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A polymorphism in the base excision repair gene PARP2 is associated with differential prognosis by chemotherapy among postmenopausal breast cancer patients.

Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany. p.seibold@dkfz.de. Division of Epigenomics and Cancer Risk Factors, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69124, Heidelberg, Germany. p.schmezer@dkfz.de. Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany. s.behrens@dkfz.de. Department of Public Health and Primary Care, Centre for Cancer Genetic Epidemiology, University of Cambridge, Cambridge, UK. km533@medschl.cam.ac.uk. Department of Public Health and Primary Care, Centre for Cancer Genetic Epidemiology, University of Cambridge, Cambridge, UK. mkh39@medschl.cam.ac.uk. Department of Public Health and Primary Care, Centre for Cancer Genetic Epidemiology, University of Cambridge, Cambridge, UK. qw232@medschl.cam.ac.uk. Department of Cancer Epidemiology/Clinical Cancer Registry, University Cancer Center Hamburg (UCCH), Hamburg, Germany. flesch-janys@uke.de. Department of Medical Biometrics and Epidemiology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany. flesch-janys@uke.de. Department of Obstetrics and Gynecology, University of Helsinki and Helsinki University Central Hospital, Helsinki, Finland. Heli.Nevanlinna@hus.fi. Department of Obstetrics and Gynecology, University of Helsinki and Helsinki University Central Hospital, Helsinki, Finland. rainer.fagerholm@helsinki.fi. Department of Clinical Genetics, University of Helsinki and Helsinki University Central Hospital, Helsinki, Finland. kristiina.aittomaki@hus.fi. Department of Oncology, University of Helsinki and Helsinki University Central Hospital, Helsinki, Finland. carl.blomqvist@helsinki.fi. Department of Oncology - Pathology, Karolinska Institutet, Stockholm, Sweden. Sara.Margolin@karolinska.se. School of Medicine, Institute of Clinical Medicine, Pathology and Forensic Medicine, University of Eastern Finland, Kuopio, Finland. arto.mannermaa@uef.fi. Cancer Center of Eastern Finland, University of Eastern Finland, Kuopio, Finland. arto.mannermaa@uef.fi. Imaging Center, Department of Clinical Pathology, Kuopio University Hospital, Kuopio, Finland. arto.mannermaa@uef.fi. School of Medicine, Institute of Clinical Medicine, Pathology and Forensic Medicine, University of Eastern Finland, Kuopio, Finland. vesa.kataja@ksshp.fi. Central Finland Health Care District, Jyväskylä Central Hospital, Jyväskylä, Finland. vesa.kataja@ksshp.fi. School of Medicine, Institute of Clinical Medicine, Pathology and Forensic Medicine, University of Eastern Finland, Kuopio, Finland. veli-matti.kosma@uef.fi. Cancer Center of Eastern Finland, University of Eastern Finland, Kuopio, Finland. veli-matti.kosma@uef.fi. Imaging Center, Department of Clinical Pathology, Kuopio University Hospital, Kuopio, Finland. veli-matti.kosma@uef.fi. School of Medicine, Institute of Clinical Medicine, Pathology and Forensic Medicine, University of Eastern Finland, Kuopio, Finland. jaana.hartikainen@uef.fi. Cancer Center of Eastern Finland, University of Eastern Finland, Kuopio, Finland. jaana.hartikainen@uef.fi. Imaging Center, Department of Clinical Pathology, Kuopio University Hospital, Kuopio, Finland. jaana.hartikainen@uef.fi. Vesalius Research Center (VRC), VIB, Leuven, Belgium. Diether.Lambrechts@med.kuleuven.be. Department of Oncology, Laboratory for Translational Genetics, University of Leuven, Leuven, Belgium. Diether.Lambrechts@med.kuleuven.be. Department of General Medical Oncology, Multidisciplinary Breast Center, University Hospitals Leuven, Leuven, Belgium. Hans.Wildiers@uzleuven.be. Department of Cancer Genetics, Institute for Cancer Research, Oslo University Hospital, Radiumhospitalet, Oslo, Norway. v.i.kristensen@medisin.uio.no. Institute of Clinical Medicine, K.G. Jebsen Center for Breast Cancer Research, Faculty of Medicine, University of Oslo (UiO), Oslo, Norway. v.i.kristensen@medisin.uio.no. Department of Clinical Molecular Biology (EpiGen), Akershus University Hospital, University of Oslo (UiO), Oslo, Norway. v.i.kristensen@medisin.uio.no. Department of Cancer Genetics, Institute for Cancer Research, Oslo University Hospital, Radiumhospitalet, Oslo, Norway. greal@rr-research.no. Department of Cancer Genetics, Institute for Cancer Research, Oslo University Hospital, Radiumhospitalet, Oslo, Norway. silje.nord@rr-research.no. Department of Cancer Genetics, Institute for Cancer Research, Oslo University Hospital, Radiumhospitalet, Oslo, Norway. a.l.borresen-dale@medisin.uio.no. Institute of Clinical Medicine, K.G. Jebsen Center for Breast Cancer Research, Faculty of Medicine, University of Oslo (UiO), Oslo, Norway. a.l.borresen-dale@medisin.uio.no. Department of Medical Oncology, Erasmus MC Cancer Institute, Rotterdam, The Netherlands. m.hooning@erasmusmc.nl. Department of Medical Oncology, Erasmus MC Cancer Institute, Rotterdam, The Netherlands. a.hollestelle@erasmusmc.nl. Department of Medical Oncology, Erasmus MC Cancer Institute, Rotterdam, The Netherlands. a.jager@erasmusmc.nl. Department of Medical Oncology, Erasmus MC Cancer Institute, Rotterdam, The Netherlands. c.seynaeve@erasmusmc.nl. Human Genetics Division, Genome Institute of Singapore, Singapore, Singapore. jingmei@gmail.com. Human Genetics Division, Genome Institute of Singapore, Singapore, Singapore. liuj3@gis.a-star.edu.sg. Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden. Keith.Humphreys@ki.se. Department of Oncology, Public Health and Primary Care, Centre for Cancer Genetic Epidemiology, University of Cambridge, Cambridge, UK. amd24@medschl.cam.ac.uk. Department of Oncology, Public Health and Primary Care, Centre for Cancer Genetic Epidemiology, University of Cambridge, Cambridge, UK. vr264@medschl.cam.ac.uk. Department of Oncology, Public Health and Primary Care, Centre for Cancer Genetic Epidemiology, University of Cambridge, Cambridge, UK. ms483@medschl.cam.ac.uk. Molecular Genetics of Breast Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany. m.kabisch@dkfz.de. Molecular Genetics of Breast Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany. dianatlopez@yahoo.com. Institute of Human Genetics, Pontificia Universidad Javeriana, Bogota, Colombia. dianatlopez@yahoo.com. Frauenklinik der Stadtklinik Baden-Baden, Baden-Baden, Germany. hu.ulmer@klinikum-mittelbaden.de. Molecular Genetics of Breast Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany. u.hamann@dkfz-heidelberg.de. Department of Community and Family Medicine, Duke University Medical Center, Durham, North Carolina, USA. joellen@virginia.edu. Department of Oncology, Wayne State University School of Medicine and Karmanos Cancer Institute, Detroit, Michigan, USA. purringk@karmanos.org. Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Michigan, USA. couch.fergus@mayo.edu. Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden. Per.Hall@ki.se. Department of Oncology, Public Health and Primary Care, Centre for Cancer Genetic Epidemiology, University of Cambridge, Cambridge, UK. pp10001@medschl.cam.ac.uk. Department of Public Health and Primary Care, Centre for Cancer Genetic Epidemiology, University of Cambridge, Cambridge, UK. dfe20@medschl.cam.ac.uk. Netherlands Cancer Institute, Antoni van Leeuwenhoek Hospital, Amsterdam, The Netherlands. mk.schmidt@nki.nl. Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany. j.chang-claude@dkfz.de. Division of Epigenomics and Cancer Risk Factors, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69124, Heidelberg, Germany. o.popanda@dkfz.de.

