Article open access publication

Fine-Mapping of the 1p11.2 Breast Cancer Susceptibility Locus

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

Volume 11, 8, 2016

DOI:10.1371/journal.pone.0160316, Dimensions: pub.1022831528, PMC: PMC4996485, PMID: 27556229,

Authors

Horne, Hisani N (1) (2)
Yu, Kai (2)
Wang, Qin (3)
Muir, Kenneth (6) (7)
Burwinkel, Barbara (13) (14)
Marme, Frederik (13) (15)
Guénel, Pascal (16) (17)
Truong, Thérèse (16) (17)
Bojesen, Stig E. (18) (19)
Benitez, Javier (20) (21)
Brauch, Hiltrud (14) (26) (27)
Mannermaa, Arto (33) (34)
Kosma, Veli-Matti (33) (34)
Wu, Anna H (36)
Zhao, Hui (38) (39)
Giles, Graham G (4) (44)
Milne, Roger L. (4) (44)
Teo, Soo H. (47) (48)
Kristensen, Vessela (49) (50) (51)
Zheng, Wei (52)
Winqvist, Robert (53) (54)
Andrulis, Irene L. (56) (57)
Knight, Julia A. (57) (58)
Lu, Wei (61)
Blot, William (52) (63)
Hartman, Mikael (65) (66)
Torres, Diana (14) (67)
Shen, Chen-Yang (72) (73)
Orr, Nick (10)
Hall, Per (32)
Figueroa, Jonine D * (2) (76)

* Corresponding author

Affiliations

Organisations

  1. (1) United States Food and Drug Administration, grid.417587.8
  2. (2) National Cancer Institute, grid.48336.3a
  3. (3) University of Cambridge, grid.5335.0
  4. (4) University of Melbourne, grid.1008.9
  5. (5) Antoni van Leeuwenhoek Hospital, grid.430814.a
  6. (6) University of Manchester, grid.5379.8
  7. (7) University of Warwick, grid.7372.1
  8. (8) University of California, Los Angeles, grid.19006.3e
  9. (9) Department of Gynaecology and Obstetrics, University Hospital Erlangen, Friedrich Alexander University Erlangen-Nuremberg, Comprehensive Cancer Center Erlangen-EMN, Erlangen, Germany
  10. (10) Institute of Cancer Research, grid.18886.3f
  11. (11) King's College London, grid.13097.3c
  12. (12) University of Oxford, grid.4991.5
  13. (13) Heidelberg University, grid.7700.0
  14. (14) German Cancer Research Center, grid.7497.d
  15. (15) National Center for Tumor Diseases, University of Heidelberg, Heidelberg, Germany
  16. (16) French Institute of Health and Medical Research, grid.7429.8
  17. (17) University of Paris-Sud, grid.5842.b
  18. (18) University of Copenhagen, grid.5254.6, KU
  19. (19) Herlev Hospital, grid.411900.d, Capital Region
  20. (20) Centro de Investigación en Red de Enfermedades Raras, Valencia, Spain
  21. (21) Spanish National Cancer Research Centre, grid.7719.8
  22. (22) University of California, Irvine, grid.266093.8
  23. (23) City Of Hope National Medical Center, grid.410425.6
  24. (24) Technical University of Munich, grid.6936.a
  25. (25) University Hospital Cologne, grid.411097.a
  26. (26) Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology, grid.502798.1
  27. (27) University of Tübingen, grid.10392.39
  28. (28) Department of Obstetrics and Gynecology, Helsinki University Hospital, University of Helsinki, Helsinki, Finland
  29. (29) Kyushu University, grid.177174.3
  30. (30) Aichi Cancer Center, grid.410800.d
  31. (31) Hannover Medical School, grid.10423.34
  32. (32) Karolinska Institute, grid.4714.6
  33. (33) Kuopio University Hospital, grid.410705.7
  34. (34) University of Eastern Finland, grid.9668.1
  35. (35) QIMR Berghofer Medical Research Institute, grid.1049.c
  36. (36) University of Southern California, grid.42505.36
  37. (37) Universitair Ziekenhuis Leuven, grid.410569.f
  38. (38) KU Leuven, grid.5596.f
  39. (39) Vesalius Research Center, Leuven, Belgium
  40. (40) University Cancer Center Hamburg, grid.412315.0
  41. (41) Fondazione IRCCS Istituto Nazionale dei Tumori, grid.417893.0
  42. (42) European Institute of Oncology, grid.15667.33
  43. (43) Mayo Clinic, grid.66875.3a
  44. (44) Cancer Council Victoria, grid.3263.4
  45. (45) University of Hawaii at Manoa, grid.410445.0
  46. (46) McGill University, grid.14709.3b
  47. (47) Cancer Research Initiatives Foundation, grid.427737.2
  48. (48) University Malaya Medical Centre, grid.413018.f
  49. (49) Department of Clinical Molecular Biology, Oslo University Hospital, University of Oslo, Oslo, Norway
  50. (50) Oslo University Hospital, grid.55325.34
  51. (51) University of Oslo, grid.5510.1
  52. (52) Division of Epidemiology, Department of Medicine, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, TN, United States of America
  53. (53) Laboratory of Cancer Genetics and Tumor Biology, Northern Finland Laboratory Centre NordLab, Oulu, Finland
  54. (54) University of Oulu, grid.10858.34
  55. (55) Department of Oncology, Oulu University Hospital, University of Oulu, Oulu, Finland
  56. (56) Lunenfeld-Tanenbaum Research Institute, grid.250674.2
  57. (57) University of Toronto, grid.17063.33
  58. (58) Mount Sinai Hospital, grid.416166.2
  59. (59) Leiden University Medical Center, grid.10419.3d
  60. (60) Erasmus University Medical Center, grid.5645.2
  61. (61) Shanghai Center for Disease Control and Prevention, Shanghai, China
  62. (62) University of Sheffield, grid.11835.3e
  63. (63) International Epidemiology Institute, grid.419344.f
  64. (64) Seoul National University, grid.31501.36
  65. (65) National University Health System, grid.410759.e
  66. (66) National University of Singapore, grid.4280.e
  67. (67) Pontificia Universidad Javeriana, grid.41312.35
  68. (68) Pomeranian Medical University, grid.107950.a
  69. (69) National Cancer Institute of Thailand, grid.419173.9
  70. (70) International Agency For Research On Cancer, grid.17703.32
  71. (71) National Centre of Scientific Research Demokritos, grid.6083.d
  72. (72) China Medical University, grid.254145.3
  73. (73) Institute of Biomedical Sciences, Academia Sinica, grid.482251.8
  74. (74) Cancer Center and Department of Surgery, Chung-Ho Memorial Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan
  75. (75) Laval University, grid.23856.3a
  76. (76) University of Edinburgh, grid.4305.2

