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JAMA. 2015 Apr 7;313(13):1347-61. doi: 10.1001/jama.2014.5985.

Association of type and location of BRCA1 and BRCA2 mutations with risk of breast and ovarian cancer.

Rebbeck TR1, Mitra N2, Wan F2, Sinilnikova OM3, Healey S4, McGuffog L5, Mazoyer S3, Chenevix-Trench G4, Easton DF5, Antoniou AC5, Nathanson KL6; CIMBA Consortium, Laitman Y7, Kushnir A8, Paluch-Shimon S7, Berger R9, Zidan J10, Friedman E7, Ehrencrona H11, Stenmark-Askmalm M12, Einbeigi Z13, Loman N14, Harbst K14, Rantala J15, Melin B16, Huo D17, Olopade OI17, Seldon J18, Ganz PA18, Nussbaum RL19, Chan SB20, Odunsi K21, Gayther SA22, Domchek SM6, Arun BK23, Lu KH23, Mitchell G24, Karlan BY25, Walsh C25, Lester J25, Godwin AK26, Pathak H26, Ross E27, Daly MB28, Whittemore AS20, John EM29, Miron A30, Terry MB31, Chung WK32, Goldgar DE33, Buys SS34, Janavicius R35, Tihomirova L36, Tung N37, Dorfling CM38, van Rensburg EJ38, Steele L39, Neuhausen SL39, Ding YC39, Ejlertsen B40, Gerdes AM40, Hansen Tv41, Ramón y Cajal T42, Osorio A43, Benitez J44, Godino J45, Tejada MI46, Duran M47, Weitzel JN48, Bobolis KA48, Sand SR48, Fontaine A48, Savarese A49, Pasini B50, Peissel B51, Bonanni B52, Zaffaroni D51, Vignolo-Lutati F53, Scuvera G51, Giannini G54, Bernard L55, Genuardi M56, Radice P57, Dolcetti R58, Manoukian S51, Pensotti V59, Gismondi V60, Yannoukakos D61, Fostira F61, Garber J30, Torres D62, Rashid MU63, Hamann U64, Peock S5, Frost D5, Platte R5, Evans DG65, Eeles R66, Davidson R67, Eccles D68, Cole T69, Cook J70, Brewer C71, Hodgson S72, Morrison PJ73, Walker L74, Porteous ME75, Kennedy MJ76, Izatt L77, Adlard J78, Donaldson A79, Ellis S5, Sharma P80, Schmutzler RK81, Wappenschmidt B81, Becker A81, Rhiem K81, Hahnen E81, Engel C82, Meindl A83, Engert S83, Ditsch N83, Arnold N84, Plendl HJ85, Mundhenke C84, Niederacher D86, Fleisch M86, Sutter C87, Bartram CR87, Dikow N87, Wang-Gohrke S88, Gadzicki D89, Steinemann D89, Kast K90, Beer M91, Varon-Mateeva R92, Gehrig A93, Weber BH94, Stoppa-Lyonnet D95, Sinilnikova OM96, Mazoyer S97, Houdayer C98, Belotti M99, Gauthier-Villars M99, Damiola F97, Boutry-Kryza N100, Lasset C101, Sobol H102, Peyrat JP103, Muller D104, Fricker JP104, Collonge-Rame MA105, Mortemousque I106, Nogues C107, Rouleau E108, Isaacs C109, De Paepe A110, Poppe B110, Claes K110, De Leeneer K110, Piedmonte M111, Rodriguez G112, Wakely K113, Boggess J114, Blank SV115, Basil J116, Azodi M117, Phillips KA24, Caldes T118, de la Hoya M118, Romero A118, Nevanlinna H119, Aittomäki K120, van der Hout AH121, Hogervorst FB122, Verhoef S122, Collée JM123, Seynaeve C124, Oosterwijk JC121, Gille JJ125, Wijnen JT126, Gómez Garcia EB127, Kets CM128, Ausems MG129, Aalfs CM130, Devilee P131, Mensenkamp AR128, Kwong A132, Olah E133, Papp J133, Diez O134, Lazaro C135, Darder E136, Blanco I137, Salinas M137, Jakubowska A138, Lubinski J138, Gronwald J138, Jaworska-Bieniek K139, Durda K138, Sukiennicki G138, Huzarski T138, Byrski T138, Cybulski C138, Toloczko-Grabarek A138, Złowocka-Perłowska E138, Menkiszak J140, Arason A141, Barkardottir RB141, Simard J142, Laframboise R143, Montagna M144, Agata S144, Alducci E144, Peixoto A145, Teixeira MR146, Spurdle AB4, Lee MH147, Park SK148, Kim SW149, Friebel TM2, Couch FJ150, Lindor NM151, Pankratz VS151, Guidugli L152, Wang X152, Tischkowitz M153, Foretova L154, Vijai J155, Offit K155, Robson M156, Rau-Murthy R156, Kauff N156, Fink-Retter A157, Singer CF157, Rappaport C157, Gschwantler-Kaulich D157, Pfeiler G157, Tea MK157, Berger A157, Greene MH158, Mai PL158, Imyanitov EN159, Toland AE160, Senter L161, Bojesen A162, Pedersen IS163, Skytte AB162, Sunde L164, Thomassen M165, Moeller ST165, Kruse TA165, Jensen UB164, Caligo MA166, Aretini P166, Teo SH167, Selkirk CG168, Hulick PJ168, Andrulis I169.

