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

Research output: Contribution to journalJournal articleResearchpeer-review

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 Knight & 31 others Christian 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, kConFab Investigators

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
JournalOncoTarget
Volume6
Issue number35
Pages (from-to)37979-94
Number of pages16
ISSN1949-2553
DOIs
Publication statusPublished - 10 Nov 2015

ID: 160866687