Description

The Cancer Genetic Markers of Susceptibility genome-wide association study (GWAS) originally identified a single nucleotide polymorphism (SNP) rs11249433 at 1p11.2 associated with breast cancer risk. To fine-map this locus, we genotyped 92 SNPs in a 900kb region (120,505,799-121,481,132) flanking rs11249433 in 45,276 breast cancer cases and 48,998 controls of European, Asian and African ancestry from 50 studies in the Breast Cancer Association Consortium. Genotyping was done using iCOGS, a custom-built array. Due to the complicated nature of the region on chr1p11.2: 120,300,000-120,505,798, that lies near the centromere and contains seven duplicated genomic segments, we restricted analyses to 429 SNPs excluding the duplicated regions (42 genotyped and 387 imputed). Per-allelic associations with breast cancer risk were estimated using logistic regression models adjusting for study and ancestry-specific principal components. The strongest association observed was with the original identified index SNP rs11249433 (minor allele frequency (MAF) 0.402; per-allele odds ratio (OR) = 1.10, 95% confidence interval (CI) 1.08-1.13, P = 1.49 x 10-21). The association for rs11249433 was limited to ER-positive breast cancers (test for heterogeneity P≤8.41 x 10-5). Additional analyses by other tumor characteristics showed stronger associations with moderately/well differentiated tumors and tumors of lobular histology. Although no significant eQTL associations were observed, in silico analyses showed that rs11249433 was located in a region that is likely a weak enhancer/promoter. Fine-mapping analysis of the 1p11.2 breast cancer susceptibility locus confirms this region to be limited to risk to cancers that are ER-positive.

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Times Cited: 9

Field Citation Ratio (FCR): 2.34

Relative Citation ratio (RCR): 0.41

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