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, kConFab Investigators, 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 D 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

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15 Citations (Scopus)

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
Externally publishedYes

Keywords

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

Cite this

Jamshidi, M., Fagerholm, R., Khan, S., Aittomäki, K., Czene, K., Darabi, H., Li, J., Andrulis, I. L., Chang-Claude, J., Devilee, P., Fasching, P. A., Michailidou, K., Bolla, M. K., Dennis, J., Wang, Q., Guo, Q., Rhenius, V., Cornelissen, S., Rudolph, A., ... Nevanlinna, H. (2015). SNP-SNP interaction analysis of NF-κB signaling pathway on breast cancer survival. Oncotarget, 6(35), 37979-37994. https://doi.org/10.18632/oncotarget.4991