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 | |
| State | Published - May 2018 |
| Externally published | Yes |
Bibliographical note
Publisher Copyright:© 2018 Wiley Periodicals, Inc.
Funding
The HEBON study is supported by the Dutch Cancer Society grants NKI1998-1854, NKI2004-3088, NKI2007-3756, the Netherlands Organisation of Scientific Research grant NWO 91109024, the Pink Ribbon grants 110005 and 2014-187.WO76, the BBMRI grant NWO 184.021.007/CP46 and the Transcan grant JTC 2012 Cancer 12-054. BFBOCC is partly supported by: Lithuania (BFBOCC-LT): Research Council of Lithuania grant SEN-18/2015 CI received support from the Non-Therapeutic Subject Registry Shared Resource at Georgetown University (NIH/NCI grant P30-CA051008), the Fisher Center for Familial Cancer Research, and Swing Fore the Cure. UKFOCR was supported by a project grant from CRUK to Paul Pharoah. The IHCC was supported by Grant PBZ_KBN_122/P05/2004 OSUCCG is supported by the Ohio State University Comprehensive Cancer Center. This study was in part supported by Liga Portuguesa Contra o Cancro. This work has been supported by the Russian Federation for Basic Research (grants 14-04-93959 and 15-04-01744). This work was supported by the Canadian Institutes of Health Research for the “CIHR Team in Familial Risks of Breast Cancer” program, the Canadian Breast Cancer Research Alliance-grant #019511 and the Ministry of Economic Development, Innovation and Export Trade – grant # PSR-SIIRI-701. This work was partially supported by FISPI05/2275 and Mutua Madrileña Foundation (FMMA). We wish to thank Heather Thorne, Eveline Niedermayr, all the kConFab research nurses and staff, the heads and staff of the Family Cancer Clinics, and the Clinical Follow Up Study (which has received funding from the NHMRC, the National Breast Cancer Foundation, Cancer Australia, and the National Institute of Health (USA)) for their contributions to this resource, and the many families who contribute to kConFab. CNIO study is partially funded by the Spanish Ministry of Health PI16/00440 supported by FEDER funds, the Spanish Ministry of Economy and Competitiveness (MINECO) SAF2014-57680-R and the Spanish Research Network on Rare diseases (CIBERER) City of Hope Clinical Cancer Genomics Community Network and the Hereditary Cancer Research Registry, supported in part by the Breast Cancer Research Foundation, by Award Number RC4CA153828 (PI: J. Weitzel) from the National Cancer Institute and the Office of the Director, National Institutes of Health, and by the National Cancer Institute of the National Institutes of Health under Award Number R25CA171998 (PIs: K. Blazer and J. Weitzel). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health The study was supported by the Ligue Nationale Contre le Cancer; the Association “Le cancer du sein, parlons-en!” Award; the Canadian Institutes of Health Research for the “CIHR Team in Familial Risks of Breast Cancer” program and the French National Institute of Cancer (INCa). This study was supported by Barretos Cancer Hospital, FINEP - CT-INFRA (02/2010) and FAPESP (2013/24633-2). MSKCC is supported by grants from the Breast Cancer Research Foundation, the Robert and Kate Niehaus Clinical Cancer Genetics Initiative, the Andrew Sabin Research Fund. and the NIH/NCI Cancer Center Support Grant P30 CA008748. kConFab is supported by a grant from the National Breast Cancer Foundation, and previously by the National Health and Medical Research Council (NHMRC), the Queensland Cancer Fund, the Cancer Councils of New South Wales, Victoria, Tasmania and South Australia, and the Cancer Foundation of Western Australia; Amanda Spurdle is supported by an NHMRC Senior Research Fellowship. IOVCHBOCS is supported by Ministero della Salute and “5 × 1000” Istituto Oncologico Veneto grant. MAYO is supported by NIH grants CA116167, CA128978 and CA176785, an NCI Specialized Program of Research Excellence (SPORE) in Breast Cancer (CA116201), a grant from the Breast Cancer Research Foundation, and a generous gift from the David F. and Margaret T. Grohne Family Foundation. Beth Y. Karlan was supported by the American Cancer Society Early Detection