Research Papers:
SNP-SNP interaction analysis of NF-κB signaling pathway on breast cancer survival
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Abstract
Maral Jamshidi1, Rainer Fagerholm1, Sofia Khan1, Kristiina Aittomäki2, Kamila Czene3, Hatef Darabi3, Jingmei Li3, Irene L. Andrulis4,5, Jenny Chang-Claude6,7, Peter Devilee8,9, Peter A. Fasching10,11, Kyriaki Michailidou12, Manjeet K. Bolla12, Joe Dennis12, Qin Wang12, Qi Guo13, Valerie Rhenius13, Sten Cornelissen14, Anja Rudolph7, Julia A. Knight15,16, Christian R. Loehberg17, Barbara Burwinkel18,19, Frederik Marme19,20, John L. Hopper21, Melissa C. Southey22, Stig E. Bojesen23,24, Henrik Flyger25, Hermann Brenner26,27,28, Bernd Holleczek29, Sara Margolin30, Arto Mannermaa31,32,33, Veli-Matti Kosma31,32,33, kConFab Investigators34, Laurien Van Dyck35,36, Ines Nevelsteen37, Fergus J. Couch38, Janet E. Olson39, Graham G. Giles40,41, Catriona McLean42, Christopher A. Haiman43, Brian E. Henderson43, Robert Winqvist44,45, Katri Pylkäs44,45, Rob A.E.M. Tollenaar46, Montserrat García-Closas47,48, Jonine Figueroa49, Maartje J. Hooning50, John W.M. Martens50, Angela Cox51, Simon S. Cross52, Jacques Simard53, Alison M. Dunning13, Douglas F. Easton12,13, Paul D.P. Pharoah12,13, Per Hall3, Carl Blomqvist54, Marjanka K. Schmidt14 and Heli Nevanlinna1
1 Department of Obstetrics and Gynecology, University of Helsinki and Helsinki University Hospital, Helsinki, FI-00029 HUS, Finland
2 Department of Clinical Genetics, University of Helsinki and Helsinki University Hospital, Helsinki, FI-00029 HUS, Finland
3 Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm SE-17177, Sweden
4 Lunenfeld-Tanenbaum Research Institute of Mount Sinai Hospital, Toronto, ON, M5G 1X5, Canada
5 Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada
6 Department of Obstetrics and Gynecology, University of Ulm, Ulm, Germany
7 Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany
8 Department of Pathology, Leiden University Medical Center, Leiden, The Netherlands
9 Department of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands
10 Department of Gynecology and Obstetrics, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nuremberg, Erlangen, Germany
11 Department of Medicine, Division of Hematology and Oncology, University of California at Los Angeles, Los Angeles, CA, USA
12 Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK
13 Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Cambridge, UK
14 Netherlands Cancer Institute, Antoni van Leeuwenhoek hospital, Amsterdam, The Netherlands
15 Prosserman Centre for Health Research, Lunenfeld-Tanenbaum Research Institute of Mount Sinai Hospital, Toronto, ON, M5G 1X5, Canada
16 Division of Epidemiology, Dalla Lana School of Public Health, University of Toronto, Toronto, ON, M5S 1A8, Canada
17 Department of Gynaecology and Obstetrics, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nuremberg, Comprehensive Cancer Center Erlangen-EMN, Erlangen, Germany
18 Molecular Epidemiology Group, German Cancer Research Center, Heidelberg, Germany
19 Department of Obstetrics and Gynecology, University of Heidelberg, Heidelberg, Germany
20 National Center for Tumor Diseases, University of Heidelberg, Heidelberg, Germany
21 Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, Victoria, Australia
22 Department of Pathology, The University of Melbourne, Melbourne, Victoria, Australia
23 Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
24 Department of Clinical Biochemistry, Herlev Hospital, Copenhagen University Hospital, Herlev, Denmark
25 Department of Breast Surgery, Herlev Hospital, Copenhagen University Hospital, Herlev, Denmark
26 Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany
27 Division of Preventive Oncology, German Cancer Research Center (DKFZ) and National Center for Tumor Diseases (NCT), Heidelberg, Germany
28 German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany
29 Saarland Cancer Registry, Saarbrücken, Germany
30 Department of Oncology - Pathology, Karolinska Institutet, Stockholm, Sweden
31 School of Medicine, Institute of Clinical Medicine, Pathology and Forensic Medicine, University of Eastern Finland, Kuopio, Finland
32 Cancer Center of Eastern Finland, University of Eastern Finland, Kuopio, Finland
33 Imaging Center, Department of Clinical Pathology, Kuopio University Hospital, Kuopio, Finland
34 Peter MacCallum Cancer Center, Melbourne, Victoria, Australia
35 Vesalius Research Center (VRC), VIB, Leuven, Belgium
36 Laboratory for Translational Genetics, Department of Oncology, University of Leuven, Leuven, Belgium
37 Multidisciplinary Breast Center, Medical Oncology, University Hospital Leuven, Leuven, Belgium
38 Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA
39 Department of Health Sciences Research, Mayo Clinic, Rochester, MN, USA
40 Cancer Epidemiology Centre, Cancer Council Victoria, Melbourne, Australia
41 Centre for Epidemiology and Biostatistics, School of Population and Global health, The University of Melbourne, Melbourne, Australia
42 Anatomical Pathology, The Alfred Hospital, Melbourne, Australia
43 Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
44 Laboratory of Cancer Genetics and Tumor Biology, Cancer Research and Translational Medicine, Biocenter Oulu, University of Oulu, Oulu, Finland
45 Laboratory of Cancer Genetics and Tumor Biology, Northern Finland Laboratory Centre NordLab, Oulu, Finland
46 Department of Surgical Oncology, Leiden University Medical Center, Leiden, The Netherlands
47 Division of Genetics and Epidemiology, Institute of Cancer Research, Sutton, SM2 5NG, UK
48 Breakthrough Breast Cancer Research Centre, Division of Breast Cancer Research, The Institute of Cancer Research, London, SW3 6JB, UK
49 Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD, USA
50 Department of Medical Oncology, Erasmus MC Cancer Institute, AE Rotterdam, The Netherlands
51 Sheffield Cancer Research, Department of Oncology, University of Sheffield, Sheffield, UK
52 Academic Unit of Pathology, Department of Neuroscience, University of Sheffield, Sheffield, UK
53 Centre Hospitalier Universitaire de Québec Research Center, Laval University, Québec City, Canada
54 Department of Oncology, University of Helsinki and Helsinki University Central Hospital, Helsinki, HUS, Finland
Correspondence to:
Heli Nevanlinna, email:
Keywords: breast cancer, survival analysis, SNP-SNP interaction, NF-κB pathway
Received: April 09, 2015 Accepted: July 16, 2015 Published: July 22, 2015
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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