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PLoS One. 2016 May 5;11(5):e0153788. doi: 10.1371/journal.pone.0153788. eCollection 2016.

RAD51B in Familial Breast Cancer.

Author information

1
Department of Obstetrics and Gynecology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.
2
Laboratory of Cancer Genetics and Tumor Biology, Cancer Research and Translational Medicine, Biocenter Oulu, University of Oulu, Oulu, Finland.
3
BioMediTech, University of Tampere, Tampere, Finland.
4
Department of Medical Biochemistry and Genetics, University of Turku, Turku, Finland.
5
Tyks Microbiology and Genetics, Department of Medical Genetics, Turku University Hospital, Turku, Finland.
6
Laboratory of Cancer Genetics and Tumor Biology, Northern Finland Laboratory Centre NordLab, Oulu, Finland.
7
Fimlab Laboratories, Tampere, Finland.
8
Gynaecology Research Unit, Hannover Medical School, Hannover, Germany.
9
Radiation Oncology Research Unit, Hannover Medical School, Hannover, Germany.
10
Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, Maryland, United States of America.
11
Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Cambridge, United Kingdom.
12
Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, United Kingdom.
13
Netherlands Cancer Institute, Antoni van Leeuwenhoek hospital, Amsterdam, The Netherlands.
14
Division of Genetics and Epidemiology, The Institute of Cancer Research, London, United Kingdom.
15
Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global health, The University of Melbourne, Melbourne, Australia.
16
Department of Pathology, The University of Melbourne, Melbourne, Australia.
17
Department of Gynaecology and Obstetrics, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nuremberg, Comprehensive Cancer Center Erlangen-EMN, Erlangen, Germany.
18
David Geffen School of Medicine, Department of Medicine, Division of Hematology and Oncology, University of California Los Angeles, Los Angeles, California, United States of America.
19
Department of Non-Communicable Disease Epidemiology, London School of Hygiene and Tropical Medicine, London, United Kingdom.
20
Research Oncology, Guy's Hospital, King's College London, London, United Kingdom.
21
Wellcome Trust Centre for Human Genetics and Oxford NIHR Biomedical Research Centre, University of Oxford, Oxford, United Kingdom.
22
Department of Obstetrics and Gynecology, University of Heidelberg, Heidelberg, Germany.
23
Molecular Epidemiology Group, German Cancer Research Center (DKFZ), Heidelberg, Germany.
24
Environmental Epidemiology of Cancer, Center for Research in Epidemiology and Population Health, INSERM, Villejuif, France.
25
University Paris-Sud, Villejuif, France.
26
Copenhagen General Population Study, Herlev Hospital, Copenhagen University Hospital, Herlev, Denmark.
27
Department of Clinical Biochemistry, Herlev Hospital, Copenhagen University Hospital, Herlev, Denmark.
28
Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
29
Human Cancer Genetics Program, Spanish National Cancer Research Centre, Madrid, Spain.
30
Centro de Investigación en Red de Enfermedades Raras, Valencia, Spain.
31
Beckman Research Institute of City of Hope, Duarte, California, United States of America.
32
Department of Epidemiology, University of California Irvine, Irvine, California, United States of America.
33
Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany.
34
German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany.
35
Division of Preventive Oncology, German Cancer Research Center (DKFZ) and National Center for Tumor Diseases (NCT), Heidelberg, Germany.
36
Division of Gynaecology and Obstetrics, Technische Universität München, Munich, Germany.
37
Center for Hereditary Breast and Ovarian Cancer, University Hospital of Cologne, Cologne, Germany.
38
Center for Integrated Oncology (CIO), University Hospital of Cologne, Cologne, Germany.
39
Center for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany.
40
Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology, Stuttgart, Germany.
41
University of Tübingen, Tübingen, Germany.
42
Institute for Prevention and Occupational Medicine of the German Social Accident Insurance, Institute of the Ruhr University Bochum, Bochum, Germany.
43
Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.
44
Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden.
45
Cancer Center, Kuopio University Hospital, Kuopio, Finland.
46
Institute of Clinical Medicine, Pathology and Forensic Medicine, University of Eastern Finland, Kuopio, Finland.
47
Imaging Center, Department of Clinical Pathology, Kuopio University Hospital, Kuopio, Finland.
48
Department of Genetics, QIMR Berghofer Medical Research Institute, Brisbane, Australia.
49
Vesalius Research Center, VIB, Leuven, Belgium.
50
Laboratory for Translational Genetics, Department of Oncology, University of Leuven, Leuven, Belgium.
51
Leuven Multidisciplinary Breast Center, Leuven Cancer Institute, University Hospitals Leuven, Leuven, Belgium.
52
Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
53
University Cancer Center Hamburg (UCCH), University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
54
Unit of Molecular Bases of Genetic Risk and Genetic Testing, Department of Preventive and Predictive Medicine, Fondazione IRCCS (Istituto Di Ricovero e Cura a Carattere Scientifico) Istituto Nazionale dei Tumori (INT), Milan, Italy.
55
IFOM, Fondazione Istituto FIRC (Italian Foundation of Cancer Research) di Oncologia Molecolare, Milan, Italy.
56
Department of Health Sciences Research, Mayo Clinic, Rochester, Minnesota, United States of America.
57
Cancer Epidemiology Centre, Cancer Council Victoria, Melbourne, Australia.
58
Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California, United States of America.
59
Genomics Center, Centre Hospitalier Universitaire de Québec Research Center, Laval University, Québec City, Canada.
60
Department of Genetics, Institute for Cancer Research, Oslo University Hospital Radiumhospitalet, Oslo, Norway.
61
K.G. Jebsen Center for Breast Cancer Research, Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway.
62
Department of Clinical Molecular Biology, Oslo University Hospital, University of Oslo, Oslo, Norway.
63
Division of Epidemiology, Department of Medicine, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, Tennessee, United States of America.
64
Department of Surgery, Oulu University Hospital, University of Oulu, Oulu, Finland.
65
Lunenfeld-Tanenbaum Research Institute of Mount Sinai Hospital, Toronto, Canada.
66
Department of Molecular Genetics, University of Toronto, Toronto, Canada.
67
Department of Pathology, Leiden University Medical Center, Leiden, The Netherlands.
68
Department of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands.
69
Department of Medical Oncology, Family Cancer Clinic, Erasmus MC Cancer Institute, Rotterdam, The Netherlands.
70
Department of Clinical Genetics, Erasmus University Medical Center, Rotterdam, The Netherlands.
71
Sheffield Cancer Research, Department of Oncology, University of Sheffield, Sheffield, United Kingdom.
72
Academic Unit of Pathology, Department of Neuroscience, University of Sheffield, Sheffield, United Kingdom.
73
Clinical Gerontology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, United Kingdom.
74
Molecular Genetics of Breast Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany.
75
Institute of Human Genetics, Pontificia Universidad Javeriana, Bogota, Colombia.
76
Department of Genetics and Pathology, Pomeranian Medical University, Szczecin, Poland.
77
Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota, United States of America.
78
Molecular Diagnostics Laboratory, IRRP, National Centre for Scientific Research "Demokritos", Athens, Greece.
79
Breakthrough Breast Cancer Research Centre, The Institute of Cancer Research, London, United Kingdom.
80
Division of Breast Cancer Research, The Institute of Cancer Research, London, United Kingdom.
81
Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
82
Department of Oncology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.
83
Department of Clinical Genetics, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.

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.

PMID:
27149063
PMCID:
PMC4858276
DOI:
10.1371/journal.pone.0153788
[Indexed for MEDLINE]
Free PMC Article

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