Article open access publication

Identification and characterization of novel associations in the CASP8/ALS2CR12 region on chromosome 2 with breast cancer risk

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

Volume 24, 1, 2015

DOI:10.1093/hmg/ddu431, Dimensions: pub.1008310337, PMC: PMC4334820, PMID: 25168388,

Authors

Lin, Wei-Yu (1) (2)
Muir, Kenneth (10) (11)
Fasching, Peter A. (13) (14)
Wang, Qin (4)
Marmé, Frederik (21) (22)
Surowy, Harald M. (22) (23)
Burwinkel, Barbara (22) (23)
Guénel, Pascal (24) (25)
Truong, Thérèse (24) (25)
Menegaux, Florence (24) (25)
Bojesen, Stig E. (27) (28) (29)
Nordestgaard, Børge G. (27) (28) (29)
Nielsen, Sune F. (28) (29)
Benitez, Javier (31) (32)
Brenner, Hermann (38) (39)
Brauch, Hiltrud (39) (45) (46)
Nevanlinna, Heli (22) (50)
Blomqvist, Carl (50) (52)
Khan, Sofia (22) (50)
Mannermaa, Arto (60) (61)
Kataja, Vesa (62) (63)
Kosma, Veli-Matti (60) (61)
Wu, Anna H (64)
Wauters, Els (66) (67)
Giles, Graham G (6) (78)
Milne, Roger L. (6) (78)
Goldberg, Mark S (82) (83)
Teo, Soo Hwang (85) (86)
Zheng, Wei (90)
Andrulis, Irene L. (93) (94)
Knight, Julia A. (95) (96)
Jager, Agnes (100)
Li, Jingmei (108)
Liu, Jianjun (109)
Lu, Wei (108)
Gao, Yu-Tang (110)
Cai, Hui (90)
Blot, William (90) (112)
Signorello, Lisa B. (90) (112)
Pharoah, Paul D P (4) (113)
Shah, Mitul (113)
Kang, Dae Hee (114) (115)
Hartman, Mikael (117) (118) (119)
Miao, Hui (118) (119)
Chia, Kee Seng (118) (119)
Hamann, Ute (120)
Mckay, James (123)
Shen, Chen-Yang (126) (127)
Wu, Pei-Ei (128)
Orr, Nick (130)
Swerdlow, Anthony J (103) (130) (131)
Hein, Rebecca (39) (135)
Muranen, Taru A (22) (50)
Heikkinen, Tuomas (22) (50)
Hall, Per (106)
Easton, Douglas F. (4) (113)

