| Title: |
Aggregation tests identify new gene associations with breast cancer in populations with diverse ancestry |
| Authors: |
Mueller, S.H.; Lai, A.G.; Valkovskaya, M.; Michailidou, K.; Bolla, M.K.; Wang, Q.; Dennis, J.; Lush, M.; Abu-Ful, Z.; Ahearn, T.U.; Andrulis, I.L.; Anton-Culver, H.; Antonenkova, N.N.; Arndt, V.; Aronson, K.J.; Augustinsson, A.; Baert, T.; Freeman, L.E.B.; Beckmann, M.W.; Behrens, S.; Benitez, J.; Bermisheva, M.; Blomqvist, C.; Bogdanova, N.V.; Bojesen, S.E.; Bonanni, B.; Brenner, H.; Brucker, S.Y.; Buys, S.S.; Castelao Fernández, José Esteban; Chan, T.L.; Chang-Claude, J.; Chanock, S.J.; Choi, J.-Y.; Chung, W.K.; Sahlberg, K.K.; Børresen-Dale, A.-L.; Ottestad, L.; Kåresen, R.; Schlichting, E.; Holmen, M.M.; Sauer, T.; Haakensen, V.; Engebråten, O.; Naume, B.; Fosså, A.; Kiserud, C.E.; Reinertsen, K.V.; Helland, Å.; Riis, M.; Geisler, J.; Grenaker Alnaes, G.I.; Colonna, S.V.; Cornelissen, S.; Couch, F.J.; Czene, K.; Daly, M.B.; Devilee, P.; Dörk, T.; Dossus, L.; Dwek, M.; Eccles, D.M.; Ekici, A.B.; Eliassen, A.H.; Engel, C.; Evans, D.G.; Fasching, P.A.; Fletcher, O.; Flyger, H.; Gago Dominguez, Manuela; Gao, Y.-T.; García-Closas, M.; García-Sáenz, J.A.; Genkinger, J.; Gentry-Maharaj, A.; Grassmann, F.; Guénel, P.; Gündert, M.; Haeberle, L.; Hahnen, E.; Haiman, C.A.; Håkansson, N.; Hall, P.; Harkness, E.F.; Harrington, P.A.; Hartikainen, J.M.; Hartman, M.; Hein, A.; Ho, W.-K.; Hooning, M.J.; Hoppe, R.; Hopper, J.L.; Houlston, R.S.; Howell, A.; Hunter, D.J.; Huo, D.; Marsh, D.; Scott, R.; Baxter, R.; Yip, D.; Carpenter, J.; Davis, A.; Pathmanathan, N.; Simpson, P.; Graham, D.; Sachchithananthan, M.; Ito, H.; Iwasaki, M.; Jakubowska, A.; Janni, W.; John, E.M.; Jones, M.E.; Jung, A.; Kaaks, R.; Kang, D.; Khusnutdinova, E.K.; Kim, S.-W.; Kitahara, C.M.; Koutros, S.; Kraft, P.; Kristensen, V.N.; Kubelka-Sabit, K.; Kurian, A.W.; Kwong, A.; Lacey, J.V.; Lambrechts, D.; Le Marchand, L.; Li, J.; Linet, M.; Lo, W.-Y.; Long, J.; Lophatananon, A.; Mannermaa, A.; Manoochehri, M.; Margolin, S.; Matsuo, K.; Mavroudis, D.; Menon, U.; Muir, K.; Murphy, R.A.; Nevanlinna, H.; Newman, W.G.; Niederacher, D.; O'Brien, K.M.; Obi, N.; Offit, K.; Olopade, O.I.; Olshan, A.F.; Olsson, H.; Park, S.K.; Patel, A.V.; Patel, A.; Perou, C.M.; Peto, J.; Pharoah, P.D.P.; Plaseska-Karanfilska, D.; Presneau, N.; Rack, B.; Radice, P.; Ramachandran, D.; Rashid, M.U.; Rennert, G.; Romero, A.; Ruddy, K.J.; Ruebner, M.; Saloustros, E.; Sandler, D.P.; Sawyer, E.J.; Schmidt, M.K.; Schmutzler, R.K.; Schneider, M.O.; Scott, C.; Shah, M.; Sharma, P.; Shen, C.-Y.; Shu, X.-O.; Simard, J.; Surowy, H.; Tamimi, R.M.; Tapper, W.J.; Taylor, J.A.; Teo, S.H.; Teras, L.R.; Toland, A.E.; Tollenaar, R.A.E.M.; Torres, D.; Torres-Mejía, G.; Troester, M.A.; Truong, T.; Vachon, C.M.; Vijai, J.; Weinberg, C.R.; Wendt, C.; Winqvist, R.; Wolk, A.; Wu, A.H.; Yamaji, T.; Yang, X.R.; Yu, J.-C.; Zheng, W.; Ziogas, A.; Ziv, E.; Dunning, A.M.; Easton, D.F.; Hemingway, H.; Hamann, U.; Kuchenbaecker, K.B. |
| Publication Year: |
2023 |
| Subject Terms: |
Humans; Female; Breast Neoplasms; Genetic Predisposition to Disease; Black People; Genetic Testing; Genome-Wide Association Study; Polymorphism; Single Nucleotide; Formins; AS Vigo; CHUVI; AS Santiago; IDIS |
| Description: |
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. ; This result is part of a project that has received funding from the European Research Council (ERC) under the European Union's Horizon 2020 research and innovation programme (Grant agreement No. 948561). BCAC is ... |
| Document Type: |
article in journal/newspaper |
| Language: |
English |
| Relation: |
