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

Maral Jamshidi, Rainer Fagerholm, Sofia Khan, Kristiina Aittomäki, Kamila Czene, Hatef Darabi, Jingmei Li, Irene L. Andrulis, Jenny Chang-Claude, Peter Devilee, Peter A. Fasching, Kyriaki Michailidou, Manjeet K. Bolla, Joe Dennis, Qin Wang, Qi Guo, Valerie Rhenius, Sten Cornelissen, Anja Rudolph, Julia A. KnightChristian R. Loehberg, Barbara Burwinkel, Frederik Marme, John L. Hopper, Melissa C. Southey, Stig E. Bojesen, Henrik Flyger, Hermann Brenner, Bernd Holleczek, Sara Margolin, Arto Mannermaa, Veli Matti Kosma, Laurien Van Dyck, Ines Nevelsteen, Fergus J. Couch, Janet E. Olson, Graham G. Giles, Catriona McLean, Christopher A. Haiman, Brian E. Henderson, Robert Winqvist, Katri Pylkäs, Rob A E M Tollenaar, Montserrat García-Closas, Jonine Figueroa, Maartje J. Hooning, John W M Martens, Angela Cox, Simon S. Cross, Jacques Simard, Alison M. Dunning, Douglas F. Easton, Paul D P Pharoah, Per Hall, Carl Blomqvist, Marjanka K. Schmidt, Heli Nevanlinna*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish
Pages (from-to)37979-37994
Number of pages16
JournalOncotarget
Volume6
Issue number35
DOIs
Publication statusPublished - 2015

Keywords

  • Breast cancer
  • NF-κB pathway
  • SNP-SNP interaction
  • Survival analysis

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