Author information

1
Abramson Cancer Center, Perelman School of Medicine at the University of Pennsylvania, Philadelphia2Center for Clinical Epidemiology and Biostatistics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia.
2
Center for Clinical Epidemiology and Biostatistics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia.
3
Centre de Recherche en Cancérologie de Lyon, UMR Inserm, Centre Léon Bérard, Lyon, France.
4
Department of Genetics and Computational Biology, Queensland Institute of Medical Research, Brisbane, Australia.
5
Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, United Kingdom.
6
Abramson Cancer Center, Perelman School of Medicine at the University of Pennsylvania, Philadelphia6Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia.
7
Sheba Medical Center, Tel Aviv, Israel.
8
Susanne Levy Gertner Oncogenetics Unit, Sheba Medical Center, Tel Hashomer, Israel.
9
Oncology Institute, Sheba Medical Center, Tel Hashomer, Israel.
10
Oncology Institute, Rivkah Ziv Medical Center Zefat, Israel.
11
Department of Oncology, Lund University, Lund, Sweden12Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden.
12
Division of Clinical Genetics, Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden.
13
Department of Oncology, Sahlgrenska University Hospital, Gothenburg, Sweden.
14
Department of Oncology, Lund University, Lund, Sweden.
15
Department of Clinical Genetics, Karolinska University Hospital, Stockholm, Sweden.
16
Department of Radiation Sciences, Oncology, Umeå University, Umeå, Sweden.
17
Center for Clinical Cancer Genetics and Global Health, University of Chicago Medical Center, Chicago, Illinois.
18
UCLA Schools of Medicine and Public Health, Division of Cancer Prevention and Control Research, Jonsson Comprehensive Cancer Center, Los Angeles, California.
19
Department of Medicine and Genetics, University of California, San Francisco.
20
Cancer Risk Program, Helen Diller Family Cancer Center, University of California, San Francisco.
21
Department of Gynecologic Oncology, Roswell Park Cancer Institute, Buffalo, New York.
22
Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles.
23
University of Texas MD Anderson Cancer Center, Houston.
24
Division of Cancer Medicine, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia 25Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, Australia.
25
Women's Cancer Program at the Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, California.
26
Department of Pathology and Laboratory Medicine, University of Kansas Medical Center, Kansas City.
27
Fox Chase Cancer Center, Philadelphia, Pennsylvania.
28
Department of Health Research and Policy, Stanford University School of Medicine, Stanford, California.
29
Department of Epidemiology, Cancer Prevention Institute of California, Fremont.
30
Dana-Farber Cancer Institute, Boston, Massachusetts.
31
Department of Epidemiology, Columbia University, New York, New York.
32
Departments of Pediatrics and Medicine, Columbia University, New York, New York.
33
Department of Dermatology, University of Utah School of Medicine, Salt Lake City.
34
Department of Oncological Sciences, Huntsman Cancer Institute, University of Utah School of Medicine, Salt Lake City.
35
Vilnius University Hospital Santariskiu Clinics, Hematology, Oncology, and Transfusion Medicine Center, Department of Molecular and Regenerative Medicine, State Research Institute Innovative Medicine Center, Vilnius, Lithuania.
36
Latvian Biomedical Research and Study Centre, Riga, Latvia.
37
Department of Medical Oncology, Beth Israel Deaconess Medical Center, Boston, Massachusetts.
38
Department of Genetics, University of Pretoria, Pretoria, South Africa.
