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Aggregation tests identify new gene associations with breast cancer in populations with diverse ancestry.
Genome Med. 15:7 (2023)
BACKGROUND: Low-frequency variants play an important role in breast cancer (BC) susceptibility. Gene-based methods can increase power by combining multiple variants in the same gene and help identify target genes. METHODS: We evaluated the potential of gene-based aggregation in the Breast Cancer Association Consortium cohorts including 83,471 cases and 59,199 controls. Low-frequency variants were aggregated for individual genes' coding and regulatory regions. Association results in European ancestry samples were compared to single-marker association results in the same cohort. Gene-based associations were also combined in meta-analysis across individuals with European, Asian, African, and Latin American and Hispanic ancestry. RESULTS: In European ancestry samples, 14 genes were significantly associated (q < 0.05) with BC. Of those, two genes, FMNL3 (P = 6.11 × 10-6) and AC058822.1 (P = 1.47 × 10-4), represent new associations. High FMNL3 expression has previously been linked to poor prognosis in several other cancers. Meta-analysis of samples with diverse ancestry discovered further associations including established candidate genes ESR1 and CBLB. Furthermore, literature review and database query found further support for a biologically plausible link with cancer for genes CBLB, FMNL3, FGFR2, LSP1, MAP3K1, and SRGAP2C. CONCLUSIONS: Using extended gene-based aggregation tests including coding and regulatory variation, we report identification of plausible target genes for previously identified single-marker associations with BC as well as the discovery of novel genes implicated in BC development. Including multi ancestral cohorts in this study enabled the identification of otherwise missed disease associations as ESR1 (P = 1.31 × 10-5), demonstrating the importance of diversifying study cohorts.
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Publication type
Article: Journal article
Document type
Scientific Article
Keywords
Breast Cancer Susceptibility ; Diverse Ancestry ; Gene Regulation ; Genome-wide Association Study ; Rare Variants; Genome-wide Association; Ligase Cbl-b; Functional Annotation; Metastasis; Risk; Heritability; Identification; Phenotype; Variants; Pathways
ISSN (print) / ISBN
1756-994X
e-ISSN
1756-994X
Journal
Genome Medicine
Quellenangaben
Volume: 15,
Issue: 1,
Article Number: 7
Publisher
BioMed Central
Publishing Place
Campus, 4 Crinan St, London N1 9xw, England
Non-patent literature
Publications
Reviewing status
Peer reviewed
Institute(s)
Institute of Diabetes Research Type 1 (IDF)
Grants
European Research Council (ERC)
Avon Foundation for Women
Dr. Ralph and Marian Falk Medical Research Trust
MRC core funding
National Institute for Health Research University College London Hospitals Biomedical Research Centre
NIHR Biomedical Research Centre - Eve Appeal (The Oak Foundation)
NHS
Institute of Cancer Research (ICR), London
Breast Cancer Now
Lon V Smith Foundation
Taiwan Biobank project of the Institute of Biomedical Sciences, Academia Sinica, Taiwan
David F. and Margaret T. Grohne Family Foundation
Specialized Program of Research Excellence (SPORE) in Breast Cancer
DKFZ - Swedish Cancer Foundation
Susan G. Komen for the Cure
Intramural Research Program of the NIH, National Institute of Environmental Health Sciences
National University Health System, Singapore
NMRC Clinician Scientist Award (SI Category) - Ministry of Health, Singapore
Breast Cancer Prevention Programme, Asian Breast Cancer Research Fund
National University Cancer Institute Singapore (NCIS) Centre Grant
National Research Foundation Singapore, NUS start-up Grant
BRL (Basic Research Laboratory) program through the National Research Foundation of Korea - Ministry of Education, Science and Technology
NHS in the East of England through the Clinical Academic Reserve
UK National Institute for Health Research Biomedical Research Centre at the University of Cambridge
Sheffield Experimental Cancer Medicine Centre - Cancer Research UK
Genetic Associations and Mechanisms in Oncology (GAME-ON) Network
Breast Cancer Campaign
Division of Cancer Prevention, National Cancer Institute, National Institutes of Health - Cancer Research UK
Intramural Research Program of the Division of Cancer Epidemiology and Genetics
Intramural Research Program of the National Institutes of Health, NCI, Division of Cancer Epidemiology and Genetics
Intramural Research Funds of the National Cancer Institute, Department of Health and Human Services, USA
Biobanking and Biomolecular Resources Research Infrastructure (BBMRI-NL)
National Cancer Center Research and Development Fund (Japan)
North Carolina University Cancer Research Fund
USA National Cancer Institute of the National Institutes of Health - Komen Foundation
Norwegian Cancer Society
Research Council of Norway grant
K.G. Jebsen Centre for Breast Cancer Research
Yayasan Sime Darby LPGA Tournament
Cancer Research Malaysia
Malaysian Ministry of Higher Education
Robert and Kate Niehaus Clinical Cancer Genetics Initiative - Wellcome Trust
Berta Kamprad Foundation
Swedish Research Council
NIH Specialized Program of Research Excellence (SPORE) in Breast Cancer
NIH
Italian Association for Cancer Research (AIRC)
Hamburg Cancer Society
Deutsche Krebshilfe e.V.