European Research Council (ERC) under the European Union [948561]; European Union's Horizon 2020 Research and Innovation Programme [634935, 633,784]; Government of Canada through Genome Canada; Canadian Institutes of Health Research; Ministere de l'Economie et de l'Innovation du Quebec through Genome Quebec; Quebec Breast Cancer Foundation; EU; National Cancer Institute Intramural Research Program, National Institutes of Health - NIH [U19 CA148065]; Cancer UK [C1287/A16563]; Ministere de l'Economie, Science et Innovation du Quebec through Genome Quebec [PSRSIIRI-701]; European Community's Seventh Framework Programme [223,175 (HEALTH-F2-2009-223,175)]; Cancer Research UK [14,136, C570/A16491, C8221/A19170]; National Institutes of Health [CA128978, 1U19 CA148537, 1U19 CA148065]; Department of Defence [W81XWH-10-1-0341]; Canadian Institutes of Health Research (CIHR); Komen Foundation for the Cure; Breast Cancer Research Foundation; Ovarian Cancer Research Fund; European Union Horizon 2020 research and innovation program BRIDGES [634,935]; Wellcome Trust [v203477/Z/16/Z]; Dutch Cancer Society [RUL 1997-1505]; National Health and Medical Research Council of Australia; Cancer Institute NSW; National Breast Cancer Foundation - Breast Cancer Research Trust, UK; NIHR Manchester Biomedical Research Centre [IS-BRC-1215-20,007]; Allan Turing Institute under the EPSRC [EP/N510129/1]; intramural research program of the National Institutes of Health; National Cancer Institute [P50 CA058223, U54 CA156733, U01 CA179715]; National Institute of Environmental Health Sciences [Z01-ES049030]; ELAN-Fond of the University Hospital of Erlangen - Cancer Research UK; Breast Cancer Now and acknowledges NHS; National Cancer Research Network (NCRN) [UM1 CA164920]; Breast Cancer Research Foundation (BCRF) - Accion Estrategica de Salud del Instituto de Salud Carlos III [FIS PI12/02125/Cofinanciado]; FEDER PI17/00918/Cofinanciado FEDER; Accion Estrategica de Salud del Instituto de Salud Carlos III FIS Intrasalud [PI13/01136]; Programa Grupos Emergentes; Instituto de Investigacion Biomedica Galicia Sur; Instituto de Salud Carlos III, Spain [10CSA012E]; 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 [EC11-192]; Fomento de la Investigacion Clinica Independiente, Ministerio de Sanidad, Servicios Sociales e Igualdad, Spain; Ministerio de Economia y Competitividad, Xunta de Galicia, Spain; Dietmar-Hopp Foundation; Helmholtz Society; German Cancer Research Center (DKFZ) - Consejo Nacional de Ciencia y Tecnologia (CONACyT) [SALUD2002-C01-7462]; Canadian Cancer Society [313,404]; University of Crete; Fondation de France; Institut National du Cancer (INCa); Ligue Nationale contre le Cancer, Agence Nationale de Securite Sanitaire, de l'Alimentation, de l'Environnement et du Travail (ANSES); Agence Nationale de la Recherche (ANR); Chief Physician Johan Boserup and Lise Boserup Fund; Danish Medical Research Council; Herlev and Gentofte Hospital; German Cancer Research Center (DKFZ), Heidelberg, Germany; Alexander von Humboldt Foundation; American Cancer Society funds the creation, maintenance; California Teachers Study (CTS); National Cancer Institute of the National Institutes of Health [R01 CA89085, P50 CA125183, D43 TW009112, SAC110026]; California Department of Public Health; Centers for Disease Control and Prevention's National Program of Cancer Registries [5NU58DP006344]; National Cancer Institute's Surveillance, Epidemiology and End Results Program [HHSN261201800032I, HHSN261201800015I, HHSN261201800009I]; National Institutes of Health - Against Breast Cancer Registered Charity [1121258]; NCRN; European Commission (DG-SANCO); International Agency for Research on Cancer; Ligue Contre le Cancer; Institut Gustave Roussy; Mutuelle Generale de l'Education Nationale; Institut National