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Cancer Res. 2017 Jun 1;77(11):2789-2799. doi: 10.1158/0008-5472.CAN-16-2568. Epub 2017 Mar 10.

BRCA2 Hypomorphic Missense Variants Confer Moderate Risks of Breast Cancer.

Shimelis H1, Mesman RLS2, Von Nicolai C3, Ehlen A3, Guidugli L4, Martin C5, Calléja FMGR2, Meeks H6, Hallberg E7, Hinton J7, Lilyquist J7, Hu C1, Aalfs CM8, Aittomäki K9, Andrulis I10,11, Anton-Culver H12, Arndt V13, Beckmann MW14, Benitez J15,16, Bogdanova NV17,18, Bojesen SE19,20,21, Bolla MK22, Borresen-Dale AL23,24, Brauch H25,26,27, Brennan P28, Brenner H13,27,29, Broeks A30, Brouwers B31,32, Brüning T33, Burwinkel B34,35, Chang-Claude J36,37, Chenevix-Trench G, Cheng CY38, Choi JY39,40, Collée JM41, Cox A42, Cross SS43, Czene K44, Darabi H44, Dennis J22, Dörk T18, Dos-Santos-Silva I45, Dunning AM46, Fasching PA14,47, Figueroa J48,49, Flyger H50, García-Closas M49, Giles GG51,52, Glendon G10, Guénel P53, Haiman CA54, Hall P44, Hamann U55, Hartman M56,57, Hogervorst FB30, Hollestelle A58, Hopper JL52, Ito H59,60, Jakubowska A61, Kang D39,40,62, Kosma VM63,64,65, Kristensen V, Lai KN66,67, Lambrechts D68,69, Marchand LL70, Li J44, Lindblom A71, Lophatananon A72, Lubinski J61, Machackova E73, Mannermaa A63,64,65, Margolin S74, Marme F34,75, Matsuo K60,76, Miao H56, Michailidou K22,77, Milne RL51,52, Muir K72,78, Neuhausen SL79, Nevanlinna H80, Olson JE7, Olswold C7, Oosterwijk JJC81, Osorio A15,16, Peterlongo P82, Peto J45, Pharoah PDP22,46, Pylkäs K83,84, Radice P85, Rashid MU55,86, Rhenius V46, Rudolph A36, Sangrajrang S87, Sawyer EJ88, Schmidt MK30, Schoemaker MJ89,90, Seynaeve C58, Shah M46, Shen CY91,92, Shrubsole M93, Shu XO93, Slager S7, Southey MC94, Stram DO54, Swerdlow A89,90, Teo SH66,67, Tomlinson I95, Torres D55,96, Truong T53, van Asperen CJ8, van der Kolk LE30, Wang Q22, Winqvist R83,84, Wu AH54, Yu JC97, Zheng W93, Zheng Y98, Leary J99, Walker L100, Foretova L73, Fostira F101, Claes KBM102, Varesco L103, Moghadasi S8, Easton DF22,46, Spurdle A104, Devilee P2, Vrieling H2, Monteiro ANA105,106, Goldgar DE107, Carreira A3, Vreeswijk MPG2, Couch FJ108,7; for kConFab/AOCS Investigators; for NBCS Collaborators.