FWO - Research Centre for Genetic Engineering and Biotechnology "Georgi D. Efremov", MASA
Stichting tegen Kanker"
National R&D Program for Cancer Control, Ministry of Health & Welfare, Republic of Korea
Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI)
University of Eastern Finland
Finnish Cancer Organizations
Cancer Fund of North Savo
special Government Funding (VTR) of Kuopio University Hospital
Marit and Hans Rausings Initiative Against Breast Cancer
Bert von Kantzows foundation
Gustav V Jubilee foundation
Swedish Cancer Society
Karolinska Institutet
Stockholm County Council
Ministry of Science and Higher Education of Russian Federation
Government of Russian Federation
Russian Foundation for Basic Research
German Federal Ministry of Research and Education
Friends of Hannover Medical School
Cancer Bio Bank Aichi
Japan Agency for Medical Research and development, AMED
National Cancer Center Research and Development Fund
Health and Labour Sciences Research Grants for Research on Applying Health Technology from Ministry Health, Labour and Welfare of Japan
Ministry Health, Labour and Welfare of Japan
Ministry of Education, Science, Sports, Culture and Technology of Japan
MEXT Kakenhi
Cancer Foundation Finland
Sigrid Juselius Foundation
Helsinki University Hospital Research Fund
Rudolf Bartling Foundation
Lower Saxonian Cancer Society
Claudia von Schilling Foundation for Breast Cancer Research
German Cancer Research Center (DKFZ)
Deutsche Krebshilfe e. V.
Evangelische Kliniken Bonn gGmbH, Johanniter Krankenhaus, Bonn, Germany
Institute for Prevention and Occupational Medicine of the German Social Accident Insurance
Robert Bosch Foundation, Stuttgart, Deutsches Krebsforschungszentrum (DKFZ), Heidelberg
Federal Ministry of Education and Research (BMBF) Germany
European Regional Development Fund and Free State of Saxony, Germany (LIFE-Leipzig Research Centre for Civilization Diseases)
GC-HBOC (German Consortium of Hereditary Breast and Ovarian Cancer)
NIHR
German Cancer Aid (Deutsche Krebshilfe)
Baden Wurttemberg Ministry of Science, Research and Arts
Medical Research Council
Basque Country, Murcia and Navarra, ISCIII RETIC
Health Research Fund (FIS)
World Cancer Research Fund (WCRF), Statistics Netherlands (The Netherlands)
Dutch ZON (Zorg Onderzoek Nederland)
Dutch Prevention Funds
Dutch Ministry of Public Health, Welfare and Sports (VWS), Netherlands Cancer Registry (NKR), LK Research Funds
National Research Council (Italy)
Associazione Italiana per la Ricerca sul Cancro-AIRC-Italy
Stavros Niarchos Foundation (Greece)
Hellenic Health Foundation
German Cancer Research Center (DKFZ), Federal Ministry of Education and Research (BMBF) (Germany)
German Cancer Aid
Institut National de la Sante et de la Recherche Medicale (INSERM) (France)
Mutuelle Generale de l'Education Nationale
Institut Gustave Roussy
Ligue Contre le Cancer
International Agency for Research on Cancer
European Commission (DG-SANCO)
NCRN
National Institutes of Health - Against Breast Cancer Registered Charity
National Cancer Institute's Surveillance, Epidemiology and End Results Program
Centers for Disease Control and Prevention's National Program of Cancer Registries
California Department of Public Health
National Cancer Institute of the National Institutes of Health
California Teachers Study (CTS)
American Cancer Society funds the creation, maintenance
Alexander von Humboldt Foundation
