title: The SNP rs6500843 in 16p13.3 is associated with survival specifically among chemotherapy-treated breast cancer patients.
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.
authors.affiliation: Department of Obstetrics and Gynecology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.
authors.forename: Rainer
authors.initials: R
authors.lastname: Fagerholm
authors.affiliation: Netherlands Cancer Institute, Antoni van Leeuwenhoek hospital, Amsterdam, The Netherlands.
authors.forename: Marjanka K
authors.initials: MK
authors.lastname: Schmidt
authors.affiliation: Department of Obstetrics and Gynecology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.
authors.forename: Sofia
authors.initials: S
authors.lastname: Khan
authors.affiliation: Faculty of Medicine, University of Southampton, Southampton General Hospital, Southampton, UK.
authors.forename: Sajjad
authors.initials: S
authors.lastname: Rafiq
authors.affiliation: Faculty of Medicine, University of Southampton, Southampton General Hospital, Southampton, UK.
authors.forename: William
authors.initials: W
authors.lastname: Tapper
authors.affiliation: Department of Clinical Genetics, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.
authors.forename: Kristiina
authors.initials: K
authors.lastname: Aittomäki
authors.affiliation: Department of Obstetrics and Gynecology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.
authors.forename: Dario
authors.initials: D
authors.lastname: Greco
authors.affiliation: Department of Obstetrics and Gynecology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.
authors.forename: Tuomas
authors.initials: T
authors.lastname: Heikkinen
authors.affiliation: Department of Obstetrics and Gynecology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.
authors.forename: Taru A
authors.initials: TA
authors.lastname: Muranen
authors.affiliation: Department of Gynecology and Obstetrics, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nuremberg, Erlangen, Germany.|Department of Medicine, Division of Hematology and Oncology, University of California at Los Angeles, Los Angeles, CA, USA.
authors.forename: Peter A
authors.initials: PA
authors.lastname: Fasching
authors.affiliation: Department of Gynecology and Obstetrics, University Hospital Ulm, Ulm, Germany.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Janni
authors.affiliation: Division of Clinical Pharmacology, Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic College of Medicine, Mayo Medical School-Mayo Foundation, Rochester, MN, USA.
authors.forename: Richard
authors.initials: R
authors.lastname: Weinshilboum
authors.affiliation: University Breast Center Franconia, Department of Gynecology and Obstetrics, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nuremberg, Comprehensive Cancer Center Erlangen-EMN, Erlangen, Germany.
authors.forename: Christian R
authors.initials: CR
authors.lastname: Loehberg
authors.affiliation: Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, Victoria, Australia.
authors.forename: John L
authors.initials: JL
authors.lastname: Hopper
authors.affiliation: Department of Pathology, The University of Melbourne, Melbourne, Victoria, Australia.
authors.forename: Melissa C
authors.initials: MC
authors.lastname: Southey
authors.affiliation: Netherlands Cancer Institute, Antoni van Leeuwenhoek hospital, Amsterdam, The Netherlands.
authors.forename: Renske
authors.initials: R
authors.lastname: Keeman
authors.affiliation: Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Annika
authors.initials: A
authors.lastname: Lindblom
authors.affiliation: Department of Oncology - Pathology, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Sara
authors.initials: S
authors.lastname: Margolin
authors.affiliation: School of Medicine, Institute of Clinical Medicine, Pathology and Forensic Medicine, University of Eastern Finland, Kuopio, Finland.|Cancer Center of Eastern Finland, University of Eastern Finland, Kuopio, Finland.|Imaging Center, Department of Clinical Pathology, Kuopio University Hospital, Kuopio, Finland.
authors.forename: Arto
authors.initials: A
authors.lastname: Mannermaa
authors.affiliation: Cancer Center, Kuopio University Hospital, Kuopio, Finland.
authors.forename: Vesa
authors.initials: V
authors.lastname: Kataja
authors.affiliation: Department of Genetics, QIMR Berghofer Medical Research Institute, Brisbane, Australia.
authors.forename: Georgia
authors.initials: G
authors.lastname: Chenevix-Trench
authors.affiliation: Vesalius Research Center (VRC), VIB, Leuven, Belgium.|Laboratory for Translational Genetics, Department of Oncology, University of Leuven, Leuven, Belgium.
authors.forename: Diether
authors.initials: D
authors.lastname: Lambrechts
authors.affiliation: Multidisciplinary Breast Center, Medical Oncology, University Hospital Leuven, Leuven, Belgium.
