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

KConFab investigators

Research output: Contribution to journalArticle

14 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 (US)
Pages (from-to)37979-37994
Number of pages16
JournalOncotarget
Volume6
Issue number35
DOIs
StatePublished - 2015

Fingerprint

Single Nucleotide Polymorphism
Breast Neoplasms
Survival
TNF Receptor-Associated Factor 2
Alleles
Receptors, Tumor Necrosis Factor, Type I
Proportional Hazards Models
Computer Simulation
Genes

Keywords

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

ASJC Scopus subject areas

  • Oncology

Cite this

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

In: Oncotarget, Vol. 6, No. 35, 2015, p. 37979-37994.

Research output: Contribution to journalArticle

KConFab investigators. / SNP-SNP interaction analysis of NF-κB signaling pathway on breast cancer survival. In: Oncotarget. 2015 ; Vol. 6, No. 35. pp. 37979-37994.
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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.",
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AU - Jamshidi, Maral

AU - Fagerholm, Rainer

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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

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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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