Article open access publication

Evidence that the 5p12 Variant rs10941679 Confers Susceptibility to Estrogen-Receptor-Positive Breast Cancer through FGF10 and MRPS30 Regulation

American Journal of Human Genetics, Elsevier, ISSN 1537-6605

Volume 99, 4, 2016

DOI:10.1016/j.ajhg.2016.07.017, Dimensions: pub.1022650523, PMC: PMC5065698, PMID: 27640304,

Authors

Wang, Qin (1)
Dicks, Ed (1)
Milne, Roger L. (6) (7)
Muir, Kenneth (8) (9)
Fasching, Peter A. (10) (11)
Burwinkel, Barbara (15) (16)
Marme, Frederik (15) (17)
Bojesen, Stig E. (19) (20) (21)
Benitez, Javier (23) (24)
Brauch, Hiltrud (16) (30) (31)
Mannermaa, Arto (37) (38)
Kosma, Veli-Matti (37) (38)
Wu, Anna H (39)
Giles, Graham G (6) (7)
Teo, Soo H. (49) (50)
Zheng, Wei (51)
Winqvist, Robert (52) (53)
Pylkäs, Katri (52) (53)
Andrulis, Irene L. (54) (55)
Figueroa, Jonine (57) (58)
Hall, Per (36)
Hartman, Mikael (63) (64)
Torres, Diana (16) (65)
Shen, Chen-Yang (69) (70)

* Corresponding author

Affiliations

Organisations

  1. (1) University of Cambridge, grid.5335.0
  2. (2) QIMR Berghofer Medical Research Institute, grid.1049.c
  3. (3) Cyprus Institute of Neurology and Genetics, grid.417705.0
  4. (4) Oslo University Hospital, grid.55325.34
  5. (5) Antoni van Leeuwenhoek Hospital, grid.430814.a
  6. (6) University of Melbourne, grid.1008.9
  7. (7) Cancer Council Victoria, grid.3263.4
  8. (8) University of Manchester, grid.5379.8
  9. (9) University of Warwick, grid.7372.1
  10. (10) University of California, Los Angeles, grid.19006.3e
  11. (11) Department of Gynaecology and Obstetrics, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nuremberg, Comprehensive Cancer Center Erlangen-EMN, 91054 Erlangen, Germany
  12. (12) Institute of Cancer Research, grid.18886.3f
  13. (13) King's College London, grid.13097.3c
  14. (14) University of Oxford, grid.4991.5
  15. (15) Heidelberg University, grid.7700.0
  16. (16) German Cancer Research Center, grid.7497.d
  17. (17) National Center for Tumor Diseases, University of Heidelberg, 69120 Heidelberg, Germany
  18. (18) Cancer Environment Group, Center for Research in Epidemiology and Population Health (CESP), INSERM, University Paris-Sud, University Paris-Saclay, 94807 Villejuif, France
  19. (19) Copenhagen General Population Study, Herlev and Gentofte Hospital, Copenhagen University Hospital, 2730 Herlev, Denmark
  20. (20) Department of Clinical Biochemistry, Herlev and Gentofte Hospital, Copenhagen University Hospital, 2730 Herlev, Denmark
  21. (21) University of Copenhagen, grid.5254.6, KU
  22. (22) Department of Breast Surgery, Herlev and Gentofte Hospital, Copenhagen University Hospital, 2730 Herlev, Denmark
  23. (23) Centro de Investigación en Red de Enfermedades Raras, 46010 Valencia, Spain
  24. (24) Spanish National Cancer Research Centre, grid.7719.8
  25. (25) City Of Hope National Medical Center, grid.410425.6
  26. (26) University of California, Irvine, grid.266093.8
  27. (27) Technical University of Munich, grid.6936.a
  28. (28) University Hospital Cologne, grid.411097.a
  29. (29) University of Cologne, grid.6190.e
  30. (30) Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology, grid.502798.1
  31. (31) University of Tübingen, grid.10392.39
  32. (32) McGill University and Génome Québec Innovation Centre, grid.411640.6
  33. (33) Department of Obstetrics and Gynecology, Helsinki University Hospital, University of Helsinki, 00029 Helsinki, Finland
  34. (34) Aichi Cancer Center, grid.410800.d
  35. (35) Hannover Medical School, grid.10423.34
  36. (36) Karolinska Institute, grid.4714.6
  37. (37) Kuopio University Hospital, grid.410705.7
  38. (38) University of Eastern Finland, grid.9668.1
  39. (39) University of Southern California, grid.42505.36
  40. (40) Flanders Institute for Biotechnology, grid.11486.3a
  41. (41) KU Leuven, grid.5596.f
  42. (42) Universitair Ziekenhuis Leuven, grid.410569.f
  43. (43) University Cancer Center Hamburg, grid.412315.0
  44. (44) Fondazione IRCCS Istituto Nazionale dei Tumori, grid.417893.0
  45. (45) European Institute of Oncology, grid.15667.33
  46. (46) Mayo Clinic, grid.66875.3a
  47. (47) University of Hawaii at Manoa, grid.410445.0
  48. (48) McGill University, grid.14709.3b
  49. (49) Cancer Research Initiatives Foundation, grid.427737.2
  50. (50) University Malaya Medical Centre, grid.413018.f
  51. (51) Division of Epidemiology, Department of Medicine, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, TN 37203, USA
  52. (52) Laboratory of Cancer Genetics and Tumor Biology, Northern Finland Laboratory Centre Oulu, 90220 Oulu, Finland
  53. (53) University of Oulu, grid.10858.34
  54. (54) Lunenfeld-Tanenbaum Research Institute, grid.250674.2
  55. (55) University of Toronto, grid.17063.33
  56. (56) Leiden University Medical Center, grid.10419.3d
  57. (57) National Cancer Institute, grid.48336.3a
  58. (58) University of Edinburgh, grid.4305.2
  59. (59) Erasmus University Medical Center, grid.5645.2
  60. (60) Shanghai Municipal Center For Disease Control Prevention, grid.430328.e
  61. (61) University of Sheffield, grid.11835.3e
  62. (62) Seoul National University, grid.31501.36
  63. (63) National University Health System, grid.410759.e
  64. (64) National University of Singapore, grid.4280.e
  65. (65) Pontificia Universidad Javeriana, grid.41312.35
  66. (66) Pomeranian Medical University, grid.107950.a
  67. (67) National Cancer Institute of Thailand, grid.419173.9
  68. (68) International Agency For Research On Cancer, grid.17703.32
  69. (69) China Medical University, grid.254145.3
  70. (70) Institute of Biomedical Sciences, Academia Sinica, grid.482251.8
  71. (71) Kaohsiung Municipal Hsiao-Kang Hospital, grid.415003.3
  72. (72) Laval University, grid.23856.3a
  73. (73) Department of Clinical Molecular Biology, Oslo University Hospital, University of Oslo, 0450 Oslo, Norway