authors.forename: Hans
authors.initials: H
authors.lastname: Wildiers
authors.affiliation: Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Jenny
authors.initials: J
authors.lastname: Chang-Claude
authors.affiliation: Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Petra
authors.initials: P
authors.lastname: Seibold
authors.affiliation: Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA.
authors.forename: Fergus J
authors.initials: FJ
authors.lastname: Couch
authors.affiliation: Department of Health Sciences Research, Mayo Clinic, Rochester, MN, USA.
authors.forename: Janet E
authors.initials: JE
authors.lastname: Olson
authors.affiliation: Lunenfeld-Tanenbaum Research Institute of Mount Sinai Hospital, Toronto, ON, Canada.|Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada.
authors.forename: Irene L
authors.initials: IL
authors.lastname: Andrulis
authors.affiliation: Prosserman Centre for Health Research, Lunenfeld-Tanenbaum Research Institute of Mount Sinai Hospital, Toronto, ON, Canada.|Division of Epidemiology, Dalla Lana School of Public Health, University of Toronto, Toronto, ON, Canada.
authors.forename: Julia A
authors.initials: JA
authors.lastname: Knight
authors.affiliation: Division of Genetics and Epidemiology, Institute of Cancer Research, Sutton, UK.|Breakthrough Breast Cancer Research Centre, Division of Breast Cancer Research, The Institute of Cancer Research, London, UK.
authors.forename: Montserrat
authors.initials: M
authors.lastname: García-Closas
authors.affiliation: Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD, USA.
authors.forename: Jonine
authors.initials: J
authors.lastname: Figueroa
authors.affiliation: Department of Medical Oncology, Erasmus MC Cancer Institute, 3008 AE Rotterdam, The Netherlands.
authors.forename: Maartje J
authors.initials: MJ
authors.lastname: Hooning
authors.affiliation: Department of Medical Oncology, Erasmus MC Cancer Institute, 3008 AE Rotterdam, The Netherlands.
authors.forename: Agnes
authors.initials: A
authors.lastname: Jager
authors.affiliation: Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, UK.
authors.forename: Mitul
authors.initials: M
authors.lastname: Shah
authors.affiliation: Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, UK.
authors.forename: Barbara J
authors.initials: BJ
authors.lastname: Perkins
authors.affiliation: Clinical Gerontology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.
authors.forename: Robert
authors.initials: R
authors.lastname: Luben
authors.affiliation: Molecular Genetics of Breast Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Ute
authors.initials: U
authors.lastname: Hamann
authors.affiliation: Molecular Genetics of Breast Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Maria
authors.initials: M
authors.lastname: Kabisch
authors.affiliation: Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Kamila
authors.initials: K
authors.lastname: Czene
authors.affiliation: Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Per
authors.initials: P
authors.lastname: Hall
authors.affiliation: Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.|Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Cambridge, UK.
authors.forename: Douglas F
authors.initials: DF
authors.lastname: Easton
authors.affiliation: Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, UK.|Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.
authors.forename: Paul D P
authors.initials: PD
authors.lastname: Pharoah
authors.affiliation: Human Genetics Division, Genome Institute of Singapore, Singapore.
authors.forename: Jianjun
authors.initials: J
authors.lastname: Liu
authors.affiliation: Faculty of Medicine, University of Southampton, Southampton General Hospital, Southampton, UK.
authors.forename: Diana
authors.initials: D
authors.lastname: Eccles
authors.affiliation: Department of Oncology, University of Helsinki and Helsinki University Hospital, Helsinki, HUS, Finland.
authors.forename: Carl
authors.initials: C
authors.lastname: Blomqvist
authors.affiliation: Department of Obstetrics and Gynecology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.
