title: SNP-SNP interaction analysis of NF-κB signaling pathway on breast cancer survival.
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.
authors: Department of Obstetrics and Gynecology, University of Helsinki and Helsinki University Hospital, Helsinki, HUS, Finland.
authors: Maral
authors: M
authors: Jamshidi
authors: Department of Obstetrics and Gynecology, University of Helsinki and Helsinki University Hospital, Helsinki, HUS, Finland.
authors: Rainer
authors: R
authors: Fagerholm
authors: Department of Obstetrics and Gynecology, University of Helsinki and Helsinki University Hospital, Helsinki, HUS, Finland.
authors: Sofia
authors: S
authors: Khan
authors: Department of Clinical Genetics, University of Helsinki and Helsinki University Hospital, Helsinki, HUS, Finland.
authors: Kristiina
authors: K
authors: Aittomäki
authors: Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
authors: Kamila
authors: K
authors: Czene
authors: Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
authors: Hatef
authors: H
authors: Darabi
authors: Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
authors: Jingmei
authors: J
authors: Li
authors: Lunenfeld-Tanenbaum Research Institute of Mount Sinai Hospital, Toronto, ON, Canada.|Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada.
authors: Irene L
authors: IL
authors: Andrulis
authors: Department of Obstetrics and Gynecology, University of Ulm, Ulm, Germany.|Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors: Jenny
authors: J
authors: Chang-Claude
authors: Department of Pathology, Leiden University Medical Center, Leiden, The Netherlands.|Department of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands.
authors: Peter
authors: P
authors: Devilee
authors: Department of Gynecology and Obstetrics, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nuremberg, Erlangen, Germany.|Department of Medicine, Division of Hematology and Oncology, University of California at Los Angeles, Los Angeles, CA, USA.
authors: Peter A
authors: PA
authors: Fasching
authors: Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.
authors: Kyriaki
authors: K
authors: Michailidou
authors: Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.
authors: Manjeet K
authors: MK
authors: Bolla
authors: Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.
authors: Joe
authors: J
authors: Dennis
authors: Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.
authors: Qin
authors: Q
authors: Wang
authors: Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Cambridge, UK.
authors: Qi
authors: Q
authors: Guo
authors: Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Cambridge, UK.
authors: Valerie
authors: V
authors: Rhenius
authors: Netherlands Cancer Institute, Antoni van Leeuwenhoek Hospital, Amsterdam, The Netherlands.
authors: Sten
authors: S
authors: Cornelissen
authors: Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors: Anja
authors: A
authors: Rudolph
authors: Prosserman Centre for Health Research, Lunenfeld-Tanenbaum Research Institute of Mount Sinai Hospital, Toronto, ON, Canada.|Division of Epidemiology, Dalla Lana School of Public Health, University of Toronto, Toronto, ON, Canada.
authors: Julia A
authors: JA
authors: Knight
authors: Department of Gynaecology and Obstetrics, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nuremberg, Comprehensive Cancer Center Erlangen-EMN, Erlangen, Germany.
authors: Christian R
authors: CR
authors: Loehberg
authors: Molecular Epidemiology Group, German Cancer Research Center, Heidelberg, Germany.|Department of Obstetrics and Gynecology, University of Heidelberg, Heidelberg, Germany.
authors: Barbara
authors: B
authors: Burwinkel
authors: Department of Obstetrics and Gynecology, University of Heidelberg, Heidelberg, Germany.|National Center for Tumor Diseases, University of Heidelberg, Heidelberg, Germany.
authors: Frederik
authors: F
authors: Marme
authors: Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, Victoria, Australia.
authors: John L
authors: JL
authors: Hopper
authors: Department of Pathology, The University of Melbourne, Melbourne, Victoria, Australia.
authors: Melissa C
authors: MC
authors: Southey
authors: Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.|Department of Clinical Biochemistry, Herlev Hospital, Copenhagen University Hospital, Herlev, Denmark.
authors: Stig E
authors: SE
authors: Bojesen
authors: Department of Breast Surgery, Herlev Hospital, Copenhagen University Hospital, Herlev, Denmark.
authors: Henrik
authors: H
authors: Flyger
authors: Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany.|Division of Preventive Oncology, German Cancer Research Center (DKFZ) and National Center for Tumor Diseases (NCT), Heidelberg, Germany.|German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors: Hermann
authors: H
authors: Brenner
authors: Saarland Cancer Registry, Saarbrücken, Germany.
authors: Bernd
authors: B
authors: Holleczek
authors: Department of Oncology - Pathology, Karolinska Institutet, Stockholm, Sweden.
authors: Sara
authors: S
authors: Margolin
authors: School of Medicine, Institute of Clinical Medicine, Pathology and Forensic Medicine, University of Eastern Finland, Kuopio, Finland.|Cancer Center of Eastern Finland, University of Eastern Finland, Kuopio, Finland.|Imaging Center, Department of Clinical Pathology, Kuopio University Hospital, Kuopio, Finland.
