Article open access publication

Genetic modifiers of CHEK2*1100delC-associated breast cancer risk

Genetics in Medicine, Springer Nature, ISSN 1530-0366

Volume 19, 5, 2017

DOI:10.1038/gim.2016.147, Dimensions: pub.1050208064, PMC: PMC5382131, PMID: 27711073,

Authors

Hall, Per (12)
Bermisheva, Marina (11) (14)
Kristensen, Vessela (15) (16) (17)
Investigators, NBCS (15) (16) (17) (18) (19) (20) (21) (22) (23) (24) (25) (26)
Brauch, Hiltrud (29) (30) (31)
Burwinkel, Barbara (31) (32)
Marme, Frederik (32) (33)
Fasching, Peter A. (43) (44)
Andrulis, Irene L. (45) (46)
Knight, Julia A. (46) (47)
Giles, Graham G (50) (51)
Milne, Roger L. (50) (51)
Mannermaa, Arto (52) (53)
Kosma, Veli-Matti (52) (53)
John, Esther M (55) (56) (57)
Wang, Qin (6)

* Corresponding author

Affiliations

Organisations

  1. (1) Department of Obstetrics and Gynecology, Helsinki University Hospital, University of Helsinki, Helsinki, Finland
  2. (2) Finnish Institute of Occupational Health, grid.6975.d
  3. (3) Department of Oncology, Helsinki University Hospital, University of Helsinki, Helsinki, Finland
  4. (4) Department of Clinical Genetics, Helsinki University Hospital, University of Helsinki, Helsinki, Finland
  5. (5) Antoni van Leeuwenhoek Hospital, grid.430814.a
  6. (6) University of Cambridge, grid.5335.0
  7. (7) Herlev Hospital, grid.411900.d, Capital Region
  8. (8) University of Copenhagen, grid.5254.6, KU
  9. (9) Institute of Cancer Research, grid.18886.3f
  10. (10) National Cancer Institute, grid.48336.3a
  11. (11) Hannover Medical School, grid.10423.34
  12. (12) Karolinska Institute, grid.4714.6
  13. (13) Bashkir State University, grid.77269.3d
  14. (14) Institute of Biochemistry and Genetics of Ufa Scientific Centre, grid.429129.5
  15. (15) Department of Genetics, Institute for Cancer Research, Radiumhospitalet, Oslo University Hospital, University of Oslo, Oslo, Norway
  16. (16) K.G. Jebsen Center for Breast Cancer Research, Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway
  17. (17) Oslo University Hospital, grid.55325.34
  18. (18) Akershus University Hospital, grid.411279.8
  19. (19) Department of Oncology, Radiumhospitalet, Oslo University Hospital, University of Oslo, Oslo, Norway
  20. (20) Department of Oncology, Ullevaal University Hospital, University of Oslo, Oslo, Norway
  21. (21) Department of Radiology, Radiumhospitalet, Oslo University Hospital, University of Oslo, Oslo, Norway
  22. (22) Haukeland University Hospital, grid.412008.f
  23. (23) National Resource Centre for Long-term Studies after Cancer, Cancer Clinic, Radiumhospitalet, Oslo University Hospital, University of Oslo, Oslo, Norway
  24. (24) The Arctic University of Norway, grid.10919.30
  25. (25) University Hospital of North Norway, grid.412244.5
  26. (26) University of Bergen, grid.7914.b
  27. (27) London School of Hygiene & Tropical Medicine, grid.8991.9
  28. (28) Mayo Clinic, grid.66875.3a
  29. (29) Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology, grid.502798.1
  30. (30) University of Tübingen, grid.10392.39
  31. (31) German Cancer Research Center, grid.7497.d
  32. (32) Heidelberg University, grid.7700.0
  33. (33) National Center for Tumor Diseases, University of Heidelberg, Heidelberg, Germany
  34. (34) Technical University of Munich, grid.6936.a
  35. (35) University Hospital Cologne, grid.411097.a
  36. (36) University of Cologne, grid.6190.e
  37. (37) University of Sheffield, grid.11835.3e
  38. (38) King's College London, grid.13097.3c
  39. (39) University of Oxford, grid.4991.5
  40. (40) Flanders Institute for Biotechnology, grid.11486.3a
  41. (41) KU Leuven, grid.5596.f
  42. (42) Erasmus University Medical Center, grid.5645.2
  43. (43) University of California, Los Angeles, grid.19006.3e
  44. (44) Department of Gynaecology and Obstetrics, University Hospital Erlangen, Friedrich Alexander University Erlangen-Nuremberg, Comprehensive Cancer Center Erlangen-EMN, Erlangen, Germany
  45. (45) Lunenfeld-Tanenbaum Research Institute, grid.250674.2
  46. (46) University of Toronto, grid.17063.33
  47. (47) Mount Sinai Hospital, grid.416166.2
  48. (48) Peter MacCallum Cancer Center, The University of Melbourne, Melbourne, Australia
  49. (49) University of California, Irvine, grid.266093.8
  50. (50) Cancer Council Victoria, grid.3263.4
  51. (51) University of Melbourne, grid.1008.9
  52. (52) Kuopio University Hospital, grid.410705.7
  53. (53) University of Eastern Finland, grid.9668.1
  54. (54) Leiden University Medical Center, grid.10419.3d
  55. (55) Cancer Prevention Institute of California, grid.280669.3
  56. (56) Department of Health Research and Policy - Epidemiology,
  57. (57) Stanford University, grid.168010.e
  58. (58) Cyprus Institute of Neurology and Genetics, grid.417705.0

Description

PURPOSE: CHEK2*1100delC is a founder variant in European populations that confers a two- to threefold increased risk of breast cancer (BC). Epidemiologic and family studies have suggested that the risk associated with CHEK2*1100delC is modified by other genetic factors in a multiplicative fashion. We have investigated this empirically using data from the Breast Cancer Association Consortium (BCAC). METHODS: Using genotype data from 39,139 (624 1100delC carriers) BC patients and 40,063 (224) healthy controls from 32 BCAC studies, we analyzed the combined risk effects of CHEK2*1100delC and 77 common variants in terms of a polygenic risk score (PRS) and pairwise interaction. RESULTS: The PRS conferred odds ratios (OR) of 1.59 (95% CI: 1.21-2.09) per standard deviation for BC for CHEK2*1100delC carriers and 1.58 (1.55-1.62) for noncarriers. No evidence of deviation from the multiplicative model was found. The OR for the highest quintile of the PRS was 2.03 (0.86-4.78) for CHEK2*1100delC carriers, placing them in the high risk category according to UK NICE guidelines. The OR for the lowest quintile was 0.52 (0.16-1.74), indicating a lifetime risk close to the population average. CONCLUSION: Our results confirm the multiplicative nature of risk effects conferred by CHEK2*1100delC and the common susceptibility variants. Furthermore, the PRS could identify carriers at a high lifetime risk for clinical actions.Genet Med advance online publication 06 October 2016.

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Research area: Medicine

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Research area: Medicine

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Times Cited: 29

Field Citation Ratio (FCR): 9.08

Relative Citation ratio (RCR): 1.63

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