Mutational spectrum in a worldwide study of 29,700 families with BRCA1 or BRCA2 mutations

emBRAce; GEMO Study Collaborators; HEBON

doi:10.1002/humu.23406

Mutational spectrum in a worldwide study of 29,700 families with BRCA1 or BRCA2 mutations

emBRAce, GEMO Study Collaborators, HEBON

Clinical Departments

Research output: Contribution to journal › Article › peer-review

233 Scopus citations

Abstract

The prevalence and spectrum of germline mutations in BRCA1 and BRCA2 have been reported in single populations, with the majority of reports focused on White in Europe and North America. The Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA) has assembled data on 18,435 families with BRCA1 mutations and 11,351 families with BRCA2 mutations ascertained from 69 centers in 49 countries on six continents. This study comprehensively describes the characteristics of the 1,650 unique BRCA1 and 1,731 unique BRCA2 deleterious (disease-associated) mutations identified in the CIMBA database. We observed substantial variation in mutation type and frequency by geographical region and race/ethnicity. In addition to known founder mutations, mutations of relatively high frequency were identified in specific racial/ethnic or geographic groups that may reflect founder mutations and which could be used in targeted (panel) first pass genotyping for specific populations. Knowledge of the population-specific mutational spectrum in BRCA1 and BRCA2 could inform efficient strategies for genetic testing and may justify a more broad-based oncogenetic testing in some populations.

Original language	English
Pages (from-to)	593-620
Number of pages	28
Journal	Human Mutation
Volume	39
Issue number	5
DOIs	https://doi.org/10.1002/humu.23406
State	Published - May 2018

