5) (65)
Milne, Roger L. (5) (65)
Goldberg, Mark S (70) (71)
Zheng, Wei (75)
Andrulis, Irene L. (79) (80)
Knight, Julia A. (81) (82)
Hall, Per (47)
Ashworth, Alan (1) (2)
Muir, Kenneth (98) (99)
Ito, Hidema (102)
Wu, Anna H (67)
Teo, Soo Hwang (103) (104)
Kang, Peter (104)
Lu, Wei (106)
Gao, Yu-Tang (107)
Cai, Hui (75)
Kang, Dae Hee (108) (109)
Park, Sue K. (108) (109)
Hartman, Mikael (105) (110) (111)
Miao, Hui (110) (111)
Lim, Wei Yen (110) (111)
Lee, Soo Chin (105) (111)
Mckay, James (113)
Wu, Pei-Ei (114) (115)
Shen, Chen-Yang (116) (118)
Blot, William (75) (119)
Signorello, Lisa B. (120) (121)
Dennis, Joe (124)
Easton, Douglas F. (4) (124)

Affiliations

Organisations

  1. (1) Division of Breast Cancer Research and
  2. (2) The Breakthrough Breast CancerResearch Centre,
  3. (3) London School of Hygiene & Tropical Medicine, grid.8991.9
  4. (4) Centre for Cancer Genetic Epidemiology, Department of Oncology and
  5. (5) Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health and
  6. (6) University of Melbourne, grid.1008.9
  7. (7) University of Western Australia, grid.1012.2
  8. (8) Antoni van Leeuwenhoek Hospital, grid.430814.a
  9. (9) University of California, Los Angeles, grid.19006.3e
  10. (10) University Breast Center Franconia, Department of Gynecology and Obstetrics, University Hospital Erlangen and
  11. (11) Institute of Human Genetics, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nuremberg, Comprehensive Cancer Center Erlangen-EMN, 91054 Erlangen, Germany,
  12. (12) Department of Clinical Pharmacology, William Harvey Research Institute, Barts and The London School of Medicine and
  13. (13) Queen Mary University of London, grid.4868.2
  14. (14) King's College London, grid.13097.3c
  15. (15) University of Oxford, grid.4991.5
  16. (16) University Hospital Galway, grid.412440.7
  17. (17) Department of Obstetrics and Gynecology and
  18. (18) German Cancer Research Center, grid.7497.d
  19. (19) National Center for Tumor Diseases, University of Heidelberg, 69120 Heidelberg, Germany,
  20. (20) French Institute of Health and Medical Research, grid.7429.8
  21. (21) University of Paris-Sud, grid.5842.b
  22. (22) Copenhagen General Population Study and
  23. (23) Herlev Hospital, grid.411900.d, Capital Region
  24. (24) Department of Breast Surgery, Herlev Hospital, Copenhagen University Hospital, Copenhagen, Denmark,
  25. (25) Centro de Investigación en Red de Enfermedades Raras (CIBERER), 46010 Valencia, Spain,
  26. (26) Spanish National Cancer Research Centre, grid.7719.8
  27. (27) Hospital Universitario La Paz, grid.81821.32
  28. (28) Servicio de Cirugía General y Especialidades and
  29. (29) Hospital Monte Naranco, grid.414858.4
  30. (30) University of California, Irvine, grid.266093.8
  31. (31) City Of Hope National Medical Center, grid.410425.6
  32. (32) Division of Clinical Epidemiology and Aging Research,
  33. (33) Krebsregister Saarland, grid.482902.5
  34. (34) Molecular Genetics of Breast Cancer and
  35. (35) Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology, grid.502798.1
  36. (36) University of Tübingen, grid.10392.39
  37. (37) Institute for Prevention and Occupational Medicine of the German Social Accident Insurance, Institute of the Ruhr—University Bochum (IPA), Bochum, Germany,
  38. (38) Department of Internal Medicine, Evangelische Kliniken Bonn gGmbH, Johanniter Krankenhaus, Bonn, Germany,
  39. (39) University of Bonn, grid.10388.32
  40. (40) University Medical Center Hamburg-Eppendorf, grid.13648.38
  41. (41) Department of Obstetrics and Gynecology,
  42. (42) Department of Clinical Genetics and
  43. (43) Helsinki University Central Hospital, grid.15485.3d
  44. (44) Department of Radiation Oncology and
  45. (45) Hannover Medical School, grid.10423.34
  46. (46) Department of Molecular Medicine and Surgery and
  47. (47) Karolinska Institute, grid.4714.6
  48. (48) Imaging Center, Department of Clinical Pathology and
  49. (49) School of Medicine, Institute of Clinical Medicine, Pathology and Forensic Medicine and
  50. (50) Central Finland Health Care District, grid.460356.2
  51. (51) Kuopio University Hospital, grid.410705.7
  52. (52) University of Eastern Finland, grid.9668.1
  53. (53) QIMR Berghofer Medical Research Institute, grid.1049.c