German Cancer Research Center (DKFZ), Heidelberg, Germany
Herlev and Gentofte Hospital
Danish Medical Research Council
Chief Physician Johan Boserup and Lise Boserup Fund
Agence Nationale de la Recherche (ANR)
Ligue Nationale contre le Cancer, Agence Nationale de Securite Sanitaire, de l'Alimentation, de l'Environnement et du Travail (ANSES)
Institut National du Cancer (INCa)
Fondation de France
University of Crete
Canadian Cancer Society
German Cancer Research Center (DKFZ) - Consejo Nacional de Ciencia y Tecnologia (CONACyT)
Helmholtz Society
Dietmar-Hopp Foundation
Ministerio de Economia y Competitividad, Xunta de Galicia, Spain
Fomento de la Investigacion Clinica Independiente, Ministerio de Sanidad, Servicios Sociales e Igualdad, Spain
Conselleria de Industria Programa Sectorial de Investigacion Aplicada, PEME I + D e I + D Suma del Plan Gallego de Investigacion, Desarrollo e Innovacion Tecnologica de la Conselleria de Industria de la Xunta de Galicia, Spain
Instituto de Salud Carlos III, Spain
Instituto de Investigacion Biomedica Galicia Sur
Programa Grupos Emergentes
Accion Estrategica de Salud del Instituto de Salud Carlos III FIS Intrasalud
FEDER PI17/00918/Cofinanciado FEDER
Breast Cancer Research Foundation (BCRF) - Accion Estrategica de Salud del Instituto de Salud Carlos III
National Cancer Research Network (NCRN)
Breast Cancer Now and acknowledges NHS
ELAN-Fond of the University Hospital of Erlangen - Cancer Research UK
National Institute of Environmental Health Sciences
National Cancer Institute
intramural research program of the National Institutes of Health
Allan Turing Institute under the EPSRC
NIHR Manchester Biomedical Research Centre
National Breast Cancer Foundation - Breast Cancer Research Trust, UK
Cancer Institute NSW
National Health and Medical Research Council of Australia
Dutch Cancer Society
Wellcome Trust
European Union Horizon 2020 research and innovation program BRIDGES
Ovarian Cancer Research Fund
Breast Cancer Research Foundation
Komen Foundation for the Cure
Canadian Institutes of Health Research (CIHR)
Department of Defence
National Institutes of Health
Cancer Research UK
European Community's Seventh Framework Programme
Ministere de l'Economie, Science et Innovation du Quebec through Genome Quebec
Cancer UK
National Cancer Institute Intramural Research Program, National Institutes of Health - NIH
EU
Quebec Breast Cancer Foundation
Ministere de l'Economie et de l'Innovation du Quebec through Genome Quebec
Canadian Institutes of Health Research
Government of Canada through Genome Canada
European Union's Horizon 2020 Research and Innovation Programme
European Research Council (ERC) under the European Union
Avon Foundation for Women
Dr. Ralph and Marian Falk Medical Research Trust
MRC core funding
National Institute for Health Research University College London Hospitals Biomedical Research Centre
NIHR Biomedical Research Centre - Eve Appeal (The Oak Foundation)
NHS
Institute of Cancer Research (ICR), London
Breast Cancer Now
Lon V Smith Foundation
Taiwan Biobank project of the Institute of Biomedical Sciences, Academia Sinica, Taiwan
David F. and Margaret T. Grohne Family Foundation
Specialized Program of Research Excellence (SPORE) in Breast Cancer
DKFZ - Swedish Cancer Foundation
Susan G. Komen for the Cure
Intramural Research Program of the NIH, National Institute of Environmental Health Sciences
