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The SNP rs6500843 in 16p13.3 is associated with survival specifically among chemotherapy-treated breast cancer patients

2015; Impact Journals LLC; Volume: 6; Issue: 10 Linguagem: Inglês

10.18632/oncotarget.3506

1949-2553

Rainer Fagerholm, Marjanka K. Schmidt, Sofia Khan, Sajjad Rafiq, William Tapper, Kristiina Aittomäki, Dario Greco, Tuomas Heikkinen, Taru Muranen, Peter A. Fasching, Wolfgang Janni, Richard M. Weinshilboum, Christian R. Loehberg, John L. Hopper, Melissa C. Southey, Renske Keeman, Annika Lindblom, Sara Margolin, Graham J. Mann, Vesa Kataja, Georgia Chenevix‐Trench, kConFab Investigators, Diether Lambrechts, Hans Wildiers, Jenny Chang‐Claude, Petra Seibold, Fergus J. Couch, Janet E. Olson, Irene L. Andrulis, Julia A. Knight, Montserrat García‐Closas, Jonine D. Figueroa, Maartje J. Hooning, Agnes Jager, Mitul Shah, Barbara Perkins, Robert Luben, Ute Hamann, Maria Kabisch, Kamila Czene, Per Hall, Douglas F. Easton, Paul D.P. Pharoah, Jianjun Liu, Diana Eccles, Carl Blomqvist, Heli Nevanlinna,