Author information

1
Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota.
2
Department of Human Genetics, Leiden University Medical Center, Leiden, the Netherlands.
3
Genotoxic Stress and Cancer, Institut Curie, Orsay, France.
4
Department of Human Genetics, University of Chicago, Chicago, Illinois.
5
Research Center, Institute Curie, Orsay, France.
6
Cancer Control and Population Sciences, University of Utah, Salt Lake City, Utah.
7
Department of Health Sciences Research, Mayo Clinic, Rochester, Minnesota.
8
Department of Clinical Genetics, Leiden University Medical Center, Leiden, the Netherlands.
9
Department of Clinical Genetics, Helsinki University Hospital, University of Helsinki, Helsinki, Finland.
10
Lunenfeld-Tanenbaum Research Institute of Mount Sinai Hospital, Toronto, Canada.
11
Department of Molecular Genetics, University of Toronto, Toronto, Canada.
12
Department of Epidemiology, University of California Irvine, Irvine, California.
13
Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany.
14
Department of Gynaecology and Obstetrics, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nuremberg, Comprehensive Cancer Center Erlangen-EMN, Erlangen, Germany.
15
Human Cancer Genetics Program, Spanish National Cancer Research Centre, Madrid, Spain.
16
Centro de Investigación en Red de Enfermedades Raras (CIBERER), Valencia, Spain.
17
Department of Radiation Oncology, Hannover Medical School, Hannover, Germany.
18
Gynaecology Research Unit, Hannover Medical School, Hannover, Germany.
19
Copenhagen General Population Study, Herlevand Gentofte Hospital, Copenhagen University Hospital, Herlev, Denmark.
20
Department of Clinical Biochemistry, Herlev and Gentofte Hospital, Copenhagen University Hospital, Herlev, Denmark.
21
Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
22
Department of Public Health and Primary Care, University of Cambridge, Cambridge, United Kingdom.
23
Department of Cancer Genetics, Institute for Cancer Research, Oslo University Hospital Radiumhospitalet, Oslo, Norway.
24
K.G. Jebsen Center for Breast Cancer Research, Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway.
25
Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology, Stuttgart, Germany.
26
University of Tübingen, Tübingen, Germany.
27
German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany.
28
International Agency for Research on Cancer, Lyon, France.
29
Division of Preventive Oncology, German Cancer Research Center (DKFZ) and National Center for Tumor Diseases (NCT), Heidelberg, Germany.
30
Netherlands Cancer Institute, Antoni van Leeuwenhoek Hospital, Amsterdam, the Netherlands.
31
Laboratory of Experimental Oncology, Department of Oncology, University Hospitals Leuven, Leuven, Belgium.
32
Department of General Medical Oncology, Leuven Cancer Institute, University Hospitals Leuven, Leuven, Belgium.
33
Institute for Prevention and Occupational Medicine of the German Social Accident Insurance, Institute of the Ruhr University Bochum, Bochum, Germany.
34
Department of Obstetrics and Gynecology, University of Heidelberg, Heidelberg, Germany.
35
Molecular Epidemiology Group, German Cancer Research Center (DKFZ), Heidelberg, Germany.
36
Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
37
University Cancer Center Hamburg (UCCH), University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
38
Singapore Eye Research Institute, National University of Singapore, Singapore, Singapore.
39
Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, Korea.
40
Cancer Research Institute, Seoul National University, Seoul, Korea.
41
Department of Clinical Genetics, Erasmus University Medical Center, Rotterdam, the Netherlands.
42
Sheffield Cancer Research, Department of Oncology and Metabolism, University of Sheffield, Sheffield, United Kingdom.
43
Academic Unit of Pathology, Department of Neuroscience, University of Sheffield, Sheffield, United Kingdom.
44
Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
45
Department of Non-Communicable Disease Epidemiology, London School of Hygiene and Tropical Medicine, London, United Kingdom.
46
Department of Oncology, University of Cambridge, Cambridge, United Kingdom.
47
Department of Medicine, Division of Hematology and Oncology, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, California.
48
Usher Institute of Population Health Sciences and Informatics, The University of Edinburgh Medical School, Edinburgh, United Kingdom.
49
Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, Maryland.
50
Department of Breast Surgery, Herlev and Gentofte Hospital, Copenhagen University Hospital, Herlev, Denmark.
51
Cancer Epidemiology Centre, Cancer Council Victoria, Melbourne, Australia.
52
Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, Australia.
53
Cancer & Environment Group, Center for Research in Epidemiology and Population Health (CESP), INSERM, University Paris-Sud, University Paris-Saclay, Villejuif, France.
54
Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California.
55
Molecular Genetics of Breast Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany.
56
Saw Swee Hock School of Public Health, National University of Singapore, Singapore, Singapore.
57
Department of Surgery, National University Health System, Singapore, Singapore.
58
Department of Medical Oncology, Family Cancer Clinic, Erasmus MC Cancer Institute, Rotterdam, the Netherlands.
59
Division of Epidemiology and Prevention, Aichi Cancer Center Research Institute, Nagoya, Japan.
60
Department of Epidemiology, Nagoya University Graduate School of Medicine, Nagoya, Japan.
61
Department of Genetics and Pathology, Pomeranian Medical University, Szczecin, Poland.
62
Department of Preventive Medicine, Seoul National University College of Medicine, Seoul, Korea.
63
Cancer Center of Eastern Finland, University of Eastern Finland, Kuopio, Finland.
64
Institute of Clinical Medicine, Pathology and Forensic Medicine, University of Eastern Finland, Kuopio, Finland.
65
Imaging Center, Department of Clinical Pathology, Kuopio University Hospital, Kuopio, Finland.
66
Cancer Research Initiatives Foundation, Subang Jaya, Selangor, Malaysia.
67
Breast Cancer Research Unit, Cancer Research Institute, University Malaya Medical Centre, Kuala Lumpur, Malaysia.
68
Vesalius Research Center, Leuven, Belgium.
69
Laboratory for Translational Genetics, Department of Oncology, University of Leuven, Leuven, Belgium.
70
University of Hawaii Cancer Center, Honolulu, Hawaii.
71
Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.
72
Division of Health Sciences, Warwick Medical School, Warwick University, Coventry, United Kingdom.
73
Department of Cancer Epidemiology and Genetics, Masaryk Memorial Cancer Institute, Brno, Czech Republic.
74
Department of Oncology - Pathology, Karolinska Institutet, Stockholm, Sweden.
75
National Center for Tumor Diseases, University of Heidelberg, Heidelberg, Germany.
76
Division of Molecular Medicine, Aichi Cancer Center Research Institute, Nagoya, Japan.
77
Department of Electron Microscopy/Molecular Pathology, The Cyprus Institute of Neurology and Genetics, Nicosia, Cyprus.
78
Institute of Population Health, University of Manchester, Manchester, United Kingdom.
79
Department of Population Sciences, Beckman Research Institute of City of Hope, Duarte, California.
80
Department of Obstetrics and Gynecology, Helsinki University Hospital, University of Helsinki, Helsinki, Finland.
81
Department of Genetics, University of Groningen, Groningen, the Netherlands.
82
IFOM, The FIRC (Italian Foundation for Cancer Research) Institute of Molecular Oncology, Milan, Italy.
83
Laboratory of Cancer Genetics and Tumor Biology, Cancer and Translational Medicine Research Unit, Biocenter Oulu, University of Oulu, Oulu, Finland.
84
Laboratory of Cancer Genetics and Tumor Biology, Northern Finland Laboratory Centre Oulu, Oulu, Finland.
85
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.
86
Department of Basic Sciences, Shaukat Khanum Memorial Cancer Hospital and Research Centre, Lahore, Pakistan.
87
National Cancer Institute, Bangkok, Thailand.
88
Research Oncology, Guy's Hospital, King's College London, London, United Kingdom.
89
Division of Genetics and Epidemiology, The Institute of Cancer Research, London, United Kingdom.
90
Division of Breast Cancer Research, The Institute of Cancer Research, London, United Kingdom.
91
School of Public Health, China Medical University, Taichung, Taiwan.
92
Taiwan Biobank, Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan.
93
Division of Epidemiology, Department of Medicine, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, Tennessee.
94
Department of Pathology, The University of Melbourne, Melbourne, Australia.
95
Wellcome Trust Centre for Human Genetics and Oxford NIHR Biomedical Research Centre, University of Oxford, Oxford, United Kingdom.
96
Institute of Human Genetics, Pontificia Universidad Javeriana, Bogota, Colombia.
97
Department of Surgery, National Taiwan University Hospital, Taipei, Taiwan.
98
Shanghai Municipal Center for Disease Control and Prevention, Shanghai, China.
99
Westmead Millenium Institute for Medical Research, University of Sydney, Sydney, Australia.
100
Department of Pathology, University of Otago, Christchurch, New Zealand.
101
Molecular Diagnostics Laboratory, Institute of Radioisotopes and Radiodiagnostic Products (IRRP), Athens, Greece.
102
Center for Medical Genetics, Ghent University Hospita, Ghent, Belgium.
103
Unit of Hereditary Cancers, IRCCS AOU San Martino, Genova, Italy.
104
Department of Genetics and Computational Biology, QIMR Berghofer Medical Research Institute, Brisbane, Australia.
105
Cancer Epidemiology Program, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida.
106
Department of Oncologic Science, University of South Florida, Tampa, Florida.
107
Huntsman Cancer Institute and Department of Dermatology, University of Utah, Salt Lake City, Utah.
108
Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota. couch.fergus@mayo.edu.