Professorship (SIOP-06-258-06-COUN) and the National Center for Advancing Translational Sciences (NCATS), Grant UL1TR000124 Kevin Sweet, Caroline Craven, Julia Cooper, and Michelle O'Conor were instrumental in accrual of study participants, ascertainment of medical records and database management. Jewish General Hospital Weekend to End Breast Cancer, Quebec Ministry of Economic Development, Innovation and Export Trade MODSQUAD was supported by MH CZ - DRO (MMCI, 00209805) and by the project MEYS-NPS ILO1413, and by Charles University in Prague project UNCE204024 (MZ). This project was partially funded through a grant by the Israel cancer association and the funding for the Israeli Inherited breast cancer consortium Dr J Ngeow is supported by grants from National Medical Research Council of Singapore; Ministry of Health Health Services Research Grant Singapore and Lee Foundation Singapore The research of Drs. MH Greene, PL Mai, and JT Loud was supported by the Intramural Research Program of the US National Cancer Institute, NIH, and by support services contracts NO2-CP-11019-50 and N02-CP-65504 with Westat, Inc, Rockville, MD. Was supported by a grant RD12/0036/0006 and 15/00059 from ISCIII (Spain), partially supported by European Regional Development FEDER funds The HEBCS was financially supported by the Helsinki University Hospital Research Fund, Academy of Finland (266528), the Finnish Cancer Society and the Sigrid Juselius Foundation. This research has been supported by R01-CA08534 and R01-CA102776 to TRR._______ This research has been co-financed by the European Union (European Social Fund – ESF) and Greek national funds through the Operational Program “Education and Lifelong Learning” of the National Strategic Reference Framework (NSRF) - Research Funding Program of the General Secretariat for Research & Technology: SYN11_10_19 NBCA. Investing in knowledge society through the European Social Fund.___________________ This Breast Cancer Family Registry (BCFR) is supported by grant UM1 CA164920 from the USA National Cancer Institute. The content of this manuscript does not necessarily reflect the views or policies of the National Cancer Institute or any of the collaborating centers in the BCFR, nor does mention of trade names, commercial products, or organizations imply endorsement by the USA Government or the BCFR. KOHBRA is partially supported by a grant from the National R&D Program for Cancer Control, Ministry for Health, Welfare and Family Affairs, Republic of Korea (1020350 & 1420190). Associazione Italiana Ricerca sul Cancro (AIRC; IG2014 no.15547) to P. Radice; Funds from Italian citizens who allocated the 5 × 1000 share of their tax payment in support of the Fondazione IRCCS Istituto Nazionale Tumori, according to Italian laws (INT-Institutional strategic projects ‘5 × 1000′) to S Manoukian; Associazione Italiana per la Ricerca sul Cancro IG17734; Italian Ministry of University and Research, PRIN projects; Istituto Pasteur-Fondazione Cenci Bolognetti to G. Giannini; FiorGen Foundation for Pharmacogenomics to L. Papi; Funds from Italian citizens who allocated the 5 × 1000 share of their tax payment in support of the IRCCS AOU San Martino - IST according to Italian laws (institutional project) to L. Varesco; Associazione Italiana Ricerca sul Cancro (AIRC; IG2015 no.16732) to P. Peterlongo This work is funded by CONICET and Instituto Nacional del Cancer, Ministerio de Salud de la Nacion Argentina (1995/15) EMBRACE is supported by Cancer Research UK Grants C1287/A10118 and C1287/A11990. D. Gareth Evans and Fiona Lalloo are supported by an NIHR grant to the Biomedical Research Centre, Manchester. The Investigators at The Institute of Cancer Research and The Royal Marsden NHS Foundation Trust are supported by an NIHR grant to the Biomedical Research Centre at The Institute of Cancer Research and The Royal Marsden NHS Foundation Trust. Ros Eeles and Elizabeth Bancroft are supported by Cancer Research UK Grant C5047/A8385. Ros Eeles is also supported by NIHR support to the Biomedical Research Centre at The Institute of Cancer Research and The Royal Marsden NHS Foundation Trust The authors acknowledge