Microtubule and mitosis dynamics

// Rainer Fagerholm 1 , Marjanka K. Schmidt 2 , Sofia Khan 1 , Sajjad Rafiq 3 , William Tapper 3 , Kristiina Aittomäki 4 , Dario Greco 1 , Tuomas Heikkinen 1 , Taru A. Muranen 1 , Peter A. Fasching 5,6 , Wolfgang Janni 7 , Richard Weinshilboum 8 , Christian R. Loehberg 9 , John L. Hopper 10 , Melissa C. Southey 11 , Renske Keeman 2 , Annika Lindblom 12 , Sara Margolin 13 , Arto Mannermaa 14,15,16 , Vesa Kataja 17 , Georgia Chenevix-Trench 18 , kConFab Investigators 19 , Diether Lambrechts 20,21 , Hans Wildiers 22 , Jenny Chang-Claude 23 , Petra Seibold 23 , Fergus J. Couch 24 , Janet E. Olson 25 , Irene L. Andrulis 26,27 , Julia A. Knight 28,29 , Montserrat García-Closas 30,31 , Jonine Figueroa 32 , Maartje J. Hooning 33 , Agnes Jager 33 , Mitul Shah 34 , Barbara J. Perkins 34 , Robert Luben 35 , Ute Hamann 36 , Maria Kabisch 36 , Kamila Czene 37 , Per Hall 37 , Douglas F. Easton 38,39 , Paul D.P. Pharoah 34,38 , Jianjun Liu 40 , Diana Eccles 3 , Carl Blomqvist 41 and Heli Nevanlinna 1 1 Department of Obstetrics and Gynecology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland 2 Netherlands Cancer Institute, Antoni van Leeuwenhoek hospital, Amsterdam, The Netherlands 3 Faculty of Medicine, University of Southampton, Southampton General Hospital, Southampton, UK 4 Department of Clinical Genetics, University of Helsinki and Helsinki University Hospital, Helsinki, Finland 5 Department of Gynecology and Obstetrics, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nuremberg, Erlangen, Germany 6 Department of Medicine, Division of Hematology and Oncology, University of California at Los Angeles, Los Angeles, CA, USA 7 Department of Gynecology and Obstetrics, University Hospital Ulm, Ulm, Germany 8 Division of Clinical Pharmacology, Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic College of Medicine, Mayo Medical School-Mayo Foundation, Rochester, MN, USA 9 University Breast Center Franconia, Department of Gynecology and Obstetrics, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nuremberg, Comprehensive Cancer Center Erlangen-EMN, Erlangen, Germany 10 Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, Victoria, Australia 11 Department of Pathology, The University of Melbourne, Melbourne, Victoria, Australia 12 Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden 13 Department of Oncology - Pathology, Karolinska Institutet, Stockholm, Sweden 14 School of Medicine, Institute of Clinical Medicine, Pathology and Forensic Medicine, University of Eastern Finland, Kuopio, Finland 15 Cancer Center of Eastern Finland, University of Eastern Finland, Kuopio, Finland 16 Imaging Center, Department of Clinical Pathology, Kuopio University Hospital, Kuopio, Finland 17 Cancer Center, Kuopio University Hospital, Kuopio, Finland 18 Department of Genetics, QIMR Berghofer Medical Research Institute, Brisbane, Australia 19 Peter MacCallum Cancer Center, Melbourne, Victoria, Australia 20 Vesalius Research Center (VRC), VIB, Leuven, Belgium 21 Laboratory for Translational Genetics, Department of Oncology, University of Leuven, Leuven, Belgium 22 Multidisciplinary Breast Center, Medical Oncology, University Hospital Leuven, Leuven, Belgium 23 Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany 24 Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA 25 Department of Health Sciences Research, Mayo Clinic, Rochester, MN, USA 26 Lunenfeld-Tanenbaum Research Institute of Mount Sinai Hospital, Toronto, ON, Canada 27 Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada 28 Prosserman Centre for Health Research, Lunenfeld-Tanenbaum Research Institute of Mount Sinai Hospital, Toronto, ON, Canada 29 Division of Epidemiology, Dalla Lana School of Public Health, University of Toronto, Toronto, ON, Canada 30 Division of Genetics and Epidemiology, Institute of Cancer Research, Sutton, UK 31 Breakthrough Breast Cancer Research Centre, Division of Breast Cancer Research, The Institute of Cancer Research, London, UK 32 Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD, USA 33 Department of Medical Oncology, Erasmus MC Cancer Institute, 3008 AE Rotterdam, The Netherlands 34 Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, UK 35 Clinical Gerontology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK 36 Molecular Genetics of Breast Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany 37 Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden 38 Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK 39 Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Cambridge, UK 40 Human Genetics Division, Genome Institute of Singapore, Singapore 41 Department of Oncology, University of Helsinki and Helsinki University Hospital, Helsinki, HUS, Finland Correspondence to: Heli Nevanlinna, email: // Keywords : breast cancer, survival, SNP, chemotherapy, cell cycle Received : December 19, 2015 Accepted : January 03, 2015 Published : March 08, 2015 Abstract We have utilized a two-stage study design to search for SNPs associated with the survival of breast cancer patients treated with adjuvant chemotherapy. Our initial GWS data set consisted of 805 Finnish breast cancer cases (360 treated with adjuvant chemotherapy). The top 39 SNPs from this stage were analyzed in three independent data sets: iCOGS (n=6720 chemotherapy-treated cases), SUCCESS-A (n=3596), and POSH (n=518). Two SNPs were successfully validated: rs6500843 (any chemotherapy; per-allele HR 1.16, 95% C.I. 1.08-1.26, p=0.0001, p (adjusted) =0.0091), and rs11155012 (anthracycline therapy; per-allele HR 1.21, 95% C.I. 1.08-1.35, p=0.0010, p (adjusted) =0.0270). The SNP rs6500843 was found to specifically interact with adjuvant chemotherapy, independently of standard prognostic markers (p (interaction) =0.0009), with the rs6500843-GG genotype corresponding to the highest hazard among chemotherapy-treated cases (HR 1.47, 95% C.I. 1.20-1.80). Upon trans -eQTL analysis of public microarray data, the rs6500843 locus was found to associate with the expression of a group of genes involved in cell cycle control, notably AURKA, the expression of which also exhibited differential prognostic value between chemotherapy-treated and untreated cases in our analysis of microarray data. Based on previously published information, we propose that the eQTL genes may be connected to the rs6500843 locus via a RBFOX1-FOXM1 -mediated regulatory pathway.