authors.forename: Heli
authors.initials: H
authors.lastname: Nevanlinna
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D018943:Anthracyclines / Q000008:administration & dosage; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000401:mortality / Q000601:surgery; D017024:Chemotherapy, Adjuvant; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives; D005260:Female; D055106:Genome-Wide Association Study; D006801:Humans; D008875:Middle Aged; D015999:Multivariate Analysis; D020641:Polymorphism, Single Nucleotide; D011379:Prognosis; D040641:Quantitative Trait Loci; D016019:Survival Analysis; D043823:Taxoids / Q000008:administration & dosage; D055815:Young Adult; D000093542:Gemcitabine
chemical_list: D018943:Anthracyclines; D043823:Taxoids; D003841:Deoxycytidine; D000093542:Gemcitabine
keywords: SNP; breast cancer; cell cycle; chemotherapy; survival
references.citation: Eur J Cancer. 2000 Jun;36(9):1143-8
references.pmid: 10854948
references.citation: J Natl Cancer Inst. 2000 Sep 20;92(18):1529-31
references.pmid: 10995809
references.citation: Nat Genet. 2000 Dec;26(4):411-4
references.pmid: 11101836
references.citation: J Clin Oncol. 2001 Sep 15;19(18):3817-27
references.pmid: 11559719
references.citation: Nat Genet. 2002 May;31(1):55-9
references.pmid: 11967536
references.citation: Am J Hum Genet. 2002 Aug;71(2):432-8
references.pmid: 12094328
references.citation: Cell. 1995 Nov 17;83(4):655-66
references.pmid: 7585968
references.citation: Int J Cancer. 2005 Feb 10;113(4):575-80
references.pmid: 15472904
references.citation: Clin Cancer Res. 2005 Jul 15;11(14):5098-103
references.pmid: 16033823
references.citation: Proc Natl Acad Sci U S A. 2005 Aug 16;102(33):11651-6
references.pmid: 16087863
references.citation: EMBO J. 2006 Jan 11;25(1):163-73
references.pmid: 16362037
references.citation: Oncogene. 2006 Mar 2;25(9):1391-9
references.pmid: 16331276
references.citation: N Engl J Med. 2006 May 18;354(20):2103-11
references.pmid: 16707747
references.citation: Nat Genet. 2007 Oct;39(10):1181-6
references.pmid: 17898773
references.citation: BMC Cancer. 2007;7:160
references.pmid: 17697367
references.citation: Nat Genet. 2008 Jul;40(7):844-53
references.pmid: 18511948
references.citation: Nat Protoc. 2009;4(1):44-57
references.pmid: 19131956
references.citation: Nucleic Acids Res. 2009 Jan;37(1):1-13
references.pmid: 19033363
references.citation: J Clin Oncol. 2009 Jun 1;27(16):2660-7
references.pmid: 19414679
references.citation: Cancer Res. 2009 Oct 15;69(20):8035-42
references.pmid: 19789344
references.citation: J Clin Oncol. 2009 Dec 10;27(35):5958-64
references.pmid: 19826121
references.citation: Breast Cancer Res. 2009;11(6):R89
references.pmid: 20021639
references.citation: Cancer Sci. 2010 May;101(5):1261-9
references.pmid: 20331625
references.citation: Mol Oncol. 2010 Jun;4(3):174-91
references.pmid: 20542480
references.citation: Breast Cancer Res Treat. 2010 Oct;123(3):725-31
references.pmid: 20020197
references.citation: Breast Cancer Res Treat. 2011 Apr;126(3):717-27
references.pmid: 20872241
references.citation: Nucleic Acids Res. 2012 Jan;40(Database issue):D930-4
references.pmid: 22064851
references.citation: Surg Oncol. 2012 Jun;21(2):125-31
references.pmid: 21334875
references.citation: Bioinformatics. 2012 May 15;28(10):1353-8
references.pmid: 22492648
references.citation: Nature. 2012 Jun 21;486(7403):346-52
references.pmid: 22522925
references.citation: Int J Cancer. 2011 Oct 15;129(8):1848-58
references.pmid: 21154748
references.citation: Genet Epidemiol. 2012 Sep;36(6):538-48
references.pmid: 22685040
references.citation: Hum Mol Genet. 2012 Oct 1;21(19):4171-86
references.pmid: 22730494
references.citation: Nature. 2012 Oct 4;490(7418):61-70
references.pmid: 23000897
references.citation: BMC Cancer. 2012;12:422
references.pmid: 23006423
references.citation: Int J Cancer. 2013 May 1;132(9):2044-55
references.pmid: 23034890
references.citation: Cancer Res. 2013 Mar 15;73(6):1883-91
references.pmid: 23319801
references.citation: Nat Genet. 2013 Apr;45(4):353-61, 361e1-2
references.pmid: 23535729
references.citation: J Natl Cancer Inst. 2013 Jul 3;105(13):978-88
references.pmid: 23723422
references.citation: Cancer Genet. 2013 May;206(5):191-205
references.pmid: 23830731
references.citation: Breast. 2013 Oct;22(5):817-23
references.pmid: 23489758
references.citation: Biochim Biophys Acta. 2014 May;1843(5):934-44
references.pmid: 24480460
references.citation: PLoS One. 2014;9(5):e96989
references.pmid: 24824601
references.citation: Genome Biol. 2013;14(1):R6
references.pmid: 23347430