National University Health System, Singapore
NMRC Clinician Scientist Award (SI Category) - Ministry of Health, Singapore
Breast Cancer Prevention Programme, Asian Breast Cancer Research Fund
National University Cancer Institute Singapore (NCIS) Centre Grant
National Research Foundation Singapore, NUS start-up Grant
BRL (Basic Research Laboratory) program through the National Research Foundation of Korea - Ministry of Education, Science and Technology
NHS in the East of England through the Clinical Academic Reserve
UK National Institute for Health Research Biomedical Research Centre at the University of Cambridge
Sheffield Experimental Cancer Medicine Centre - Cancer Research UK
Genetic Associations and Mechanisms in Oncology (GAME-ON) Network
Breast Cancer Campaign
Division of Cancer Prevention, National Cancer Institute, National Institutes of Health - Cancer Research UK
Intramural Research Program of the Division of Cancer Epidemiology and Genetics
Intramural Research Program of the National Institutes of Health, NCI, Division of Cancer Epidemiology and Genetics
Intramural Research Funds of the National Cancer Institute, Department of Health and Human Services, USA
Biobanking and Biomolecular Resources Research Infrastructure (BBMRI-NL)
National Cancer Center Research and Development Fund (Japan)
North Carolina University Cancer Research Fund
USA National Cancer Institute of the National Institutes of Health - Komen Foundation
Norwegian Cancer Society
Research Council of Norway grant
K.G. Jebsen Centre for Breast Cancer Research
Yayasan Sime Darby LPGA Tournament
Cancer Research Malaysia
Malaysian Ministry of Higher Education
Robert and Kate Niehaus Clinical Cancer Genetics Initiative - Wellcome Trust
Berta Kamprad Foundation
Swedish Research Council
NIH Specialized Program of Research Excellence (SPORE) in Breast Cancer
NIH
Italian Association for Cancer Research (AIRC)
Hamburg Cancer Society
Deutsche Krebshilfe e.V.
FWO - Research Centre for Genetic Engineering and Biotechnology "Georgi D. Efremov", MASA
Stichting tegen Kanker"
National R&D Program for Cancer Control, Ministry of Health & Welfare, Republic of Korea
Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI)
University of Eastern Finland
Finnish Cancer Organizations
Cancer Fund of North Savo
special Government Funding (VTR) of Kuopio University Hospital
Marit and Hans Rausings Initiative Against Breast Cancer
Bert von Kantzows foundation
Gustav V Jubilee foundation
Swedish Cancer Society
Karolinska Institutet
Stockholm County Council
Ministry of Science and Higher Education of Russian Federation
Government of Russian Federation
Russian Foundation for Basic Research
German Federal Ministry of Research and Education
Friends of Hannover Medical School
Cancer Bio Bank Aichi
Japan Agency for Medical Research and development, AMED
National Cancer Center Research and Development Fund
Health and Labour Sciences Research Grants for Research on Applying Health Technology from Ministry Health, Labour and Welfare of Japan
Ministry Health, Labour and Welfare of Japan
Ministry of Education, Science, Sports, Culture and Technology of Japan
MEXT Kakenhi
Cancer Foundation Finland
Sigrid Juselius Foundation
Helsinki University Hospital Research Fund
Rudolf Bartling Foundation
Lower Saxonian Cancer Society
Claudia von Schilling Foundation for Breast Cancer Research
German Cancer Research Center (DKFZ)
Deutsche Krebshilfe e. V.
