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

Jamshidi M, Fagerholm R, Khan S, Aittomaki K, Czene K, Darabi H, Li J, Andrulis IL, Chang-Claude J, Devilee P, Fasching P, Michailidou K, Bolla MK, Dennis J, Wang Q, Guo Q, Rhenius V, Cornelissen S, Rudolph A, Knight JA, Löhberg C, Burwinkel B, Marme F, Hopper JL, Southey MC, Bojesen SE, Flyger H, Brenner H, Holleczek B, Margolin S, Mannermaa A, Kosma VM, Van Dyck L, Nevelsteen I, Couch FJ, Olson JE, Giles GG, Mclean C, Haiman CA, Henderson BE, Winqvist R, Pylkas K, Tollenaar RAEM, Garcia-Closas M, Figueroa J, Hooning MJ, Martens JWM, Cox A, Cross SS, Simard J, Dunning AM, Easton DF, Pharoah PDP, Hall P, Blomqvist C, Schmidt MK, Nevanlinna H (2015)

Publication Type: Journal article

Publication year: 2015

Journal

Book Volume: 6

Pages Range: 37979-94

Journal Issue: 35

DOI: 10.18632/oncotarget.4991

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.

Authors with CRIS profile

Involved external institutions

Helsingin yliopisto / University of Helsinki Finland (FI) Antoni van Leeuwenhoek Netherlands (NL) Karolinska Institute Sweden (SE) University of Cambridge United Kingdom (GB) Université Laval (UL) Canada (CA) University of Sheffield United Kingdom (GB) Erasmus University Medical Center (MC) Netherlands (NL) National Cancer Institute (NCI) United States (USA) (US) University College London (UCL) United Kingdom (GB) Leiden University Netherlands (NL) Oulun Yliopisto / University of Oulo Finland (FI) University of Southern California (USC) United States (USA) (US) Monash University Australia (AU) Cancer Council Victoria Australia (AU) Mayo Clinic United States (USA) (US) University Hospital Leuven (UZ) / Universitaire ziekenhuizen Leuven Belgium (BE) Flanders Institute for Biotechnology / Vlaams Instituut voor Biotechnologie (VIB) Belgium (BE) University of Eastern Finland Finland (FI) Krebsregister Saarland / Saarland Cancer Registry Germany (DE) Deutsches Krebsforschungszentrum (DKFZ) Germany (DE) Copenhagen University Hospital Denmark (DK) University of Copenhagen Denmark (DK) The University of Melbourne Australia (AU) Ruprecht-Karls-Universität Heidelberg Germany (DE) Mount Sinai Hospital (MSH) Canada (CA) Universität Ulm Germany (DE) Helsinki University Central Hospital (HUCH) / Helsingin seudun yliopistollinen keskussairaala (HYKS) Finland (FI)

How to cite

APA:

Jamshidi, M., Fagerholm, R., Khan, S., Aittomaki, K., Czene, K., Darabi, H.,... Nevanlinna, H. (2015). SNP-SNP interaction analysis of NF-?B signaling pathway on breast cancer survival. Oncotarget, 6(35), 37979-94. https://dx.doi.org/10.18632/oncotarget.4991

MLA:

Jamshidi, Maral, et al. "SNP-SNP interaction analysis of NF-?B signaling pathway on breast cancer survival." Oncotarget 6.35 (2015): 37979-94.

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