39
Department of Population Sciences, Beckman Research Institute of City of Hope, Duarte, California.
40
Departments of Oncology or Clinical Genetics, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark.
41
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark.
42
Oncology Service, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain.
43
Human Genetics Group, Spanish National Cancer Centre (CNIO), and Biomedical Network on Rare Diseases (CIBERER), Madrid, Spain.
44
Human Genetics Group and Genotyping Unit, Spanish National Cancer Centre (CNIO), and Biomedical Network on Rare Diseases (CIBERER), Madrid, Spain.
45
Hospital clinico Universitario "Lozano Blesa," Instituto de investigación sanitaria de Aragón (IIS), Zaragoza, Spain.
46
Molecular Genetics Laboratory (Department of Genetics), Cruces University Hospital Barakaldo, Bizkaia, Spain.
47
Institute of Biology and Molecular Genetics. Universidad de Valladolid (IBGM-UVA), Valladolid, Spain.
48
Clinical Cancer Genetics, City of Hope Clinical Cancer Genetics Community Research Network, Duarte, California.
49
Unit of Genetic Counselling, Medical Oncology Department, Istituto Nazionale Tumori Regina Elena, Rome, Italy.
50
Department of Medical Science, University of Turin, and AO Città della Salute e della Scienza, Turin, Italy.
51
Unit of Medical Genetics, Department of Preventive and Predictive Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori (INT), Milan, Italy.
52
Division of Cancer Prevention and Genetics, Istituto Europeo di Oncologia, Milan, Italy.
53
AO Città della Salute e della Scienza, Turin, Italy.
54
Department of Molecular Medicine, University La Sapienza, Rome, Italy.
55
Department of Experimental Oncology, Istituto Europeo di Oncologia, Milan, Italy57Cogentech Cancer Genetic Test Laboratory, Milan, Italy.
56
Institute of Medical Genetics, Catholic University, "A. Gemelli" Hospital, Rome, Italy.
57
Unit of Molecular Bases of Genetic Risk and Genetic Testing, Department of Preventive and Predictive Medicine, Fondazione IRCCS Istituto Nazionale Tumori (INT), Milan, Italy60IFOM, Fondazione Istituto FIRC di Oncologia Molecolare, Milan, Italy.
58
Cancer Bioimmunotherapy Unit, Centro di Riferimento Oncologico, IRCCSCRO Aviano National Cancer Institute, Aviano (PN), Italy.
59
Cogentech Cancer Genetic Test Laboratory, Milan, Italy60IFOM, Fondazione Istituto FIRC di Oncologia Molecolare, Milan, Italy.
60
Unit of Hereditary Cancer, IRCCS AOU San Martino-IST Istituto Nazionale per la Ricerca sul Cancro, Genoa, Italy.
61
Molecular Diagnostics Laboratory, IRRP, National Centre for Scientific Research "Demokritos" Aghia Paraskevi Attikis, Athens, Greece.
62
Instituto de Genética Humana, Pontificia Universidad Javeriana, Bogotá, Colombia65Molecular Genetics of Breast Cancer, Deutsches Krebsforschungszentrum (DKFZ), Heidelberg, Germany.
63
Molecular Genetics of Breast Cancer, Deutsches Krebsforschungszentrum (DKFZ), Heidelberg, Germany 66Department of Basic Sciences, Shaukat Khanum Memorial Cancer Hospital and Research Centre (SKMCH & RC), Lahore, Pakistan.
64
Molecular Genetics of Breast Cancer, Deutsches Krebsforschungszentrum (DKFZ), Heidelberg, Germany.
65
Genetic Medicine, Manchester Academic Health Sciences Centre, Central Manchester University Hospitals, NHS Foundation Trust, Manchester, United Kingdom.
66
Oncogenetics Team, Institute of Cancer Research and Royal Marsden, NHS Foundation Trust, London, United Kingdom.
67
Ferguson-Smith Centre for Clinical Genetics, Yorkhill Hospitals, Glasgow, United Kingdom.
68
Wessex Clinical Genetics Service, Princess Anne Hospital, Southampton, United Kingdom.
69