Description

Genome-wide association studies (GWASs) have revealed increased breast cancer risk associated with multiple genetic variants at 5p12. Here, we report the fine mapping of this locus using data from 104,660 subjects from 50 case-control studies in the Breast Cancer Association Consortium (BCAC). With data for 3,365 genotyped and imputed SNPs across a 1 Mb region (positions 44,394,495-45,364,167; NCBI build 37), we found evidence for at least three independent signals: the strongest signal, consisting of a single SNP rs10941679, was associated with risk of estrogen-receptor-positive (ER+) breast cancer (per-g allele OR ER+ = 1.15; 95% CI 1.13-1.18; p = 8.35 × 10-30). After adjustment for rs10941679, we detected signal 2, consisting of 38 SNPs more strongly associated with ER-negative (ER-) breast cancer (lead SNP rs6864776: per-a allele OR ER- = 1.10; 95% CI 1.05-1.14; p conditional = 1.44 × 10-12), and a single signal 3 SNP (rs200229088: per-t allele OR ER+ = 1.12; 95% CI 1.09-1.15; p conditional = 1.12 × 10-05). Expression quantitative trait locus analysis in normal breast tissues and breast tumors showed that the g (risk) allele of rs10941679 was associated with increased expression of FGF10 and MRPS30. Functional assays demonstrated that SNP rs10941679 maps to an enhancer element that physically interacts with the FGF10 and MRPS30 promoter regions in breast cancer cell lines. FGF10 is an oncogene that binds to FGFR2 and is overexpressed in ∼10% of human breast cancers, whereas MRPS30 plays a key role in apoptosis. These data suggest that the strongest signal of association at 5p12 is mediated through coordinated activation of FGF10 and MRPS30, two candidate genes for breast cancer pathogenesis.

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University of Copenhagen

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2016: Unused

Research area: Medicine

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2016: Level 2

Research area: Medicine

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Times Cited: 29

Field Citation Ratio (FCR): 7.55

Relative Citation ratio (RCR): 1.37

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