Article open access publication

Association of breast cancer risk with genetic variants showing differential allelic expression: Identification of a novel breast cancer susceptibility locus at 4q21

Oncotarget, Impact Journals, LLC, ISSN 1949-2553

Volume 5, 0, 2016

DOI:10.18632/oncotarget.12818, Dimensions: pub.1050238192, PMC: PMC5340257, PMID: 27792995,

Authors

Adoue, Véronique (2) (3) (4)
Bojesen, Stig E. (14) (15) (16)
Brauch, Hiltrud (11) (20) (21)
Brenner, Hermann (11) (22)
Burwinkel, Barbara (11) (23)
Fasching, Peter A (29) (30)
Figueroa, Jonine (31) (32)
Giles, Graham G (34) (35)
Kataja, Vesa (43) (44)
Mannermaa, Arto (44) (48)
Marme, Frederik (23) (49)
Milne, Roger L. (34) (35)
Pylkäs, Katri (54) (55)
Torres, Diana (11) (60)
Wang, Qin (6)
Winqvist, Robert (54) (55)
Zheng, Wei (58)
Benitez, Javier (37) (62)
Hall, Per (19)
Pastinen, Tomi (36) (65)

Affiliations

Organisations

  1. (1) Laval University, grid.23856.3a
  2. (2) 2, Institut National de la Santé et de la Recherche Médicale U1043, Toulouse, France
  3. (3) 4, Université de Toulouse, Université Paul Sabatier, Centre de Physiopathologie de Toulouse Purpan, Toulouse, France
  4. (4) Délégation Midi Pyrénées, grid.457025.1
  5. (5) Cyprus Institute of Neurology and Genetics, grid.417705.0
  6. (6) University of Cambridge, grid.5335.0
  7. (7) Antoni van Leeuwenhoek Hospital, grid.430814.a
  8. (8) Mount Sinai Hospital, grid.416166.2
  9. (9) University of Toronto, grid.17063.33
  10. (10) University of California, Irvine, grid.266093.8
  11. (11) German Cancer Research Center, grid.7497.d
  12. (12) 14, Department of Oncology, Helsinki University Hospital, University of Helsinki, Helsinki, Finland
  13. (13) Hannover Medical School, grid.10423.34
  14. (14) 17, Copenhagen General Population Study, Herlevand Gentofte Hospital, Copenhagen University Hospital, Herlev, Denmark
  15. (15) 18, Department of Clinical Biochemistry, Herlev and Gentofte Hospital, Copenhagen University Hospital, Herlev, Denmark
  16. (16) University of Copenhagen, grid.5254.6, KU
  17. (17) European Institute of Oncology, grid.15667.33
  18. (18) Oslo University Hospital, grid.55325.34
  19. (19) Karolinska Institute, grid.4714.6
  20. (20) Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology, grid.502798.1
  21. (21) University of Tübingen, grid.10392.39
  22. (22) University Hospital Heidelberg, grid.5253.1
  23. (23) Heidelberg University, grid.7700.0
  24. (24) University Cancer Center Hamburg, grid.412315.0
  25. (25) Mayo Clinic, grid.66875.3a
  26. (26) University of Sheffield, grid.11835.3e
  27. (27) Leiden University Medical Center, grid.10419.3d
  28. (28) London School of Hygiene & Tropical Medicine, grid.8991.9
  29. (29) University of California, Los Angeles, grid.19006.3e
  30. (30) 48, Department of Gynaecology and Obstetrics, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nuremberg, Comprehensive Cancer Center Erlangen-EMN, Erlangen, Germany
  31. (31) University of Edinburgh, grid.4305.2
  32. (32) National Cancer Institute, grid.48336.3a
  33. (33) 52, Department of Breast Surgery, Herlev and Gentofte Hospital, Copenhagen University Hospital, Herlev, Denmark
  34. (34) University of Melbourne, grid.1008.9
  35. (35) Cancer Council Victoria, grid.3263.4
  36. (36) McGill University, grid.14709.3b
  37. (37) Spanish National Cancer Research Centre, grid.7719.8
  38. (38) 58, Cancer & Environment Group, Center for Research in Epidemiology and Population Health (CESP), INSERM, University Paris-Sud, University Paris-Saclay, VilleJuif, France
  39. (39) University of Southern California, grid.42505.36
  40. (40) Erasmus University Medical Center, grid.5645.2
  41. (41) Pomeranian Medical University, grid.107950.a
  42. (42) Institute of Cancer Research, grid.18886.3f
  43. (43) Central Finland Health Care District, grid.460356.2
  44. (44) University of Eastern Finland, grid.9668.1
  45. (45) 67, Vesalius Research Center, Leuven, Belgium
  46. (46) KU Leuven, grid.5596.f
  47. (47) University of Hawaii at Manoa, grid.410445.0
  48. (48) Kuopio University Hospital, grid.410705.7
  49. (49) 74, National Center for Tumor Diseases, University of Heidelberg, Heidelberg, Germany
  50. (50) City Of Hope National Medical Center, grid.410425.6
  51. (51) 76, Department of Obstetrics and Gynecology, Helsinki University Hospital, University of Helsinki, Helsinki, Finland
  52. (52) Universitair Ziekenhuis Leuven, grid.410569.f
  53. (53) Macedonian Academy of Sciences and Arts, grid.419383.4
  54. (54) 80, Laboratory of Cancer Genetics and Tumor Biology, Northern Finland Laboratory Centre Oulu, Oulu, Finland
  55. (55) University of Oulu, grid.10858.34
  56. (56) Fondazione IRCCS Istituto Nazionale dei Tumori, grid.417893.0
  57. (57) King's College London, grid.13097.3c
  58. (58) 83, Division of Epidemiology, Department of Medicine, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, TN, USA
  59. (59) University of Oxford, grid.4991.5
  60. (60) Pontificia Universidad Javeriana, grid.41312.35
  61. (61) 90, Peter MacCallum Cancer Center, the University of Melbourne, Melbourne, Australia
  62. (62) 91, Centro de Investigación en Red de Enfermedades Raras, Valencia, Spain
  63. (63) QIMR Berghofer Medical Research Institute, grid.1049.c
  64. (64) 93, Department of Clinical Molecular Biology, Oslo University Hospital, University of Oslo, Oslo, Norway
  65. (65) McGill University and Génome Québec Innovation Centre, grid.411640.6