West Midlands Regional Genetics Service, Birmingham Women's Hospital Healthcare NHS Trust, Edgbaston, Birmingham, United Kingdom.
70
Sheffield Clinical Genetics Service, Sheffield Children's Hospital, Sheffield, United Kingdom.
71
Department of Clinical Genetics, Royal Devon and Exeter Hospital, Exeter, United Kingdom.
72
Clinical Genetics Department, St Georges Hospital, University of London, United Kingdom.
73
Northern Ireland Regional Genetics Centre, Belfast City Hospital, Belfast, United Kingdom.
74
Oxford Regional Genetics Service, Churchill Hospital, Oxford, United Kingdom.
75
South East of Scotland Regional Genetics Service, Western General Hospital, Edinburgh, United Kingdom.
76
Academic Unit of Clinical and Molecular Oncology, Trinity College Dublin and St James's Hospital, Dublin, Eire.
77
South East Thames Regional Genetics Service, Guy's Hospital London, United Kingdom.
78
Yorkshire Regional Genetics Service, Leeds, United Kingdom.
79
South West Regional Genetics Service, Bristol, United Kingdom.
80
Department of Hematology and Oncology, University of Kansas Medical Center, Kansas City.
81
Center for Hereditary Breast and Ovarian Cancer, Center for Integrated Oncology (CIO), and Center for Molecular Medicine Cologne (CMMC), Medical Faculty, University of Cologne and University Hospital Cologne, Cologne, Germany.
82
Institute for Medical Informatics, Statistics and Epidemiology, University of Leipzig, Leipzig, Germany.
83
Department of Gynaecology and Obstetrics, Division of Tumor Genetics, Klinikum rechts der Isar, Technical University Munich, Munich, Germany.
84
Department of Gynecology and Obstetrics, University Medical Center Schleswig-Holstein, Campus Kiel, Germany.
85
Institute of Human Genetics, University Medical Center Schleswig-Holstein, Campus Kiel, Germany.
86
Department of Gynaecology and Obstetrics, University Hospital Düsseldorf, Heinrich-Heine University Düsseldorf, Düsseldorf, Germany.
87
Institute of Human Genetics, Department of Human Genetics, University Hospital Heidelberg, Heidelberg, Germany.
88
Department of Gynaecology and Obstetrics, University Hospital Ulm, Ulm, Germany.
89
Institute of Cell and Molecular Pathology, Hannover Medical School, Hannover, Germany.
90
Department of Gynaecology and Obstetrics, University Hospital Carl Gustav Carus, Technical University Dresden, Dresden, Germany.
91
Institute of Human Genetics, Technical University Dresden, Dresden, Germany.
92
Institute of Human Genetics, Campus Virchov Klinikum, Charite Berlin, Berlin, Germany.
93
Centre of Familial Breast and Ovarian Cancer, Department of Medical Genetics, Institute of Human Genetics, University of Würzburg, Würzburg, Germany.
94
Institute of Human Genetics, University of Regensburg, Regensburg, Germany.
95
Institut Curie, Department of Tumour Biology, Paris, France98Institut Curie, INSERM U830, Paris, France99Université Paris Descartes, Sorbonne Paris Cité, France.
96
Unité Mixte de Génétique Constitutionnelle des Cancers Fréquents, Hospices Civils de Lyon-Centre Léon Bérard, Lyon, France101INSERM U1052, CNRS UMR5286, Université Lyon 1, Centre de Recherche en Cancérologie de Lyon, Lyon, France.
97
INSERM U1052, CNRS UMR5286, Université Lyon 1, Centre de Recherche en Cancérologie de Lyon, Lyon, France.
98
Institut Curie, Department of Tumour Biology, Paris, France99Université Paris Descartes, Sorbonne Paris Cité, France.
99
Institut Curie, Department of Tumour Biology, Paris, France.
100
Unité Mixte de Génétique Constitutionnelle des Cancers Fréquents, Hospices Civils de Lyon-Centre Léon Bérard, Lyon, France.
101
Université Lyon 1, CNRS UMR5558, Lyon, France103Unité de Prévention et d'Epidémiologie Génétique, Centre Léon Bérard, Lyon, France.
102
