Article open access publication

SNP-SNP interaction analysis of NF-κB signaling pathway on breast cancer survival

Oncotarget, Impact Journals, LLC, ISSN 1949-2553

Volume 6, 35, 2015

DOI:10.18632/oncotarget.4991, Dimensions: pub.1026807068, PMC: PMC4741978, PMID: 26317411,



  1. (1) Helsinki University Central Hospital, grid.15485.3d
  2. (2) Karolinska Institute, grid.4714.6
  3. (3) Mount Sinai Hospital, grid.416166.2
  4. (4) University of Toronto, grid.17063.33
  5. (5) University of Ulm, grid.6582.9
  6. (6) German Cancer Research Center, grid.7497.d
  7. (7) Leiden University Medical Center, grid.10419.3d
  8. (8) 10, Department of Gynecology and Obstetrics, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nuremberg, Erlangen, Germany
  9. (9) University of California, Los Angeles, grid.19006.3e
  10. (10) University of Cambridge, grid.5335.0
  11. (11) Antoni van Leeuwenhoek Hospital, grid.430814.a
  12. (12) 17, Department of Gynaecology and Obstetrics, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nuremberg, Comprehensive Cancer Center Erlangen-EMN, Erlangen, Germany
  13. (13) Heidelberg University, grid.7700.0
  14. (14) 20, National Center for Tumor Diseases, University of Heidelberg, Heidelberg, Germany
  15. (15) University of Melbourne, grid.1008.9
  16. (16) University of Copenhagen, grid.5254.6, KU
  17. (17) Herlev Hospital, grid.411900.d, Capital Region
  18. (18) Krebsregister Saarland, grid.482902.5
  19. (19) Kuopio University Hospital, grid.410705.7
  20. (20) University of Eastern Finland, grid.9668.1
  21. (21) Flanders Institute for Biotechnology, grid.11486.3a
  22. (22) KU Leuven, grid.5596.f
  23. (23) Universitair Ziekenhuis Leuven, grid.410569.f
  24. (24) Mayo Clinic, grid.66875.3a
  25. (25) Cancer Council Victoria, grid.3263.4
  26. (26) The Alfred Hospital, grid.1623.6
  27. (27) University of Southern California, grid.42505.36
  28. (28) 45, Laboratory of Cancer Genetics and Tumor Biology, Northern Finland Laboratory Centre NordLab, Oulu, Finland
  29. (29) University of Oulu, grid.10858.34
  30. (30) Institute of Cancer Research, grid.18886.3f
  31. (31) National Cancer Institute, grid.48336.3a
  32. (32) Erasmus University Medical Center, grid.5645.2
  33. (33) University of Sheffield, grid.11835.3e
  34. (34) Laval University, grid.23856.3a


In breast cancer, constitutive activation of NF-κB has been reported, however, the impact of genetic variation of the pathway on patient prognosis has been little studied. Furthermore, a combination of genetic variants, rather than single polymorphisms, may affect disease prognosis. Here, in an extensive dataset (n = 30,431) from the Breast Cancer Association Consortium, we investigated the association of 917 SNPs in 75 genes in the NF-κB pathway with breast cancer prognosis. We explored SNP-SNP interactions on survival using the likelihood-ratio test comparing multivariate Cox' regression models of SNP pairs without and with an interaction term. We found two interacting pairs associating with prognosis: patients simultaneously homozygous for the rare alleles of rs5996080 and rs7973914 had worse survival (HRinteraction 6.98, 95% CI=3.3-14.4, P=1.42E-07), and patients carrying at least one rare allele for rs17243893 and rs57890595 had better survival (HRinteraction 0.51, 95% CI=0.3-0.6, P = 2.19E-05). Based on in silico functional analyses and literature, we speculate that the rs5996080 and rs7973914 loci may affect the BAFFR and TNFR1/TNFR3 receptors and breast cancer survival, possibly by disturbing both the canonical and non-canonical NF-κB pathways or their dynamics, whereas, rs17243893-rs57890595 interaction on survival may be mediated through TRAF2-TRAIL-R4 interplay. These results warrant further validation and functional analyses.


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