authors: Arto
authors: A
authors: Mannermaa
authors: School of Medicine, Institute of Clinical Medicine, Pathology and Forensic Medicine, University of Eastern Finland, Kuopio, Finland.|Cancer Center of Eastern Finland, University of Eastern Finland, Kuopio, Finland.|Imaging Center, Department of Clinical Pathology, Kuopio University Hospital, Kuopio, Finland.
authors: Veli-Matti
authors: VM
authors: Kosma
authors: Vesalius Research Center (VRC), VIB, Leuven, Belgium.|Laboratory for Translational Genetics, Department of Oncology, University of Leuven, Leuven, Belgium.
authors: Laurien
authors: L
authors: Van Dyck
authors: Multidisciplinary Breast Center, Medical Oncology, University Hospital Leuven, Leuven, Belgium.
authors: Ines
authors: I
authors: Nevelsteen
authors: Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA.
authors: Fergus J
authors: FJ
authors: Couch
authors: Department of Health Sciences Research, Mayo Clinic, Rochester, MN, USA.
authors: Janet E
authors: JE
authors: Olson
authors: Cancer Epidemiology Centre, Cancer Council Victoria, Melbourne, Australia.|Centre for Epidemiology and Biostatistics, School of Population and Global Health, The University of Melbourne, Melbourne, Australia.
authors: Graham G
authors: GG
authors: Giles
authors: Anatomical Pathology, The Alfred Hospital, Melbourne, Australia.
authors: Catriona
authors: C
authors: McLean
authors: Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
authors: Christopher A
authors: CA
authors: Haiman
authors: Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
authors: Brian E
authors: BE
authors: Henderson
authors: Laboratory of Cancer Genetics and Tumor Biology, Cancer Research and Translational Medicine, Biocenter Oulu, University of Oulu, Oulu, Finland.|Laboratory of Cancer Genetics and Tumor Biology, Northern Finland Laboratory Centre NordLab, Oulu, Finland.
authors: Robert
authors: R
authors: Winqvist
authors: Laboratory of Cancer Genetics and Tumor Biology, Cancer Research and Translational Medicine, Biocenter Oulu, University of Oulu, Oulu, Finland.|Laboratory of Cancer Genetics and Tumor Biology, Northern Finland Laboratory Centre NordLab, Oulu, Finland.
authors: Katri
authors: K
authors: Pylkäs
authors: Department of Surgical Oncology, Leiden University Medical Center, Leiden, The Netherlands.
authors: Rob A E M
authors: RA
authors: Tollenaar
authors: Division of Genetics and Epidemiology, Institute of Cancer Research, Sutton, UK.|Breakthrough Breast Cancer Research Centre, Division of Breast Cancer Research, The Institute of Cancer Research, London, UK.
authors: Montserrat
authors: M
authors: García-Closas
authors: Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD, USA.
authors: Jonine
authors: J
authors: Figueroa
authors: Department of Medical Oncology, Erasmus MC Cancer Institute, AE Rotterdam, The Netherlands.
authors: Maartje J
authors: MJ
authors: Hooning
authors: Department of Medical Oncology, Erasmus MC Cancer Institute, AE Rotterdam, The Netherlands.
authors: John W M
authors: JW
authors: Martens
authors: Sheffield Cancer Research, Department of Oncology, University of Sheffield, Sheffield, UK.
authors: Angela
authors: A
authors: Cox
authors: Academic Unit of Pathology, Department of Neuroscience, University of Sheffield, Sheffield, UK.
authors: Simon S
authors: SS
authors: Cross
authors: Centre Hospitalier Universitaire de Québec Research Center, Laval University, Québec City, QC, Canada.
authors: Jacques
authors: J
authors: Simard
authors: Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Cambridge, UK.
authors: Alison M
authors: AM
authors: Dunning
authors: Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.|Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Cambridge, UK.
authors: Douglas F
authors: DF
authors: Easton
authors: Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.|Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Cambridge, UK.
authors: Paul D P
authors: PD
authors: Pharoah
authors: Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
authors: Per
authors: P
authors: Hall
authors: Department of Oncology, University of Helsinki and Helsinki University Central Hospital, Helsinki, HUS, Finland.
authors: Carl
authors: C
authors: Blomqvist
authors: Netherlands Cancer Institute, Antoni van Leeuwenhoek Hospital, Amsterdam, The Netherlands.
authors: Marjanka K
authors: MK
authors: Schmidt
authors: Department of Obstetrics and Gynecology, University of Helsinki and Helsinki University Hospital, Helsinki, HUS, Finland.
authors: Heli
authors: H
authors: Nevanlinna
mesh_terms: D014408:Biomarkers, Tumor / Q000235:genetics*; D001943:Breast Neoplasms / Q000235:genetics* / Q000401:mortality* / Q000473:pathology; D005260:Female; D006801:Humans; D016328:NF-kappa B / Q000235:genetics*; D060787:Neoplasm Grading; D009361:Neoplasm Invasiveness; D009367:Neoplasm Staging; D020641:Polymorphism, Single Nucleotide / Q000502:physiology*; D011379:Prognosis; D015398:Signal Transduction; D015996:Survival Rate
chemical_list: D014408:Biomarkers, Tumor; D016328:NF-kappa B
keywords: NF-κB pathway; SNP-SNP interaction; breast cancer; survival analysis