Département Oncologie Génétique, Prévention et Dépistage, INSERM CIC-P9502, Institut Paoli-Calmettes/Université d'Aix-Marseille II, Marseille, France.
103
Laboratoire d'Oncologie Moléculaire Humaine, Centre Oscar Lambret, Lille, France.
104
Unité d'Oncogénétique, CLCC Paul Strauss, Strasbourg, France.
105
Service de Génétique Biologique-Histologie-Biologie du Développement et de la Reproduction, Centre Hospitalier Universitaire de Besançon, Besançon, France.
106
Service de Génétique, Centre Hospitalier Universitaire Bretonneau, Tours, France.
107
Oncogénétique Clinique, Hôpital René Huguenin/Institut Curie, Saint-Cloud, France.
108
Laboratoire d'Oncogénétique, Hôpital René Huguenin/Institut Curie, Saint-Cloud, France.
109
Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC.
110
Center for Medical Genetics, Ghent University, Ghent, Belgium.
111
GOG Statistical and Data Center, Buffalo, New York.
112
Evanston Hospital, Evanston, Illinois.
113
Tufts University, Medford, Massachusetts.
114
University of North Carolina, Chapel Hill.
115
New York University, New York, New York.
116
Ohio State, Good Samaritan Hospital, Cincinnati.
117
Yale University School of Medicine, New Haven, Connecticut.
118
Molecular Oncology Laboratory, Hospital Clinico San Carlos, IdISSC, Madrid, Spain.
119
Department of Obstetrics and Gynecology, University of Helsinki and Helsinki University Central Hospital, Helsinki, Finland.
120
Department of Clinical Genetics, Helsinki University Central Hospital, Helsinki, Finland.
121
Department of Genetics, University Medical Center, Groningen University, Groningen, The Netherlands.
122
Family Cancer Clinic, Netherlands Cancer Institute, Amsterdam, The Netherlands.
123
Department of Clinical Genetics, Family Cancer Clinic, Erasmus University Medical Center, Rotterdam, The Netherlands.
124
Department of Medical Oncology, Family Cancer Clinic, Erasmus University Medical Center, Rotterdam, The Netherlands.
125
Department of Clinical Genetics, VU University Medical Centre, Amsterdam, The Netherlands.
126
Department of Human Genetics and Department of Clinical Genetics, Leiden University Medical Center, Leiden, The Netherlands.
127
Department of Clinical Genetics and GROW, School for Oncology and Developmental Biology, MUMC, Maastricht, The Netherlands.
128
Department of Human Genetics, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.
129
Department of Medical Genetics, University Medical Center Utrecht, Utrecht, The Netherlands.
130
Department of Clinical Genetics, Academic Medical Center, Amsterdam, The Netherlands.
131
Department of Human Genetics and Department of Pathology, Leiden University Medical Center, Leiden, The Netherlands.
132
Hong Kong Hereditary Breast Cancer Family Registry, Hong Kong135Cancer Genetics Center, Hong Kong Sanatorium and Hospital, Hong Kong136Department of Surgery, University of Hong Kong, Hong Kong.
133
Department of Molecular Genetics, National Institute of Oncology, Budapest, Hungary.
134
Oncogenetics Laboratory, Vall d'Hebron Institute of Oncology (VHIO), Universitat Autonoma de Barcelona, Barcelona, Spain139University Hospital of Vall d'Hebron, Barcelona, Spain.
135
Molecular Diagnostic Unit, Hereditary Cancer Program, IDIBELL-Catalan Institute of Oncology, Barcelona, Spain.
136
Genetic Counseling Unit, Hereditary Cancer Program, IDIBGI-Catalan Institute of Oncology, Girona, Spain.
137
Genetic Counseling Unit, Hereditary Cancer Program, IDIBELL-Catalan Institute of Oncology, Barcelona, Spain.
138
Department of Genetics and Pathology, Pomeranian Medical University, Szczecin, Poland.
139
Department of Genetics and Pathology, Pomeranian Medical University, Szczecin, Poland144Postgraduate School of Molecular Medicine, Warsaw Medical University, Warsaw, Poland.