Funding

Funders	Funder number
Istituto Nazionale Tumori Regina Elena
Gothenburg Sahlgrenska University Hospital
Sandra Fert Ferrer
Landspítali Háskólasjúkrahús
Service de Génétique Oncologique
National Breast Cancer Foundation
PALGA
Spanish Research Network on Rare diseases
Marta Santamariña
Ohio State University Comprehensive Cancer Center
Istituto Toscano Tumori
Istituto Europeo di Oncologia
Ministerio de Educación, Cultura y Deporte
SKMCH & RC
National Institute on Handicapped Research
Government of Canada
Genome Canada
Leids Universitair Medisch Centrum
Jess and Mildred Fisher Center for Familial Cancer Research
Ligue Contre le Cancer
Morris and Horowitz Families Endowed
Ministry of Economy, Science and Innovation
Umeå University Hospital
Hospices Civils de Lyon - Centre Léon Bérard
Ovarian Cancer Research Fund
Georgetown University
Instituto de Salud Carlos III
Entertainment Industry Fund National Women's Cancer Research Alliance
IKNL
Instituto Nacional del Cáncer
University of Kansas Cancer Center
Unité Mixte de Génétique Constitutionnelle des Cancers Fréquents
Cancer Association of South Africa
Institut Curie
Oncogenetics Department and Molecular Oncology Research Center of Barretos Cancer Hospital
Ospedale di Circolo-Università dell'Insubria
Università degli Studi di Torino
Center of Molecular Diagnosis
Génome Québec
UCSF UCSF
Robert and Kate Niehaus Clinical Cancer Genetics Initiative
BCFR
Fondation du cancer du sein du Québec
Icelandic Association
Netherlands Comprehensive Cancer Organisation
National Medical Research Council
Karolinska University Hospital
Consejo Nacional de Investigaciones Científicas y Técnicas
Rijksuniversiteit Groningen
Swing Fore the Cure
Istituto Pasteur-Fondazione Cenci Bolognetti
Fonds Wetenschappelijk Onderzoek
Cancerfonden
Institut Claudius Regaud
National Institute of Oncology
National Institutes of Health
Liga Portuguesa Contra o Cancro
Ministero della Salute and “5 × 1000” Istituto Oncologico Veneto
Cancer Councils of New South Wales
CIBERER
Università degli Studi di Firenze
Ministero della Salute and “5 × 1000” Istituto Oncologico Veneto
Cecilia Zvocec
European Commission
European Social Fund
Radboud Universitair Medisch Centrum
BMBSA
FMMA
Fundación Mutua Madrileña
Israeli Inherited breast cancer consortium
Institut Gustave-Roussy
Asociación Española contra el Cáncer
Cancer Foundation of Western Australia
Fundación Cellex
National Health and Medical Research Council
Institut National du Cancer
Cancer Research Initiatives Foundation
Uppsala Universitet
KWF Kankerbestrijding
Sanatorium and Hospital
CRO Aviano National Cancer Institute
Seventh Framework Programme
Barretos Cancer Hospital
Israel Cancer Association
Lunds Universitet
Norwegian EEA Financial Mechanism Hu0115/NA/2008
Hereditary Cancer Research Registry
Dr. Ralph and Marian Falk Medical Research Trust
David F. and Margaret T. Grohne Family Foundation
Fondazione IRCCS Istituto Nazionale dei Tumori
University Hospital Vall d'Hebron
Helsingin ja Uudenmaan Sairaanhoitopiiri
Ministero dell’Istruzione, dell’Università e della Ricerca
Consejería de Salud y Familias, Junta de Andalucía
Cancer Council NSW
Istituto Nazionale per la Ricerca sul Cancro
Maastricht Universitair Medisch Centrum
German Cancer Research Center
Pontificia Universidad Javeriana
Komen Foundation for the Cure
University Medical Center Utrecht
Finnish Cancer Society
Joyce Seldon MSGC
Ministry of Health Health Services Research Grant Singapore and Lee Foundation
Hospital de Câncer de Barretos
Canada Research Chair in Oncogenetics
Netherlands Cancer Institute
Cancer Australia
Ministerio de Salud de la Nacion Argentina
Fundación Ramón Areces
Department of Biochemistry and Experimental Oncology, First Faculty of Medicine
SEABASS Ministry of Science, Technology and Innovation
Institut Paoli Calmettes
Sigrid Juséliuksen Säätiö
Susan G. Komen
Cancer Council Queensland
Institut Català de la Salut
UCLA Jonsson Comprehensive Cancer Center Foundation
Russian Foundation for Basic Research	15-04-01744, 14-04-93959
National Cancer Institute	R25CA171998, U01CA113916, U19CA148065, U01CA161032, N02-CP-65504, U01CA116167, P30CA051008, R01CA140323, U10CA027469, R01CA128978, R01CA176785, P50CA125183, UG1CA189867, U10CA037517, NO2-CP-11019-50, R01CA083855, R01CA102776, P50CA116201, U19CA148112, ZIACP010144, U19CA148537, R01CA142996, P30CA168524, UM1CA164920, P30CA016058, RC4CA153828, P30CA008748, U10CA180868, U10CA180822
Lietuvos Mokslo Taryba	SEN-18/2015, SEN-18/2015 BFBOCC-LT
Ministerio de Economía y Competitividad	SAF2014-57680-R
Cancer Research UK	C5047/A10692, C5047/A8384, C1287/A11990, C1287/A 10710, C1287/A10118, C1281/A12014, R01-CA083855, C8197/A16565, C5047/A15007
Fundação de Amparo à Pesquisa do Estado de São Paulo	2013/24633-2
Istituto Nazionale Tumori IRCCS "Fondazione G. Pascale"	5 × 1000′
National Center for Advancing Translational Sciences	UL1TR000124
BBMRI	12-054, 184.021.007/CP46
Ministry of Higher Education, Malaysia	UM.C/HlR/MOHE/06
Cancer Center, University of Kansas	FISPI05/2275, 5U01CA113916, R01CA140323, P30 CA168524
National R&D Program for Cancer Control, Ministry for Health, Welfare and Family Affairs, Republic of Korea	1020350, 1420190
Linköping University Hospital	R01 CA142996, 1U01CA161032
Univerzita Karlova v Praze	UNCE204024
Hungarian Research Grants KTIA-OTKA	CK-80745, NKFIH/ OTKA K-112228
Agentschap voor Innovatie door Wetenschap en Technologie	15/00059, RD12/0036/0006
Medical Research Council	MR/P012930/1
Norwegian EEA Financial Mechanism	Hu0115/NA/2008-3/OP-9
Associazione Italiana per la Ricerca sul Cancro	IG17734
Generalitat de Catalunya	PBZ_KBN_122/P05/2004, RD12/0036/008, ISCIIIRETIC RD06/0020/1051, PI10/00748, 2014SGR364
Dutch Cancer Society	NKI1998-1854, NKI2004-3088, NKI2007-3756
NRG Oncology Operations	U10 CA180868
Breast Cancer Research Foundation	RC4CA153828
Ministère du Développement Économique, de l’Innovation et de l’Exportation	PSR-SIIRI-701
Nederlandse Organisatie voor Wetenschappelijk Onderzoek	2014-187, 110005, NWO 91109024, 184.021.007
Institut Català de la Salut and Autonomous Government of Catalonia	2014SGR338, 2009SGR290
Helen Tsimiklis BCFR	UM1 CA164920
MMCI	MEYS-NPS ILO1413, 00209805
Andrew Sabin Research Fund	P30 CA008748
NRG SDMC	U10 CA180822
Financiadora de Estudos e Projetos	02/2010
Seventh Framework Programme	223175
NIHR Biomedical Research Centre, Royal Marsden NHS Foundation Trust/Institute of Cancer Research	C5047/A8385
American Cancer Society	SIOP-06-258-06-COUN
Research Council of Finland	266528
Kementerian Sains, Teknologi dan Inovasi	UM.C/HIR/MOHE/06
Fiorgen Foundation for Pharmacogenomics	IG2015, 16732
Canadian Institutes of Health Research	019511, CRN-87521
Istituto Nazionale Tumori	R01-CA102776, R01-CA08534
European Regional Development Fund	PI10/01422, PI13/00285, PI15/00854, PIE13/00022, PI16/00563
Spanish Ministry of Health	PI16/00440
Office of the Director	IG2014, 15547
National Strategic Reference Framework	SYN11_10_19 NBCA
U.S. Department of Defense	W81XWH-10-1-0341
Deutsche Krebshilfe	110837

