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

M Jamshidi, R Fagerholm, Salima Khan, K Aittomaki, K Czene, H Darabi, JM Li, IL Andrulis, J Chang-Claude, P Devilee, PA Fasching, K Michailidou, MK Bolla, J Dennis, Q (Qing) Wang, Q Guo, V Rhenius, S Cornelissen, A Rudolph, JA KnightCR Loehberg, B Burwinkel, F Marme, JL Hopper, MC Southey, SE Bojesen, H Flyger, H Brenner, B Holleczek, S Margolin, A Mannermaa, VM Kosma, L Van Dyck, I Nevelsteen, FJ Couch, JE Olson, GG Giles, C McLean, CA Haiman, BE Henderson, R Winqvist, K Pylkas, RAEM Tollenaar, M Garcia-Closas, J Figueroa, Maartje Hooning, John Martens, A Cox, SS Cross, J Simard, AM Dunning, DF Easton, PDP Pharoah, P Hall, C Blomqvist, MK (Marjanka) Schmidt, H Nevanlinna

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16 Citations (Scopus)

Abstract

In breast cancer, constitutive activation of NF-kappa B 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-kappa B 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-kappa B 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.
Original languageUndefined/Unknown
Pages (from-to)37979-37994
Number of pages16
JournalOncotarget
Volume6
Issue number35
Publication statusPublished - 2015

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