Evangelische Kliniken Bonn gGmbH, Johanniter Krankenhaus, Bonn, Germany
Institute for Prevention and Occupational Medicine of the German Social Accident Insurance
Robert Bosch Foundation, Stuttgart, Deutsches Krebsforschungszentrum (DKFZ), Heidelberg
Federal Ministry of Education and Research (BMBF) Germany
European Regional Development Fund and Free State of Saxony, Germany (LIFE-Leipzig Research Centre for Civilization Diseases)
GC-HBOC (German Consortium of Hereditary Breast and Ovarian Cancer)
NIHR
German Cancer Aid (Deutsche Krebshilfe)
Baden Wurttemberg Ministry of Science, Research and Arts
Medical Research Council
Basque Country, Murcia and Navarra, ISCIII RETIC
Health Research Fund (FIS)
World Cancer Research Fund (WCRF), Statistics Netherlands (The Netherlands)
Dutch ZON (Zorg Onderzoek Nederland)
Dutch Prevention Funds
Dutch Ministry of Public Health, Welfare and Sports (VWS), Netherlands Cancer Registry (NKR), LK Research Funds
National Research Council (Italy)
Associazione Italiana per la Ricerca sul Cancro-AIRC-Italy
Stavros Niarchos Foundation (Greece)
Hellenic Health Foundation
German Cancer Research Center (DKFZ), Federal Ministry of Education and Research (BMBF) (Germany)
German Cancer Aid
Institut National de la Sante et de la Recherche Medicale (INSERM) (France)
Mutuelle Generale de l'Education Nationale
Institut Gustave Roussy
Ligue Contre le Cancer
International Agency for Research on Cancer
European Commission (DG-SANCO)
NCRN
National Institutes of Health - Against Breast Cancer Registered Charity
National Cancer Institute's Surveillance, Epidemiology and End Results Program
Centers for Disease Control and Prevention's National Program of Cancer Registries
California Department of Public Health
National Cancer Institute of the National Institutes of Health
California Teachers Study (CTS)
American Cancer Society funds the creation, maintenance
Alexander von Humboldt Foundation
German Cancer Research Center (DKFZ), Heidelberg, Germany
Herlev and Gentofte Hospital
Danish Medical Research Council
Chief Physician Johan Boserup and Lise Boserup Fund
Agence Nationale de la Recherche (ANR)
Ligue Nationale contre le Cancer, Agence Nationale de Securite Sanitaire, de l'Alimentation, de l'Environnement et du Travail (ANSES)
Institut National du Cancer (INCa)
Fondation de France
University of Crete
Canadian Cancer Society
German Cancer Research Center (DKFZ) - Consejo Nacional de Ciencia y Tecnologia (CONACyT)
Helmholtz Society
Dietmar-Hopp Foundation
Ministerio de Economia y Competitividad, Xunta de Galicia, Spain
Fomento de la Investigacion Clinica Independiente, Ministerio de Sanidad, Servicios Sociales e Igualdad, Spain
Conselleria de Industria Programa Sectorial de Investigacion Aplicada, PEME I + D e I + D Suma del Plan Gallego de Investigacion, Desarrollo e Innovacion Tecnologica de la Conselleria de Industria de la Xunta de Galicia, Spain
Instituto de Salud Carlos III, Spain
Instituto de Investigacion Biomedica Galicia Sur
Programa Grupos Emergentes
Accion Estrategica de Salud del Instituto de Salud Carlos III FIS Intrasalud
FEDER PI17/00918/Cofinanciado FEDER
Breast Cancer Research Foundation (BCRF) - Accion Estrategica de Salud del Instituto de Salud Carlos III
National Cancer Research Network (NCRN)
Breast Cancer Now and acknowledges NHS
ELAN-Fond of the University Hospital of Erlangen - Cancer Research UK
National Institute of Environmental Health Sciences
National Cancer Institute
intramural research program of the National Institutes of Health
Allan Turing Institute under the EPSRC
NIHR Manchester Biomedical Research Centre
National Breast Cancer Foundation - Breast Cancer Research Trust, UK
Cancer Institute NSW
National Health and Medical Research Council of Australia
Dutch Cancer Society
Wellcome Trust
European Union Horizon 2020 research and innovation program BRIDGES
Ovarian Cancer Research Fund
Breast Cancer Research Foundation
Komen Foundation for the Cure
Canadian Institutes of Health Research (CIHR)
Department of Defence
National Institutes of Health
Cancer Research UK
European Community's Seventh Framework Programme
Ministere de l'Economie, Science et Innovation du Quebec through Genome Quebec
Cancer UK
National Cancer Institute Intramural Research Program, National Institutes of Health - NIH
EU
Quebec Breast Cancer Foundation
Ministere de l'Economie et de l'Innovation du Quebec through Genome Quebec
Canadian Institutes of Health Research
Government of Canada through Genome Canada
European Union's Horizon 2020 Research and Innovation Programme
European Research Council (ERC) under the European Union