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

2015; Impact Journals LLC; Volume: 6; Issue: 35 Linguagem: Inglês

10.18632/oncotarget.4991

1949-2553

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, Sophia Wang, Qi Guo, Valerie Rhenius, Sten Cornelissen, Anja Rudolph, Julia A. Knight, Christian R. Loehberg, Barbara Burwinkel, Frederik Marmé, John L. Hopper, Melissa C. Southey, Stig E. Bojesen, Henrik Flyger, Hermann Brenner, Bernd Holleczek, Sara Margolin, Graham J. Mann, 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 D. Figueroa, Maartje J. Hooning, John W.M. Martens, Angela Cox, Simon S. Cross, Jacques Simard, Alison M. Dunning, Douglas F. Easton, Paul D.P. Pharoah, Per Hall, Carl Blomqvist, Marjanka K. Schmidt, Heli Nevanlinna,

Natural product bioactivities and synthesis

// Maral Jamshidi 1 , Rainer Fagerholm 1 , Sofia Khan 1 , Kristiina Aittomäki 2 , Kamila Czene 3 , Hatef Darabi 3 , Jingmei Li 3 , Irene L. Andrulis 4,5 , Jenny Chang-Claude 6,7 , Peter Devilee 8,9 , Peter A. Fasching 10,11 , Kyriaki Michailidou 12 , Manjeet K. Bolla 12 , Joe Dennis 12 , Qin Wang 12 , Qi Guo 13 , Valerie Rhenius 13 , Sten Cornelissen 14 , Anja Rudolph 7 , Julia A. Knight 15,16 , Christian R. Loehberg 17 , Barbara Burwinkel 18,19 , Frederik Marme 19, 20 , John L. Hopper 21 , Melissa C. Southey 22 , Stig E. Bojesen 23,24 , Henrik Flyger 25 , Hermann Brenner 26,27,28 , Bernd Holleczek 29 , Sara Margolin 30 , Arto Mannermaa 31,32,33 , Veli-Matti Kosma 31,32,33 , kConFab Investigators 34 , Laurien Van Dyck 35,36 , Ines Nevelsteen 37 , Fergus J. Couch 38 , Janet E. Olson 39 , Graham G. Giles 40,41 , Catriona McLean 42 , Christopher A. Haiman 43 , Brian E. Henderson 43 , Robert Winqvist 44,45 , Katri Pylkäs 44,45 , Rob A.E.M. Tollenaar 46 , Montserrat García-Closas 47,48 , Jonine Figueroa 49 , Maartje J. Hooning 50 , John W.M. Martens 50 , Angela Cox 51 , Simon S. Cross 52 , Jacques Simard 53 , Alison M. Dunning 13 , Douglas F. Easton 12,13 , Paul D.P. Pharoah 12,13 , Per Hall 3 , Carl Blomqvist 54 , Marjanka K. Schmidt 14 and Heli Nevanlinna 1 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 (HR interaction 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 (HR interaction 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.