Keywords

BRCA1
BRCA2
breast cancer
ethnicity
geography
mutation
ovarian cancer

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1002/humu.23406

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@article{0521d54b869945f8bf2c31702c8b9478,

title = "Mutational spectrum in a worldwide study of 29,700 families with BRCA1 or BRCA2 mutations",

abstract = "The prevalence and spectrum of germline mutations in BRCA1 and BRCA2 have been reported in single populations, with the majority of reports focused on White in Europe and North America. The Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA) has assembled data on 18,435 families with BRCA1 mutations and 11,351 families with BRCA2 mutations ascertained from 69 centers in 49 countries on six continents. This study comprehensively describes the characteristics of the 1,650 unique BRCA1 and 1,731 unique BRCA2 deleterious (disease-associated) mutations identified in the CIMBA database. We observed substantial variation in mutation type and frequency by geographical region and race/ethnicity. In addition to known founder mutations, mutations of relatively high frequency were identified in specific racial/ethnic or geographic groups that may reflect founder mutations and which could be used in targeted (panel) first pass genotyping for specific populations. Knowledge of the population-specific mutational spectrum in BRCA1 and BRCA2 could inform efficient strategies for genetic testing and may justify a more broad-based oncogenetic testing in some populations.",

keywords = "BRCA1, BRCA2, breast cancer, ethnicity, geography, mutation, ovarian cancer",

author = "emBRAce and {GEMO Study Collaborators} and HEBON and Rebbeck, {Timothy R.} and Friebel, {Tara M.} and Eitan Friedman and Ute Hamann and Dezheng Huo and Ava Kwong and Edith Olah and Olopade, {Olufunmilayo I.} and Solano, {Angela R.} and Teo, {Soo Hwang} and Mads Thomassen and Weitzel, {Jeffrey N.} and Chan, {T. L.} and Couch, {Fergus J.} and Goldgar, {David E.} and Kruse, {Torben A.} and Palmero, {Edenir In{\^e}z} and Park, {Sue Kyung} and Diana Torres and {van Rensburg}, {Elizabeth J.} and Lesley McGuffog and Parsons, {Michael T.} and Goska Leslie and Aalfs, {Cora M.} and Julio Abugattas and Julian Adlard and Simona Agata and Kristiina Aittom{\"a}ki and Lesley Andrews and Andrulis, {Irene L.} and Adalgeir Arason and Norbert Arnold and Arun, {Banu K.} and Ella Asseryanis and Leo Auerbach and Jacopo Azzollini and Judith Balma{\~n}a and Monica Barile and Barkardottir, {Rosa B.} and Daniel Barrowdale and Javier Benitez and Andreas Berger and Raanan Berger and Blanco, {Amie M.} and Blazer, {Kathleen R.} and Blok, {Marinus J.} and Val{\'e}rie Bonadona and Bernardo Bonanni and Bradbury, {Angela R.} and Carole Brewer",

note = "Publisher Copyright: {\textcopyright} 2018 Wiley Periodicals, Inc.",

year = "2018",

month = may,

doi = "10.1002/humu.23406",

language = "אנגלית",

volume = "39",

pages = "593--620",

journal = "Human Mutation",

issn = "1059-7794",

publisher = "John Wiley and Sons Inc.",

number = "5",

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T1 - Mutational spectrum in a worldwide study of 29,700 families with BRCA1 or BRCA2 mutations

AU - emBRAce

AU - GEMO Study Collaborators

AU - HEBON

AU - Rebbeck, Timothy R.