140
Department of Surgical Gynecology and Gynecological Oncology of Adults and Adolescents, Pomeranian Medical University, Szczecin, Poland.
141
Department of Pathology, Landspitali University Hospital, Reykjavík, Iceland147BMC, Faculty of Medicine, University of Iceland, Reykjavik, Iceland.
142
Canada Research Chair in Oncogenetics, Cancer Genomics Laboratory, Centre Hospitalier Universitaire de Québec Research Center, Quebec City, Quebec, Canada149Laval University, Quebec City, Quebec, Canada.
143
Medical Genetics Division, Centre Hospitalier Universitaire de Québec, Quebec City, Quebec, Canada151Immunology and Molecular Oncology Unit, Veneto Institute of Oncology, IOV-IRCCS, Padua, Italy.
144
Immunology and Molecular Oncology Unit, Veneto Institute of Oncology, IOV-IRCCS, Padua, Italy.
145
Department of Genetics, Portuguese Oncology Institute, Porto, Portugal.
146
Department of Genetics, Portuguese Oncology Institute, Porto, Portugal153Biomedical Sciences Institute (ICBAS), University of Porto, Portugal.
147
Department of Surgery, Soonchunhyang University and Hospital, Seoul, Korea.
148
Department of Preventive Medicine, Seoul National University College of Medicine and Cancer Research Institute, Seoul National University, Seoul, Korea.
149
Department of Surgery, Daerim St Mary's Hospital, Seoul, Korea.
150
Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota159Department of Health Sciences Research, Mayo Clinic, Rochester, Minnesota.
151
Department of Health Sciences Research, Mayo Clinic, Rochester, Minnesota.
152
Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota.
153
Program in Cancer Genetics, Departments of Human Genetics and Oncology, McGill University, Montreal, Quebec, Canada161Department of Medical Genetics, University of Cambridge, Cambridge, United Kingdom.
154
Department of Cancer Epidemiology and Genetics, Masaryk Memorial Cancer Institute and MF MU, Brno, Czech Republic.
155
Clinical Genetics Service, Cancer Biology and Genetics Program, Memorial Sloan-Kettering Cancer Center, New York, New York.
156
Clinical Genetics Service, Memorial Sloan-Kettering Cancer Center, New York, New York.
157
Department of OB/GYN and Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria.
158
Clinical Genetics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Rockville, Maryland.
159
N. N. Petrov Institute of Oncology, St Petersburg, Russia.
160
Divison of Human Cancer Genetics, Departments of Internal Medicine and Molecular Virology, Immunology and Medical Genetics, Comprehensive Cancer Center, Ohio State University, Columbus.
161
Divison of Human Genetics, Department of Internal Medicine, Comprehensive Cancer Center, Ohio State University, Columbus.
162
Department of Clinical Genetics, Vejle Hospital, Vejle, Denmark.
163
Section of Molecular Diagnostics, Department of Clinical Biochemistry, Aalborg University Hospital, Aalborg, Denmark.
164
Department of Clinical Genetics, Aarhus University Hospital, Aarhus N, Denmark.
165
Department of Clinical Genetics, Odense University Hospital, Odense C, Denmark.
166
Section of Genetic Oncology, Department of Oncology, University of Pisa and University Hospital of Pisa, Pisa, Italy.
167
Cancer Research Initiatives Foundation, Sime Darby Medical Centre, Subang Jaya, Malaysia176Department of Surgery, Faculty of Medicine, University Malaya Cancer Research Institute, University Malaya, Kuala Lumpur, Malaysia.
168
NorthShore University HealthSystem, Department of Medicine, Evanston, Illinois.
169
Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital and University of Toronto, Toronto, Ontario, Canada.