Description

There are significant inter-individual differences in the levels of gene expression. Through modulation of gene expression, cis-acting variants represent an important source of phenotypic variation. Consequently, cis-regulatory SNPs associated with differential allelic expression are functional candidates for further investigation as disease-causing variants. To investigate whether common variants associated with differential allelic expression were involved in breast cancer susceptibility, a list of genes was established on the basis of their involvement in cancer related pathways and/or mechanisms. Thereafter, using data from a genome-wide map of allelic expression associated SNPs, 313 genetic variants were selected and their association with breast cancer risk was then evaluated in 46,451 breast cancer cases and 42,599 controls of European ancestry ascertained from 41 studies participating in the Breast Cancer Association Consortium. The associations were evaluated with overall breast cancer risk and with estrogen receptor negative and positive disease. One novel breast cancer susceptibility locus on 4q21 (rs11099601) was identified (OR = 1.05, P = 5.6x10-6). rs11099601 lies in a 135 kb linkage disequilibrium block containing several genes, including, HELQ, encoding the protein HEL308 a DNA dependant ATPase and DNA Helicase involved in DNA repair, MRPS18C encoding the Mitochondrial Ribosomal Protein S18C and FAM175A (ABRAXAS), encoding a BRCA1 BRCT domain-interacting protein involved in DNA damage response and double-strand break (DSB) repair. Expression QTL analysis in breast cancer tissue showed rs11099601 to be associated with HELQ (P = 8.28x10-14), MRPS18C (P = 1.94x10-27) and FAM175A (P = 3.83x10-3), explaining about 20%, 14% and 1%, respectively of the variance inexpression of these genes in breast carcinomas.

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Times Cited: 21

Field Citation Ratio (FCR): 5.43

Relative Citation ratio (RCR): 0.99

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