Affiliations

Organisations

  1. (1) Department of Neurosurgery, Chang Gung Memorial Hospital, Taoyuan County 333, Taiwan
  2. (2) University of Sheffield, grid.11835.3e
  3. (3) University of Utah, grid.223827.e
  4. (4) Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care
  5. (5) Department of Genetics
  6. (6) Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health
  7. (7) Department of Pathology
  8. (8) Centre for Molecular, Environmental, Genetic and Analytic Epidemiology, Melbourne School of Population Health
  9. (9) Antoni van Leeuwenhoek Hospital, grid.430814.a
  10. (10) University of Manchester, grid.5379.8
  11. (11) University of Warwick, grid.7372.1
  12. (12) Ministry of Public Health, grid.415836.d
  13. (13) University of California, Los Angeles, grid.19006.3e
  14. (14) University Breast Center Franconia, Department of Gynecology and Obstetrics
  15. (15) Institute of Human Genetics, University Hospital Erlangen, Friedrich Alexander University Erlangen-Nuremberg, Erlangen D-91054, Germany
  16. (16) London School of Hygiene & Tropical Medicine, grid.8991.9
  17. (17) Breakthrough Breast Cancer Research Centre
  18. (18) King's College London, grid.13097.3c
  19. (19) University of Oxford, grid.4991.5
  20. (20) National University of Ireland, Galway, grid.6142.1
  21. (21) National Center for Tumor Diseases, University of Heidelberg, Heidelberg 69117, Germany
  22. (22) Department of Obstetrics and Gynecology
  23. (23) Molecular Epidemiology Group
  24. (24) French Institute of Health and Medical Research, grid.7429.8
  25. (25) University of Paris-Sud, grid.5842.b
  26. (26) Sorbonne University, grid.462844.8
  27. (27) University of Copenhagen, grid.5254.6, KU
  28. (28) Department of Clinical Biochemistry
  29. (29) Herlev Hospital, grid.411900.d, Capital Region
  30. (30) Department of Breast Surgery, Herlev Hospital, Copenhagen University Hospital, Copenhagen 2100, Denmark
  31. (31) Centro de Investigación en Red de Enfermedades Raras (CIBERER), Valencia 28029, Spain
  32. (32) Human Genetics Group, Human Cancer Genetics Program
  33. (33) Hospital Universitario La Paz, grid.81821.32
  34. (34) Servicio de Cirugía General y Especialidades
  35. (35) Hospital Monte Naranco, grid.414858.4
  36. (36) Spanish National Cancer Research Centre, grid.7719.8
  37. (37) University of California, Irvine, grid.266093.8
  38. (38) Division of Clinical Epidemiology and Aging Research
  39. (39) German Cancer Research Center, grid.7497.d
  40. (40) Krebsregister Saarland, grid.482902.5
  41. (41) Division of Gynaecology and Obstetrics
  42. (42) Technical University of Munich, grid.6936.a
  43. (43) Philipp University of Marburg, grid.10253.35
  44. (44) Max Planck Institute of Psychiatry, grid.419548.5
  45. (45) Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology, grid.502798.1
  46. (46) University of Tübingen, grid.10392.39
  47. (47) Ruhr University Bochum, grid.5570.7
  48. (48) Department of Internal Medicine, Evangelische Kliniken Bonn gGmbH, Johanniter Krankenhaus, Bonn 53113, Germany
  49. (49) McGill University and Génome Québec Innovation Centre, grid.411640.6
  50. (50) Helsinki University Central Hospital, grid.15485.3d
  51. (51) Department of Clinical Genetics
  52. (52) University of Helsinki, grid.7737.4
  53. (53) Kyushu University, grid.177174.3
  54. (54) Aichi Cancer Center, grid.410800.d
  55. (55) Hannover Medical School, grid.10423.34
  56. (56) Department of Obstetrics and Gynaecology
  57. (57) N.N. Alexandrov Research Institute of Oncology and Medical Radiology, Minsk 223040, Belarus
  58. (58) Department of Molecular Medicine and Surgery
  59. (59) Department of Oncology–Pathology
  60. (60) Imaging Center, Department of Clinical Pathology
  61. (61) School of Medicine, Institute of Clinical Medicine, Pathology and Forensic Medicine and Cancer Center of Eastern Finland
  62. (62) Kuopio University Hospital, grid.410705.7
  63. (63) University of Eastern Finland, grid.9668.1
  64. (64) University of Southern California, grid.42505.36
  65. (65) Universitair Ziekenhuis Leuven, grid.410569.f
  66. (66) Department of Oncology
  67. (67) Flanders Institute for Biotechnology, grid.11486.3a
  68. (68) Laboratory for Translational Genetics, Department of Oncology
  69. (69) Division of Cancer Epidemiology
  70. (70) University Medical Center Hamburg-Eppendorf, grid.13648.38
  71. (71) Unit of Molecular Bases of Genetic Risk and Genetic Testing, Department of Preventive and Predictive Medicine
  72. (72) FIRC Institute of Molecular Oncology, grid.7678.e
  73. (73) Fondazione IRCCS Istituto Nazionale dei Tumori, grid.417893.0
  74. (74) European Institute of Oncology, grid.15667.33
  75. (75) Department of Laboratory Medicine and Pathology
  76. (76) Mayo Clinic, grid.66875.3a
  77. (77) Karmanos Cancer Institute, grid.477517.7
  78. (78) Cancer Council Victoria, grid.3263.4
  79. (79) The Alfred Hospital, grid.1623.6
  80. (80) University of Hawaii at Manoa, grid.410445.0
  81. (81) Centre Hospitalier Universitaire de Québec, grid.411081.d
  82. (82) McGill University, grid.14709.3b
  83. (83) Royal Victoria Hospital, grid.416229.a
  84. (84) University of Montreal, grid.14848.31
  85. (85) University Malaya Medical Centre, grid.413018.f
  86. (86) Cancer Research Initiatives Foundation, Sime Darby Medical Centre, Subang Jaya, Selangor, Malaysia
  87. (87) National University of Singapore, grid.4280.e
  88. (88) Oslo University Hospital, grid.55325.34
  89. (89) University of Oslo, grid.5510.1
  90. (90) Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, TN 37232, USA
  91. (91) Laboratory of Cancer Genetics and Tumor Biology, Department of Clinical Chemistry and Biocenter Oulu, Northern Finland Laboratory Centre NordLab
  92. (92) Department of Pathology, Oulu University Hospital, University of Oulu, Oulu 90570, Finland
  93. (93) Department of Molecular Genetics
  94. (94) Ontario Cancer Genetics Network
  95. (95) Prosserman Centre for Health Research
  96. (96) University of Toronto, grid.17063.33
  97. (97) Lunenfeld-Tanenbaum Research Institute, grid.250674.2
  98. (98) Department of Human Genetics & Department of Pathology
  99. (99) Department of Surgical Oncology
  100. (100) Family Cancer Clinic, Department of Medical Oncology, Erasmus MC Cancer InstituteRotterdam 3075 EA, The Netherlands
  101. (101) Leiden University Medical Center, grid.10419.3d
  102. (102) Breakthrough Breast Cancer Research Centre, Division of Breast Cancer Research
  103. (103) Division of Genetics and Epidemiology
  104. (104) National Cancer Institute, grid.48336.3a
  105. (105) Maria Skłodowska-Curie Memorial Cancer Center and Institute of Oncology, grid.418165.f
  106. (106) Karolinska Institute, grid.4714.6
  107. (107) Erasmus University Medical Center, grid.5645.2
  108. (108) Shanghai Center for Disease Control and Prevention, Shanghai 200336, China
  109. (109) Genome Institute of Singapore, grid.418377.e
  110. (110) Shanghai Cancer Institute, grid.419087.3
  111. (111) Department of Neuroscience, University of Sheffield, Royal Hallamshire Hospital, Sheffield S10 2JF, UK
  112. (112) International Epidemiology Institute, grid.419344.f
  113. (113) University of Cambridge, grid.5335.0
  114. (114) Department of Preventive Medicine
  115. (115) Seoul National University, grid.31501.36
  116. (116) Department of Surgery
  117. (117) Department of Surgery, Yong Loo Lin School of Medicine
  118. (118) National University Health System, grid.410759.e
  119. (119) Saw Swee Hock School of Public Health
  120. (120) Molecular Genetics of Breast Cancer
  121. (121) Pomeranian Medical University, grid.107950.a
  122. (122) National Cancer Institute of Thailand, grid.419173.9
  123. (123) International Agency For Research On Cancer, grid.17703.32
  124. (124) The Ohio State University, grid.261331.4
  125. (125) National Centre of Scientific Research Demokritos, grid.6083.d
  126. (126) China Medical University, grid.254145.3
  127. (127) Institute of Biomedical Sciences
  128. (128) Institute of Biomedical Sciences, Academia Sinica, grid.482251.8
  129. (129) Kang-Ning Junior College of Medical Care and Management, grid.459670.9
  130. (130) Institute of Cancer Research, grid.18886.3f
  131. (131) Division of Breast Cancer Research
  132. (132) Genetic Epidemiology Laboratory, Department of Pathology
  133. (133) University of Melbourne, grid.1008.9
  134. (134) Harvard University, grid.38142.3c
  135. (135) University of Cologne, grid.6190.e
  136. (136) Johannes Gutenberg University of Mainz, grid.5802.f
  137. (137) Institute for Quality and Efficiency in Health Care, grid.414694.a
  138. (138) Department of Clinical Genetics, Section Oncogenetics, VU University Medical Center, Amsterdam 1081 HZ, The Netherlands and
  139. (139) University Medical Center Utrecht, grid.7692.a

