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Oncotarget. 2015 Apr 10;6(10):7390-407.

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

Author information

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
Vesalius Research Center (VRC), VIB, Leuven, Belgium.
20
Laboratory for Translational Genetics, Department of Oncology, University of Leuven, Leuven, Belgium.
21
Multidisciplinary Breast Center, Medical Oncology, University Hospital Leuven, Leuven, Belgium.
22
Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
23
Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA.
24
Department of Health Sciences Research, Mayo Clinic, Rochester, MN, USA.
25
Lunenfeld-Tanenbaum Research Institute of Mount Sinai Hospital, Toronto, ON, Canada.
26
Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada.
27
Prosserman Centre for Health Research, Lunenfeld-Tanenbaum Research Institute of Mount Sinai Hospital, Toronto, ON, Canada.
28
Division of Epidemiology, Dalla Lana School of Public Health, University of Toronto, Toronto, ON, Canada.
29
Division of Genetics and Epidemiology, Institute of Cancer Research, Sutton, UK.
30
Breakthrough Breast Cancer Research Centre, Division of Breast Cancer Research, The Institute of Cancer Research, London, UK.
31
Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD, USA.
32
Department of Medical Oncology, Erasmus MC Cancer Institute, 3008 AE Rotterdam, The Netherlands.
33
Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, UK.
34
Clinical Gerontology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.
35
Molecular Genetics of Breast Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany.
36
Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
37
Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.
38
Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Cambridge, UK.
39
Human Genetics Division, Genome Institute of Singapore, Singapore.
40
Department of Oncology, University of Helsinki and Helsinki University Hospital, Helsinki, HUS, Finland.

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.

KEYWORDS:

SNP; breast cancer; cell cycle; chemotherapy; survival

PMID:
25823661
PMCID:
PMC4480688
DOI:
10.18632/oncotarget.3506
[Indexed for MEDLINE]
Free PMC Article

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