Abstract

Breast cancer risks conferred by many germline missense variants in the BRCA1 and BRCA2 genes, often referred to as variants of uncertain significance (VUS), have not been established. In this study, associations between 19 BRCA1 and 33 BRCA2 missense substitution variants and breast cancer risk were investigated through a breast cancer case-control study using genotyping data from 38 studies of predominantly European ancestry (41,890 cases and 41,607 controls) and nine studies of Asian ancestry (6,269 cases and 6,624 controls). The BRCA2 c.9104A>C, p.Tyr3035Ser (OR = 2.52; P = 0.04), and BRCA1 c.5096G>A, p.Arg1699Gln (OR = 4.29; P = 0.009) variant were associated with moderately increased risks of breast cancer among Europeans, whereas BRCA2 c.7522G>A, p.Gly2508Ser (OR = 2.68; P = 0.004), and c.8187G>T, p.Lys2729Asn (OR = 1.4; P = 0.004) were associated with moderate and low risks of breast cancer among Asians. Functional characterization of the BRCA2 variants using four quantitative assays showed reduced BRCA2 activity for p.Tyr3035Ser compared with wild-type. Overall, our results show how BRCA2 missense variants that influence protein function can confer clinically relevant, moderately increased risks of breast cancer, with potential implications for risk management guidelines in women with these specific variants. Cancer Res; 77(11); 2789-99. ©2017 AACR.

PMID:
28283652
PMCID:
PMC5508554
DOI:
10.1158/0008-5472.CAN-16-2568
[Indexed for MEDLINE]
Free PMC Article

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