BMC cancer. 2015;:978
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Abstract

BACKGROUND Personalized therapy considering clinical and genetic patient characteristics will further improve breast cancer survival. Two widely used treatments, chemotherapy and radiotherapy, can induce oxidative DNA damage and, if not repaired, cell death. Since base excision repair (BER) activity is specific for oxidative DNA damage, we hypothesized that germline genetic variation in this pathway will affect breast cancer-specific survival depending on treatment. METHODS We assessed in 1,408 postmenopausal breast cancer patients from the German MARIE study whether cancer specific survival after adjuvant chemotherapy, anthracycline chemotherapy, and radiotherapy is modulated by 127 Single Nucleotide Polymorphisms (SNPs) in 21 BER genes. For SNPs with interaction terms showing p<0.1 (likelihood ratio test) using multivariable Cox proportional hazard analyses, replication in 6,392 patients from nine studies of the Breast Cancer Association Consortium (BCAC) was performed. RESULTS rs878156 in PARP2 showed a differential effect by chemotherapy (p=0.093) and was replicated in BCAC studies (p=0.009; combined analysis p=0.002). Compared to non-carriers, carriers of the variant G allele (minor allele frequency=0.07) showed better survival after chemotherapy (combined allelic hazard ratio (HR)=0.75, 95% 0.53-1.07) and poorer survival when not treated with chemotherapy (HR=1.42, 95% 1.08-1.85). A similar effect modification by rs878156 was observed for anthracycline-based chemotherapy in both MARIE and BCAC, with improved survival in carriers (combined allelic HR=0.73, 95% CI 0.40-1.32). None of the SNPs showed significant differential effects by radiotherapy. CONCLUSIONS Our data suggest for the first time that a SNP in PARP2, rs878156, may together with other genetic variants modulate cancer specific survival in breast cancer patients depending on chemotherapy. These germline SNPs could contribute towards the design of predictive tests for breast cancer patients.

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Publication Type : Meta-Analysis

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