AU - Friebel, Tara M.

AU - Friedman, Eitan

AU - Hamann, Ute

AU - Huo, Dezheng

AU - Kwong, Ava

AU - Olah, Edith

AU - Olopade, Olufunmilayo I.

AU - Solano, Angela R.

AU - Teo, Soo Hwang

AU - Thomassen, Mads

AU - Weitzel, Jeffrey N.

AU - Chan, T. L.

AU - Couch, Fergus J.

AU - Goldgar, David E.

AU - Kruse, Torben A.

AU - Palmero, Edenir Inêz

AU - Park, Sue Kyung

AU - Torres, Diana

AU - van Rensburg, Elizabeth J.

AU - McGuffog, Lesley

AU - Parsons, Michael T.

AU - Leslie, Goska

AU - Aalfs, Cora M.

AU - Abugattas, Julio

AU - Adlard, Julian

AU - Agata, Simona

AU - Aittomäki, Kristiina

AU - Andrews, Lesley

AU - Andrulis, Irene L.

AU - Arason, Adalgeir

AU - Arnold, Norbert

AU - Arun, Banu K.

AU - Asseryanis, Ella

AU - Auerbach, Leo

AU - Azzollini, Jacopo

AU - Balmaña, Judith

AU - Barile, Monica

AU - Barkardottir, Rosa B.

AU - Barrowdale, Daniel

AU - Benitez, Javier

AU - Berger, Andreas

AU - Berger, Raanan

AU - Blanco, Amie M.

AU - Blazer, Kathleen R.

AU - Blok, Marinus J.

AU - Bonadona, Valérie

AU - Bonanni, Bernardo

AU - Bradbury, Angela R.

AU - Brewer, Carole

PY - 2018/5

Y1 - 2018/5

N2 - The prevalence and spectrum of germline mutations in BRCA1 and BRCA2 have been reported in single populations, with the majority of reports focused on White in Europe and North America. The Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA) has assembled data on 18,435 families with BRCA1 mutations and 11,351 families with BRCA2 mutations ascertained from 69 centers in 49 countries on six continents. This study comprehensively describes the characteristics of the 1,650 unique BRCA1 and 1,731 unique BRCA2 deleterious (disease-associated) mutations identified in the CIMBA database. We observed substantial variation in mutation type and frequency by geographical region and race/ethnicity. In addition to known founder mutations, mutations of relatively high frequency were identified in specific racial/ethnic or geographic groups that may reflect founder mutations and which could be used in targeted (panel) first pass genotyping for specific populations. Knowledge of the population-specific mutational spectrum in BRCA1 and BRCA2 could inform efficient strategies for genetic testing and may justify a more broad-based oncogenetic testing in some populations.

AB - The prevalence and spectrum of germline mutations in BRCA1 and BRCA2 have been reported in single populations, with the majority of reports focused on White in Europe and North America. The Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA) has assembled data on 18,435 families with BRCA1 mutations and 11,351 families with BRCA2 mutations ascertained from 69 centers in 49 countries on six continents. This study comprehensively describes the characteristics of the 1,650 unique BRCA1 and 1,731 unique BRCA2 deleterious (disease-associated) mutations identified in the CIMBA database. We observed substantial variation in mutation type and frequency by geographical region and race/ethnicity. In addition to known founder mutations, mutations of relatively high frequency were identified in specific racial/ethnic or geographic groups that may reflect founder mutations and which could be used in targeted (panel) first pass genotyping for specific populations. Knowledge of the population-specific mutational spectrum in BRCA1 and BRCA2 could inform efficient strategies for genetic testing and may justify a more broad-based oncogenetic testing in some populations.

KW - BRCA1

KW - BRCA2

KW - breast cancer

KW - ethnicity

KW - geography

KW - mutation

KW - ovarian cancer

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DO - 10.1002/humu.23406

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AN - SCOPUS:85043494756

SN - 1059-7794

VL - 39

SP - 593

EP - 620

JO - Human Mutation

JF - Human Mutation

IS - 5

ER -

Mutational spectrum in a worldwide study of 29,700 families with BRCA1 or BRCA2 mutations

Abstract

Funding

Keywords

UN SDGs

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