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

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  • 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
  • Christian R Loehberg
  • Barbara Burwinkel
  • Frederik Marme
  • John L Hopper
  • Melissa C Southey
  • Bojesen, Stig Egil
  • 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.

OriginalsprogEngelsk
TidsskriftOncoTarget
Vol/bind6
Udgave nummer35
Sider (fra-til)37979-94
Antal sider16
ISSN1949-2553
DOI
StatusUdgivet - 10 nov. 2015

ID: 160866687