support from The University of Kansas Cancer Center (P30 CA168524) and the Kansas Bioscience Authority Eminent Scholar Program. A.K.G. was funded by 5U01CA113916, R01CA140323, and by the Chancellors Distinguished Chair in Biomedical Sciences Professorship. The CIMBA data management and data analysis were supported by Cancer Research – UK grants C12292/A20861, C12292/A11174. ACA is a Cancer Research -UK Senior Cancer Research Fellow. GCT and ABS are NHMRC Research Fellows. iCOGS: the European Community's Seventh Framework Programme under grant agreement n◦ 223175 (HEALTH-F2-2009-223175) (COGS), Cancer Research UK (C1287/A10118, C1287/A 10710, C12292/A11174, C1281/A12014, C5047/A8384, C5047/A15007, C5047/A10692, C8197/A16565), the National Institutes of Health (CA128978) and Post-Cancer GWAS initiative (1U19 CA148537, 1U19 CA148065 and 1U19 CA148112 - the GAME-ON initiative), the Department of Defence (W81XWH-10-1-0341), the Canadian Institutes of Health Research (CIHR) for the CIHR Team in Familial Risks of Breast Cancer (CRN-87521), and the Ministry of Economic Development, Innovation and Export Trade (PSR-SIIRI-701), Komen Foundation for the Cure, the Breast Cancer Research Foundation, and the Ovarian Cancer Research Fund. The PERSPECTIVE project was supported by the Government of Canada through Genome Canada and the Canadian Institutes of Health Research, the Ministry of Economy, Science and Innovation through Genome Québec, and The Quebec Breast Cancer Foundation. The German Consortium of Hereditary Breast and Ovarian Cancer (GC-HBOC) is supported by the German Cancer Aid (grant no 110837), Rita K. Schmutzler. The ILUH group was supported by the Icelandic Association “Walking for Breast Cancer Research” and by the Landspitali University Hospital Research Fund. Ministry of Science, Technology and Innovation, Ministry of Higher Education (UM.C/HlR/MOHE/06) and Cancer Research Initiatives Foundation The DKFZ study was supported by the DKFZ and in part by the SKMCH & RC, Lahore, Pakistan and the Pontificia Universidad Javeriana, Bogota, Colombia. HRBCP is supported by The Hong Kong Hereditary Breast Cancer Family Registry and the Dr. Ellen Li Charitable Foundation, Hong Kong Drs. Greene, Mai and Loud were supported by funding from the Intramural Research Program, NCI. BRCA-gene mutations and breast cancer in South African women (BMBSA) was supported by grants from the Cancer Association of South Africa (CANSA) to Elizabeth J. van Rensburg SLN was partially supported by the Morris and Horowitz Families Endowed Professorship. This work was supported by the ITT (Istituto Toscano Tumori) grants 2011–2013. SWE-BRCA collaborators are supported by the Swedish Cancer Society
| Funders | Funder number |
|---|---|
| Autonomous Government of Catalonia | RD12/0036/008, ISCIIIRETIC RD06/0020/1051, PI10/00748, 2014SGR364 |
| BBMRI | 12-054, 184.021.007/CP46 |
| BMBSA | |
| Barretos Cancer Hospital | |
| CIBERER | |
| Cancer Councils of New South Wales | |
| Cancer Foundation of Western Australia | |
| Cancer Research Initiatives Foundation | |
| Department of Defence | W81XWH-10-1-0341 |
| Dutch Cancer Society | NKI1998-1854, NKI2004-3088, NKI2007-3756 |
| Entertainment Industry Fund National Women's Cancer Research Alliance | |
| European Regional Development FEDER | |
| FMMA | |
| Finnish Cancer Society | |
| Fiorgen Foundation for Pharmacogenomics | IG2015, 16732 |
| French National Institute of Cancer | |
| Genome Québec | |
| Helsinki University Hospital | |
| Hereditary Cancer Research Registry | |
| Hungarian Research Grants KTIA-OTKA | CK-80745, NKFIH/ OTKA K-112228 |
| Icelandic Association | |
| Instituto Nacional del Cancer | |
| Israeli Inherited breast cancer consortium | |
| MMCI | MEYS-NPS ILO1413, 00209805 |
| Malaysian Ministry of Science, Technology and Innovation | |
| Ministero della Salute and “5 × 1000” Istituto Oncologico Veneto | |
| Ministry of Economy, Science and Innovation | |
| Ministry of Health Health Services Research Grant Singapore and Lee Foundation | |
| Ministry of University and Research | |
| Morris and Horowitz Families Endowed | |
| NIH/NCI | P30-CA051008 |