Description

Previous studies have suggested that polymorphisms in CASP8 on chromosome 2 are associated with breast cancer risk. To clarify the role of CASP8 in breast cancer susceptibility, we carried out dense genotyping of this region in the Breast Cancer Association Consortium (BCAC). Single-nucleotide polymorphisms (SNPs) spanning a 1 Mb region around CASP8 were genotyped in 46 450 breast cancer cases and 42 600 controls of European origin from 41 studies participating in the BCAC as part of a custom genotyping array experiment (iCOGS). Missing genotypes and SNPs were imputed and, after quality exclusions, 501 typed and 1232 imputed SNPs were included in logistic regression models adjusting for study and ancestry principal components. The SNPs retained in the final model were investigated further in data from nine genome-wide association studies (GWAS) comprising in total 10 052 case and 12 575 control subjects. The most significant association signal observed in European subjects was for the imputed intronic SNP rs1830298 in ALS2CR12 (telomeric to CASP8), with per allele odds ratio and 95% confidence interval [OR (95% confidence interval, CI)] for the minor allele of 1.05 (1.03-1.07), P = 1 × 10(-5). Three additional independent signals from intronic SNPs were identified, in CASP8 (rs36043647), ALS2CR11 (rs59278883) and CFLAR (rs7558475). The association with rs1830298 was replicated in the imputed results from the combined GWAS (P = 3 × 10(-6)), yielding a combined OR (95% CI) of 1.06 (1.04-1.08), P = 1 × 10(-9). Analyses of gene expression associations in peripheral blood and normal breast tissue indicate that CASP8 might be the target gene, suggesting a mechanism involving apoptosis.

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Times Cited: 30

Field Citation Ratio (FCR): 4.02

Relative Citation ratio (RCR): 1.26

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