||Jamshidi M, Fagerholm R, Khan S, Aittomäki K, Czene K, Darabi H, Li J, Andrulis IL, Chang-Claude J, Devilee P, Fasching PA, Michailidou K, Bolla MK, Dennis J, Wang Q, Guo Q, Rhenius V, Cornelissen S, Rudolph A, Knight JA, Loehberg CR, Burwinkel B, Marme F, Hopper JL, Southey MC, Bojesen SE, Flyger H, Brenner H, Holleczek B, Margolin S, Mannermaa A, Kosma VM, Investigators K, Van Dyck L, Nevelsteen I, Couch FJ, Olson JE, Giles GG, McLean C, Haiman CA, Henderson BE, Winqvist R, Pylkäs K, Tollenaar RA, García-Closas M, Figueroa J, Hooning MJ, Martens JW, Cox A, Cross SS, Simard J, Dunning AM, Easton DF, Pharoah PD, Hall P, Blomqvist C, Schmidt MK, Nevanlinna H
||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.