TY - JOUR
T1 - SNP-SNP interaction analysis of NF-κB signaling pathway on breast cancer survival
AU - KConFab investigators
AU - Jamshidi, Maral
AU - Fagerholm, Rainer
AU - Khan, Sofia
AU - Aittomäki, Kristiina
AU - Czene, Kamila
AU - Darabi, Hatef
AU - Li, Jingmei
AU - Andrulis, Irene L.
AU - Chang-Claude, Jenny
AU - Devilee, Peter
AU - Fasching, Peter A.
AU - Michailidou, Kyriaki
AU - Bolla, Manjeet K.
AU - Dennis, Joe
AU - Wang, Qin
AU - Guo, Qi
AU - Rhenius, Valerie
AU - Cornelissen, Sten
AU - Rudolph, Anja
AU - Knight, Julia A.
AU - Loehberg, Christian R.
AU - Burwinkel, Barbara
AU - Marme, Frederik
AU - Hopper, John L.
AU - Southey, Melissa C.
AU - Bojesen, Stig E.
AU - Flyger, Henrik
AU - Brenner, Hermann
AU - Holleczek, Bernd
AU - Margolin, Sara
AU - Mannermaa, Arto
AU - Kosma, Veli Matti
AU - Van Dyck, Laurien
AU - Nevelsteen, Ines
AU - Couch, Fergus J.
AU - Olson, Janet E.
AU - Giles, Graham G.
AU - McLean, Catriona
AU - Haiman, Christopher A.
AU - Henderson, Brian E.
AU - Winqvist, Robert
AU - Pylkäs, Katri
AU - Tollenaar, Rob A.E.M.
AU - García-Closas, Montserrat
AU - Figueroa, Jonine
AU - Hooning, Maartje J.
AU - Martens, John W.M.
AU - Cox, Angela
AU - Cross, Simon S.
AU - Simard, Jacques
PY - 2015
Y1 - 2015
N2 - 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.
AB - 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.
KW - Breast cancer
KW - NF-κB pathway
KW - SNP-SNP interaction
KW - Survival analysis
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UR - http://www.scopus.com/inward/citedby.url?scp=84947733545&partnerID=8YFLogxK
U2 - 10.18632/oncotarget.4991
DO - 10.18632/oncotarget.4991
M3 - Article
C2 - 26317411
AN - SCOPUS:84947733545
SN - 1949-2553
VL - 6
SP - 37979
EP - 37994
JO - Oncotarget
JF - Oncotarget
IS - 35
ER -