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