  54. (54) Peter MacCallum Cancer Centre, grid.1055.1
  55. (55) Flanders Institute for Biotechnology, grid.11486.3a
  56. (56) KU Leuven, grid.5596.f
  57. (57) Universitair Ziekenhuis Leuven, grid.410569.f
  58. (58) Department of Cancer Epidemiology/Clinical Cancer Registry and
  59. (59) Unit of Molecular Bases of Genetic Risk and Genetic Testing, Department of Preventive and Predictive Medicine and
  60. (60) FIRC Institute of Molecular Oncology, grid.7678.e
  61. (61) Fondazione IRCCS Istituto Nazionale dei Tumori, grid.417893.0
  62. (62) Cogentech Cancer Genetic Test Laboratory, Milan, Italy,
  63. (63) Department of Laboratory Medicine and Pathology and
  64. (64) Mayo Clinic, grid.66875.3a
  65. (65) Cancer Council Victoria, grid.3263.4
  66. (66) The Alfred Hospital, grid.1623.6
  67. (67) University of Southern California, grid.42505.36
  68. (68) University of Hawaii at Manoa, grid.410445.0
  69. (69) Centre Hospitalier Universitaire de Québec, grid.411081.d
  70. (70) McGill University, grid.14709.3b
  71. (71) Royal Victoria Hospital, grid.416229.a
  72. (72) University of Montreal, grid.14848.31
  73. (73) Oslo University Hospital, grid.55325.34
  74. (74) University of Oslo, grid.5510.1
  75. (75) Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, TN, USA,
  76. (76) Laboratory of Cancer Genetics and Tumor Biology, Department of Clinical Genetics and Biocenter Oulu,
  77. (77) Department of Oncology and
  78. (78) Department of Surgery, Oulu University Hospital, University of Oulu, Oulu, Finland,
  79. (79) Department of Molecular Genetics and
  80. (80) Ontario Cancer Genetics Network and
  81. (81) Mount Sinai Hospital, grid.416166.2
  82. (82) University of Toronto, grid.17063.33
  83. (83) Lunenfeld-Tanenbaum Research Institute, grid.250674.2
  84. (84) Department of Human Genetics and Department of Pathology and
  85. (85) Leiden University Medical Center, grid.10419.3d
  86. (86) Erasmus University Medical Center, grid.5645.2
  87. (87) Institute of Cancer Research, grid.18886.3f
  88. (88) National Cancer Institute, grid.48336.3a
  89. (89) Maria Skłodowska-Curie Memorial Cancer Center and Institute of Oncology, grid.418165.f
  90. (90) Genome Institute of Singapore, grid.418377.e
  91. (91) University of Sheffield, grid.11835.3e
  92. (92) University of Sussex, grid.12082.39
  93. (93) Pomeranian Medical University, grid.107950.a
  94. (94) Technical University of Munich, grid.6936.a
  95. (95) University Hospital Cologne, grid.411097.a
  96. (96) The Ohio State University, grid.261331.4
  97. (97) National Centre of Scientific Research Demokritos, grid.6083.d
  98. (98) University of Manchester, grid.5379.8
  99. (99) University of Warwick, grid.7372.1
  100. (100) Ministry of Public Health, grid.415836.d
  101. (101) Kyushu University, grid.177174.3
  102. (102) Aichi Cancer Center, grid.410800.d
  103. (103) University Malaya Medical Centre, grid.413018.f
  104. (104) Cancer Research Initiatives Foundation, Sime Darby Medical Centre, Subang Jaya, Selangor, Malaysia,
  105. (105) National University of Singapore, grid.4280.e
  106. (106) Shanghai Center for Disease Control and Prevention, Shanghai, China,
  107. (107) Shanghai Cancer Institute, grid.419087.3
  108. (108) Seoul National University, grid.31501.36
  109. (109) Department of Preventive Medicine and
  110. (110) Saw Swee Hock School of Public Health and
  111. (111) National University Health System, grid.410759.e
  112. (112) National Cancer Institute of Thailand, grid.419173.9
  113. (113) International Agency For Research On Cancer, grid.17703.32
  114. (114) Institute of Biomedical Sciences, Academia Sinica, grid.482251.8
  115. (115) Taiwan Biobank and
  116. (116) Kaohsiung Medical University Chung-Ho Memorial Hospital, grid.412027.2
  117. (117) National Defense Medical Center, grid.260565.2
  118. (118) China Medical University, grid.254145.3
  119. (119) International Epidemiology Institute, grid.419344.f
  120. (120) Dana-Farber/Harvard Cancer Center, grid.477947.e
  121. (121) Department of Epidemiology and
  122. (122) McGill University and Génome Québec Innovation Centre, grid.411640.6
  123. (123) Harvard University, grid.38142.3c
  124. (124) University of Cambridge, grid.5335.0