Erratum in

Abstract

IMPORTANCE:

Limited information about the relationship between specific mutations in BRCA1 or BRCA2 (BRCA1/2) and cancer risk exists.

OBJECTIVE:

To identify mutation-specific cancer risks for carriers of BRCA1/2.

DESIGN, SETTING, AND PARTICIPANTS:

Observational study of women who were ascertained between 1937 and 2011 (median, 1999) and found to carry disease-associated BRCA1 or BRCA2 mutations. The international sample comprised 19,581 carriers of BRCA1 mutations and 11,900 carriers of BRCA2 mutations from 55 centers in 33 countries on 6 continents. We estimated hazard ratios for breast and ovarian cancer based on mutation type, function, and nucleotide position. We also estimated RHR, the ratio of breast vs ovarian cancer hazard ratios. A value of RHR greater than 1 indicated elevated breast cancer risk; a value of RHR less than 1 indicated elevated ovarian cancer risk.

EXPOSURES:

Mutations of BRCA1 or BRCA2.

MAIN OUTCOMES AND MEASURES:

Breast and ovarian cancer risks.

RESULTS:

Among BRCA1 mutation carriers, 9052 women (46%) were diagnosed with breast cancer, 2317 (12%) with ovarian cancer, 1041 (5%) with breast and ovarian cancer, and 7171 (37%) without cancer. Among BRCA2 mutation carriers, 6180 women (52%) were diagnosed with breast cancer, 682 (6%) with ovarian cancer, 272 (2%) with breast and ovarian cancer, and 4766 (40%) without cancer. In BRCA1, we identified 3 breast cancer cluster regions (BCCRs) located at c.179 to c.505 (BCCR1; RHR = 1.46; 95% CI, 1.22-1.74; P = 2 × 10(-6)), c.4328 to c.4945 (BCCR2; RHR = 1.34; 95% CI, 1.01-1.78; P = .04), and c. 5261 to c.5563 (BCCR2', RHR = 1.38; 95% CI, 1.22-1.55; P = 6 × 10(-9)). We also identified an ovarian cancer cluster region (OCCR) from c.1380 to c.4062 (approximately exon 11) with RHR = 0.62 (95% CI, 0.56-0.70; P = 9 × 10(-17)). In BRCA2, we observed multiple BCCRs spanning c.1 to c.596 (BCCR1; RHR = 1.71; 95% CI, 1.06-2.78; P = .03), c.772 to c.1806 (BCCR1'; RHR = 1.63; 95% CI, 1.10-2.40; P = .01), and c.7394 to c.8904 (BCCR2; RHR = 2.31; 95% CI, 1.69-3.16; P = .00002). We also identified 3 OCCRs: the first (OCCR1) spanned c.3249 to c.5681 that was adjacent to c.5946delT (6174delT; RHR = 0.51; 95% CI, 0.44-0.60; P = 6 × 10(-17)). The second OCCR spanned c.6645 to c.7471 (OCCR2; RHR = 0.57; 95% CI, 0.41-0.80; P = .001). Mutations conferring nonsense-mediated decay were associated with differential breast or ovarian cancer risks and an earlier age of breast cancer diagnosis for both BRCA1 and BRCA2 mutation carriers.

CONCLUSIONS AND RELEVANCE:

Breast and ovarian cancer risks varied by type and location of BRCA1/2 mutations. With appropriate validation, these data may have implications for risk assessment and cancer prevention decision making for carriers of BRCA1 and BRCA2 mutations.

PMID:
25849179
PMCID:
PMC4537700
DOI:
10.1001/jama.2014.5985
[Indexed for MEDLINE]
Free PMC Article

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