de la Sante et de la Recherche Medicale (INSERM) (France); German Cancer Aid [110837]; German Cancer Research Center (DKFZ), Federal Ministry of Education and Research (BMBF) (Germany); Hellenic Health Foundation; Stavros Niarchos Foundation (Greece); Associazione Italiana per la Ricerca sul Cancro-AIRC-Italy; National Research Council (Italy); Dutch Ministry of Public Health, Welfare and Sports (VWS), Netherlands Cancer Registry (NKR), LK Research Funds; Dutch Prevention Funds; Dutch ZON (Zorg Onderzoek Nederland); World Cancer Research Fund (WCRF), Statistics Netherlands (The Netherlands); Health Research Fund (FIS) [PI13/00061, PI13/01162]; Basque Country, Murcia and Navarra, ISCIII RETIC; Medical Research Council [1,000,143, MR/M012190/1]; Baden Wurttemberg Ministry of Science, Research and Arts; German Cancer Aid (Deutsche Krebshilfe); NIHR [PGfAR 0707-10,031]; GC-HBOC (German Consortium of Hereditary Breast and Ovarian Cancer); European Regional Development Fund and Free State of Saxony, Germany (LIFE-Leipzig Research Centre for Civilization Diseases) [713-241,202, 14,505/2470, 14,575/2470]; Federal Ministry of Education and Research (BMBF) Germany [01KH0402]; Robert Bosch Foundation, Stuttgart, Deutsches Krebsforschungszentrum (DKFZ), Heidelberg; Institute for Prevention and Occupational Medicine of the German Social Accident Insurance; Evangelische Kliniken Bonn gGmbH, Johanniter Krankenhaus, Bonn, Germany; Deutsche Krebshilfe e. V. [70492]; German Cancer Research Center (DKFZ); Claudia von Schilling Foundation for Breast Cancer Research; Lower Saxonian Cancer Society; Rudolf Bartling Foundation; Helsinki University Hospital Research Fund; Sigrid Juselius Foundation; Cancer Foundation Finland; MEXT Kakenhi [170150181, 26,253,041]; Ministry of Education, Science, Sports, Culture and Technology of Japan; Ministry Health, Labour and Welfare of Japan; Health and Labour Sciences Research Grants for Research on Applying Health Technology from Ministry Health, Labour and Welfare of Japan; National Cancer Center Research and Development Fund [15ck0106177h0001, 20ck0106553]; Japan Agency for Medical Research and development, AMED; Cancer Bio Bank Aichi; Friends of Hannover Medical School; German Federal Ministry of Research and Education [RUS08/017, 17-44-020,498, 17-29-06,014]; Russian Foundation for Basic Research [18-29-09,129, collections.007-030,164/2]; Government of Russian Federation [2020-220-08-2197]; Ministry of Science and Higher Education of Russian Federation [AAAA-A16-116,020,350,032-1]; Stockholm County Council; Karolinska Institutet; Swedish Cancer Society; Gustav V Jubilee foundation; Bert von Kantzows foundation; Marit and Hans Rausings Initiative Against Breast Cancer; special Government Funding (VTR) of Kuopio University Hospital; Cancer Fund of North Savo; Finnish Cancer Organizations; University of Eastern Finland; Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI); National R&D Program for Cancer Control, Ministry of Health & Welfare, Republic of Korea [HI16C1127, 1,020,350, 1,420,190]; Stichting tegen Kanker; FWO - Research Centre for Genetic Engineering and Biotechnology Georgi D. Efremov, MASA; Deutsche Krebshilfe e.V. [70-2892-BR I, 106,332, 108,253, 108,419, 110,826, 110828]; Hamburg Cancer Society; Italian Association for Cancer Research (AIRC); NIH [CA58860, CA92044]; NIH Specialized Program of Research Excellence (SPORE) in Breast Cancer [P50CA116201]; Swedish Research Council [VR 2017-00,644]; Berta Kamprad Foundation; Robert and Kate Niehaus Clinical Cancer Genetics Initiative - Wellcome Trust [v203477/Z/16/Z]; Malaysian Ministry of Higher Education [RP046B-15HTM]; Cancer Research Malaysia; Yayasan Sime Darby LPGA Tournament; K.G. Jebsen