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


ABSTRACT: In breast cancer, constitutive activation of NF-?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-?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-?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.

SUBMITTER: Jamshidi M 

PROVIDER: S-EPMC4741978 | biostudies-literature | 2015 Nov

REPOSITORIES: biostudies-literature

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

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

Oncotarget 20151101 35


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  ...[more]

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