Oncotarget

Research Papers:

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

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, Stig E. Bojesen, Henrik Flyger, Hermann Brenner, Bernd Holleczek, Sara Margolin, Arto Mannerma, Veli-Matti Kosma, kConFab Investigators, 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, Alison M. Dunning, Douglas F. Easton, Paul D.P. Pharoah, Per Hall, Carl Blomqvist, Marjanka K. Schmidt and Heli Nevanlinna _

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Oncotarget. 2015; 6:37979-37994. https://doi.org/10.18632/oncotarget.4991

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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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