Centre for Breast Cancer Research; Research Council of Norway grant [193,387/V50, 193,387/H10, 39,346]; Norwegian Cancer Society; USA National Cancer Institute of the National Institutes of Health - Komen Foundation; North Carolina University Cancer Research Fund; National Cancer Center Research and Development Fund (Japan); Biobanking and Biomolecular Resources Research Infrastructure (BBMRI-NL) [CP16]; Intramural Research Funds of the National Cancer Institute, Department of Health and Human Services, USA; Intramural Research Program of the National Institutes of Health, NCI, Division of Cancer Epidemiology and Genetics; Intramural Research Program of the Division of Cancer Epidemiology and Genetics; Division of Cancer Prevention, National Cancer Institute, National Institutes of Health - Cancer Research UK [C1275/A11699, C1275/C22524, C1275/A19187, C1275/A15956]; Breast Cancer Campaign [2010PR62, 2013PR044]; Genetic Associations and Mechanisms in Oncology (GAME-ON) Network [U19 CA148065]; Sheffield Experimental Cancer Medicine Centre - Cancer Research UK [C490/A10124, C490/A16561]; UK National Institute for Health Research Biomedical Research Centre at the University of Cambridge; NHS in the East of England through the Clinical Academic Reserve; BRL (Basic Research Laboratory) program through the National Research Foundation of Korea - Ministry of Education, Science and Technology [2012-0,000,347]; National Research Foundation Singapore, NUS start-up Grant; National University Cancer Institute Singapore (NCIS) Centre Grant; Breast Cancer Prevention Programme, Asian Breast Cancer Research Fund; NMRC Clinician Scientist Award (SI Category) - Ministry of Health, Singapore; National University Health System, Singapore; Intramural Research Program of the NIH, National Institute of Environmental Health Sciences [Z01-ES044005, Z01-ES102245]; Susan G. Komen for the Cure [FAS0703856]; DKFZ - Swedish Cancer Foundation; Specialized Program of Research Excellence (SPORE) in Breast Cancer [CA116201]; David F. and Margaret T. Grohne Family Foundation; Taiwan Biobank project of the Institute of Biomedical Sciences, Academia Sinica, Taiwan; Lon V Smith Foundation [LVS39420]; Breast Cancer Now; Institute of Cancer Research (ICR), London; NHS; NIHR Biomedical Research Centre - Eve Appeal (The Oak Foundation); National Institute for Health Research University College London Hospitals Biomedical Research Centre; MRC core funding [MC_UU_00004/01]; Dr. Ralph and Marian Falk Medical Research Trust; Avon Foundation for Women; National Cancer Institute [K24CA169004] Funding Source: NIH RePORTER; Cancer Research UK [14136, 16563, 10118] Funding Source: researchfish; Medical Research Council [HDR-9003, MR/M012190/1, G1000143] Funding Source: researchfish; Wellcome Trust [203477/Z/16/Z] Funding Source: researchfish; European Research Council (ERC) [948561] Funding Source: European Research Council (ERC); https://doi.org/10.1186/s13073-022-01152-5; Mueller SH, Lai AG, Valkovskaya M, Michailidou K, Bolla MK, Wang Q, et al. Aggregation tests identify new gene associations with breast cancer in populations with diverse ancestry. Genome Medicine. 2023;15(1).; https://portalcientifico.sergas.gal//documentos/63df0af06fdec82c4e7e0339; https://hdl.handle.net/20.500.11940/21033; 63df0af06fdec82c4e7e0339 |
| DOI: |
10.1186/s13073-022-01152-5 |
| Availability: |
https://hdl.handle.net/20.500.11940/21033; https://portalcientifico.sergas.gal//documentos/63df0af06fdec82c4e7e0339; https://doi.org/10.1186/s13073-022-01152-5 |
| Rights: |
Attribution 4.0 International (CC BY 4.0) ; http://creativecommons.org/licenses/by/4.0/ ; openAccess |
| Accession Number: |
edsbas.DB3316BF |
| Database: |
BASE |