title: RAD51B in Familial Breast Cancer.
abstract: Common variation on 14q24.1, close to RAD51B, has been associated with breast cancer: rs999737 and rs2588809 with the risk of female breast cancer and rs1314913 with the risk of male breast cancer. The aim of this study was to investigate the role of RAD51B variants in breast cancer predisposition, particularly in the context of familial breast cancer in Finland. We sequenced the coding region of RAD51B in 168 Finnish breast cancer patients from the Helsinki region for identification of possible recurrent founder mutations. In addition, we studied the known rs999737, rs2588809, and rs1314913 SNPs and RAD51B haplotypes in 44,791 breast cancer cases and 43,583 controls from 40 studies participating in the Breast Cancer Association Consortium (BCAC) that were genotyped on a custom chip (iCOGS). We identified one putatively pathogenic missense mutation c.541C>T among the Finnish cancer patients and subsequently genotyped the mutation in additional breast cancer cases (n = 5259) and population controls (n = 3586) from Finland and Belarus. No significant association with breast cancer risk was seen in the meta-analysis of the Finnish datasets or in the large BCAC dataset. The association with previously identified risk variants rs999737, rs2588809, and rs1314913 was replicated among all breast cancer cases and also among familial cases in the BCAC dataset. The most significant association was observed for the haplotype carrying the risk-alleles of all the three SNPs both among all cases (odds ratio (OR): 1.15, 95% confidence interval (CI): 1.11-1.19, P = 8.88 x 10-16) and among familial cases (OR: 1.24, 95% CI: 1.16-1.32, P = 6.19 x 10-11), compared to the haplotype with the respective protective alleles. Our results suggest that loss-of-function mutations in RAD51B are rare, but common variation at the RAD51B region is significantly associated with familial breast cancer risk.
authors.affiliation: Department of Obstetrics and Gynecology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.
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authors.initials: LM
authors.lastname: Pelttari
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: Laboratory of Cancer Genetics and Tumor Biology, Cancer Research and Translational Medicine, Biocenter Oulu, University of Oulu, Oulu, Finland.
authors.forename: Mikko
authors.initials: M
authors.lastname: Vuorela
authors.affiliation: Department of Obstetrics and Gynecology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.
authors.forename: Johanna I
authors.initials: JI
authors.lastname: Kiiski
authors.affiliation: Department of Obstetrics and Gynecology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.
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authors.lastname: Vilske
authors.affiliation: Department of Obstetrics and Gynecology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.
authors.forename: Viivi
authors.initials: V
authors.lastname: Nevanlinna
authors.affiliation: Department of Obstetrics and Gynecology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.
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authors.lastname: Ranta
authors.affiliation: BioMediTech, University of Tampere, Tampere, Finland.|Department of Medical Biochemistry and Genetics, University of Turku, Turku, Finland.|Tyks Microbiology and Genetics, Department of Medical Genetics, Turku University Hospital, Turku, Finland.
authors.forename: Johanna
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authors.lastname: Schleutker
authors.affiliation: Laboratory of Cancer Genetics and Tumor Biology, Cancer Research and Translational Medicine, Biocenter Oulu, University of Oulu, Oulu, Finland.|Laboratory of Cancer Genetics and Tumor Biology, Northern Finland Laboratory Centre NordLab, Oulu, Finland.
authors.forename: Robert
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authors.affiliation: BioMediTech, University of Tampere, Tampere, Finland.|Fimlab Laboratories, Tampere, Finland.
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authors.affiliation: Gynaecology Research Unit, Hannover Medical School, Hannover, Germany.
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authors.affiliation: Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, United Kingdom.
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authors.affiliation: Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, United Kingdom.
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authors.affiliation: Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, United Kingdom.
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authors.affiliation: Department of Obstetrics and Gynecology, University of Heidelberg, Heidelberg, Germany.|Molecular Epidemiology Group, German Cancer Research Center (DKFZ), Heidelberg, Germany.
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authors.initials: SE
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authors.affiliation: Department of Genetics, Institute for Cancer Research, Oslo University Hospital Radiumhospitalet, Oslo, Norway.|K.G. Jebsen Center for Breast Cancer Research, Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway.|Department of Clinical Molecular Biology, Oslo University Hospital, University of Oslo, Oslo, Norway.
authors.forename: Vessela
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authors.affiliation: Department of Genetics, Institute for Cancer Research, Oslo University Hospital Radiumhospitalet, Oslo, Norway.|K.G. Jebsen Center for Breast Cancer Research, Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway.
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authors.affiliation: Lunenfeld-Tanenbaum Research Institute of Mount Sinai Hospital, Toronto, Canada.|Department of Molecular Genetics, University of Toronto, Toronto, Canada.
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authors.affiliation: Department of Medical Oncology, Family Cancer Clinic, Erasmus MC Cancer Institute, Rotterdam, The Netherlands.
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authors.affiliation: Sheffield Cancer Research, Department of Oncology, University of Sheffield, Sheffield, United Kingdom.
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authors.affiliation: Academic Unit of Pathology, Department of Neuroscience, University of Sheffield, Sheffield, United Kingdom.
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authors.affiliation: Molecular Genetics of Breast Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany.
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authors.affiliation: Molecular Genetics of Breast Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany.|Institute of Human Genetics, Pontificia Universidad Javeriana, Bogota, Colombia.
authors.forename: Diana
authors.initials: D
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authors.affiliation: Department of Genetics and Pathology, Pomeranian Medical University, Szczecin, Poland.
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authors.affiliation: Department of Genetics and Pathology, Pomeranian Medical University, Szczecin, Poland.
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authors.affiliation: Breakthrough Breast Cancer Research Centre, The Institute of Cancer Research, London, United Kingdom.
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authors.affiliation: Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Hatef
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authors.affiliation: Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Jingmei
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authors.lastname: Li
authors.affiliation: Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Kamila
authors.initials: K
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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 Oncology, University of Cambridge, Cambridge, United Kingdom.|Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, United Kingdom.
authors.forename: Douglas F
authors.initials: DF
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authors.affiliation: Department of Oncology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.
authors.forename: Johanna
authors.initials: J
authors.lastname: Mattson
authors.affiliation: Department of Oncology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.
authors.forename: Carl
authors.initials: C
authors.lastname: Blomqvist
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: Heli
authors.initials: H
authors.lastname: Nevanlinna
mesh_terms: D001943:Breast Neoplasms / Q000209:etiology / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000502:physiology; D005260:Female; D005387:Finland; D020022:Genetic Predisposition to Disease / Q000235:genetics; D060005:Genotyping Techniques; D006239:Haplotypes / Q000235:genetics; D006579:Heterozygote; D006801:Humans; D008297:Male; D008875:Middle Aged; D020125:Mutation, Missense; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*
chemical_list: D004268:DNA-Binding Proteins; C413002:RAD51B protein, human