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

Rainer Fagerholm, Marjanka K. Schmidt, Sofia Khan, Sajjad Rafiq, William Tapper, Kristiina Aittomäki, Dario Greco, Tuomas Heikkinen, Taru A. Muranen, Peter A. Fasching, Wolfgang Janni, Richard Weinshilboum, Christian R. Loehberg, John L. Hopper, Melissa C. Southey, Renske Keeman, Annika Lindblom, Sara Margolin, Arto Mannermaa, 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 Figueroa, Maartje J. Hooning, Agnes Jager, Mitul Shah, Barbara J. Perkins, Robert Luben, Ute Hamann, Maria Kabisch, Kamila Czene, Per Hall, Douglas F. Easton, Paul D.P. Pharoah, Jianjun Liu, Diana Eccles, Carl Blomqvist and Heli Nevanlinna _

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Oncotarget. 2015; 6:7390-7407. https://doi.org/10.18632/oncotarget.3506

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Abstract

Rainer Fagerholm1, Marjanka K. Schmidt2, Sofia Khan1, Sajjad Rafiq3, William Tapper3, Kristiina Aittomäki4, Dario Greco1, Tuomas Heikkinen1, Taru A. Muranen1, Peter A. Fasching5,6, Wolfgang Janni7, Richard Weinshilboum8, Christian R. Loehberg9, John L. Hopper10, Melissa C. Southey11, Renske Keeman2, Annika Lindblom12, Sara Margolin13, Arto Mannermaa14,15,16, Vesa Kataja17, Georgia Chenevix-Trench18, kConFab Investigators19, Diether Lambrechts20,21, Hans Wildiers22, Jenny Chang-Claude23, Petra Seibold23, Fergus J. Couch24, Janet E. Olson25, Irene L. Andrulis26,27, Julia A. Knight28,29, Montserrat García-Closas30,31, Jonine Figueroa32, Maartje J. Hooning33, Agnes Jager33, Mitul Shah34, Barbara J. Perkins34, Robert Luben35, Ute Hamann36, Maria Kabisch36, Kamila Czene37, Per Hall37, Douglas F. Easton38,39, Paul D.P. Pharoah34,38, Jianjun Liu40, Diana Eccles3, Carl Blomqvist41 and Heli Nevanlinna1

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.


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