| NRG Oncology Operations | U10 CA180868 |
| NRG SDMC | CA 37517, CA 27469, U10 CA180822 |
| National institute of Health | |
| National Medical Research Council of Singapore | |
| National R&D Program for Cancer Control, Ministry for Health, Welfare and Family Affairs, Republic of Korea | 1020350, 1420190 |
| National Strategic Reference Framework | SYN11_10_19 NBCA |
| Netherlands Organisation of Scientific Research | 2014-187, 110005, NWO 91109024 |
| Norwegian EEA Financial Mechanism Hu0115/NA/2008 | |
| Ohio State University Comprehensive Cancer Center | |
| Queensland Cancer Fund | |
| Robert and Kate Niehaus Clinical Cancer Genetics Initiative | |
| Russian Federation for Basic Research | 15-04-01744, 14-04-93959 |
| SKMCH & RC | |
| Sigrid Juselius Foundation | |
| Spanish Health Research Fund | |
| Spanish Ministry of Economy and Competitiveness | |
| Spanish Ministry of Health | PI16/00440 |
| Swing Fore the Cure | |
| US National Cancer Institute | |
| USA National Cancer Institute | |
| University of Kansas Cancer Center | 5U01CA113916, R01CA140323, P30 CA168524 |
| National Institutes of Health | 1U19 CA148537, CA176785, R25CA171998, CA116167, NO2-CP-11019-50, 1U19 CA148112, N02-CP-65504, 1U19 CA148065, CA128978 |
| American Cancer Society | SIOP-06-258-06-COUN |
| National Cancer Institute | CA116201, R01 CA142996, 1U01CA161032, CA125183 |
| Office of the Director | |
| Susan G. Komen for the Cure | |
| Breast Cancer Research Foundation | RC4CA153828 |
| Ovarian Cancer Research Fund | |
| ITT Corporation | |
| National Center for Advancing Translational Sciences | UL1TR000124 |
| National Institute on Handicapped Research | |
| Jess and Mildred Fisher Center for Familial Cancer Research | |
| Univerzita Karlova v Praze | UNCE204024 |
| Fundación Mutua Madrileña | |
| Georgetown University | |
| Dr. Ralph and Marian Falk Medical Research Trust | |
| German Cancer Research Center | |
| Genome Canada | |
| David F. and Margaret T. Grohne Family Foundation | |
| Ministère du Développement Économique, de l’Innovation et de l’Exportation | PSR-SIIRI-701 |
| College of Environmental Science and Forestry, State University of New York | |
| Andrew Sabin Family Foundation | |
| CNIB | |
| NIHR Biomedical Research Centre, Royal Marsden NHS Foundation Trust/Institute of Cancer Research | C5047/A8385 |
| Fondation du cancer du sein du Québec | |
| Rare Diseases Clinical Research Network | |
| Government of Canada | |
| Canadian Institutes of Health Research | 019511, CRN-87521 |
| Cancer Research UK | C5047/A10692, C5047/A8384, C1287/A11990, C1287/A 10710, C1287/A10118, C1281/A12014, C5047/A15007, C8197/A16565 |
| European Commission | |
| National Health and Medical Research Council | |
| National Breast Cancer Foundation | |
| Cancer Australia | |
| Cancer Association of South Africa | |
| Fundação de Amparo à Pesquisa do Estado de São Paulo | 2013/24633-2 |
| Academy of Finland | 266528 |
| Ministry of Higher Education | UM.C/HlR/MOHE/06, UM.C/HIR/MOHE/06 |
| Fundación Científica Asociación Española Contra el Cáncer | |
| Cancerfonden | |
| Consejo Nacional de Investigaciones Científicas y Técnicas | |
| Ministerio de Economía y Competitividad | SAF2014-57680-R |
| Ministério da Ciência, Tecnologia e Inovação | |
| Israel Cancer Association | |
| Istituto Toscano Tumori | |
| Ligue Contre le Cancer | |
| Landspítali Háskólasjúkrahús | |
| Lietuvos Mokslo Taryba | SEN-18/2015 |
| Instituto de Salud Carlos III | |
| Istituto Pasteur-Fondazione Cenci Bolognetti | |
| Financiadora de Estudos e Projetos | 02/2010 |
| European Social Fund | |
| Seventh Framework Programme | 223175 |
| Associazione Italiana per la Ricerca sul Cancro | IG2014, 15547, IG17734 |
| Deutsche Krebshilfe | 110837 |
| European Regional Development Fund | PI10/01422, PI13/00285, PI15/00854, PI16/00563, PIE13/00022 |
| Pontificia Universidad Javeriana | |
| Liga Portuguesa Contra o Cancro | |
| Institut Català de la Salut | 2014SGR338, 2009SGR290 |
| Istituto Nazionale Tumori IRCCS "Fondazione G. Pascale" | 5 × 1000′ |
| Ministerio de Defensa, Argentina |
Keywords
- BRCA1
- BRCA2
- breast cancer
- ethnicity
- geography
- mutation
- ovarian cancer