Description

We recently identified a novel susceptibility variant, rs865686, for estrogen-receptor positive breast cancer at 9q31.2. Here, we report a fine-mapping analysis of the 9q31.2 susceptibility locus using 43 160 cases and 42 600 controls of European ancestry ascertained from 52 studies and a further 5795 cases and 6624 controls of Asian ancestry from nine studies. Single nucleotide polymorphism (SNP) rs676256 was most strongly associated with risk in Europeans (odds ratios [OR] = 0.90 [0.88-0.92]; P-value = 1.58 × 10(-25)). This SNP is one of a cluster of highly correlated variants, including rs865686, that spans ∼14.5 kb. We identified two additional independent association signals demarcated by SNPs rs10816625 (OR = 1.12 [1.08-1.17]; P-value = 7.89 × 10(-09)) and rs13294895 (OR = 1.09 [1.06-1.12]; P-value = 2.97 × 10(-11)). SNP rs10816625, but not rs13294895, was also associated with risk of breast cancer in Asian individuals (OR = 1.12 [1.06-1.18]; P-value = 2.77 × 10(-05)). Functional genomic annotation using data derived from breast cancer cell-line models indicates that these SNPs localise to putative enhancer elements that bind known drivers of hormone-dependent breast cancer, including ER-α, FOXA1 and GATA-3. In vitro analyses indicate that rs10816625 and rs13294895 have allele-specific effects on enhancer activity and suggest chromatin interactions with the KLF4 gene locus. These results demonstrate the power of dense genotyping in large studies to identify independent susceptibility variants. Analysis of associations using subjects with different ancestry, combined with bioinformatic and genomic characterisation, can provide strong evidence for the likely causative alleles and their functional basis.

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Times Cited: 29

Field Citation Ratio (FCR): 6.2

Relative Citation ratio (RCR): 1.17

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