Genome-wide association study of germline variants and breast cancer-specific mortality |
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Author: | Escala-Garcia, Maria1; Guo, Qi2; Doerk, Thilo3; |
Organizations: |
1Antoni van Leeuwenhoek Hosp, Netherlands Canc Inst, Div Mol Pathol, Amsterdam, Netherlands. 2Univ Cambridge, Dept Publ Hlth & Primary Care, Cardiovasc Epidemiol Unit, Cambridge, England. 3Hannover Med Sch, Gynaecol Res Unit, Hannover, Germany.
4Antoni van Leeuwenhoek Hosp, Netherlands Canc Inst, Div Mol Carcinogenesis, Amsterdam, Netherlands.
5Univ Cambridge, Ctr Canc Genet Epidemiol, Dept Publ Hlth & Primary Care, Cambridge, England. 6QIMR Berghofer Med Res Inst, Dept Genet & Computat Biol, Brisbane, Qld, Australia. 7Univ Cambridge, Ctr Canc Genet Epidemiol, Dept Oncol, Cambridge, England. 8Cambridge Expt Canc Med Ctr, Cambridge, England. 9Univ Cambridge NHS Fdn Hosp, Cambridge Breast Unit, Cambridge, England. 10Univ Cambridge NHS Fdn Hosp, NIHR Cambridge Biomed Res Ctr, Cambridge, England. 11Mt Sinai Hosp, Fred A Litwin Ctr Canc Genet, Lunenfeld Tanenbaum Res Inst, Toronto, ON, Canada. 12Univ Toronto, Dept Mol Genet, Toronto, ON, Canada. 13Univ Calif Irvine, Dept Epidemiol, Genet Epidemiol Res Inst, Irvine, CA USA. 14German Canc Res Ctr, Div Clin Epidemiol & Aging Res, Heidelberg, Germany. 15Fred Hutchinson Canc Res Ctr, Canc Prevent Program, 1124 Columbia St, Seattle, WA 98104 USA. 16Univ Wisconsin, Zilber Sch Publ Hlth, Milwaukee, WI 53201 USA. 17Friedrich Alexander Univ Erlangen Nuremberg, Univ Hosp Erlangen, Comprehens Canc Ctr ER EMN, Dept Gynecol & Obstet, Erlangen, Germany. 18German Canc Res Ctr, Div Canc Epidemiol, Heidelberg, Germany. 19Spanish Natl Canc Res Ctr CNIO, Human Canc Genet Programme, Madrid, Spain. 20Biomed Network Rare Dis CIBERER, Madrid, Spain. 21Russian Acad Sci, Inst Biochem & Genet, Ufa Sci Ctr, Ufa, Russia. 22City Hope Natl Med Ctr, Dept Populat Sci, Beckman Res Inst, Duarte, CA USA. 23Univ Helsinki, Helsinki Univ Hosp, Dept Oncol, Helsinki, Finland. 24Orebro Univ Hosp, Dept Oncol, Orebro, Sweden. 25VIB Ctr Canc Biol, VIB, Leuven, Belgium. 26Univ Leuven, Dept Human Genet, Lab Translat Genet, Leuven, Belgium. 27Copenhagen Univ Hosp, Herlevand Gentofte Hosp, Copenhagen Gen Populat Study, Herlev, Denmark. 28Copenhagen Univ Hosp, Herlev & Gentofte Hosp, Dept Clin Biochem, Herlev, Denmark. 29Univ Copenhagen, Fac Hlth & Med Sci, Copenhagen, Denmark. 30European Inst Oncol IRCCS Milan, Div Canc Prevent & Genet, IEO, I-20141 Milan, Italy. 31Oslo Univ Hosp, Inst Canc Res, Dept Canc Genet, Radiumhosp, Oslo, Norway. 32Univ Oslo, Fac Med, Inst Clin Med, Oslo, Norway. 33Vestre Viken Hosp, Dept Res, Drammen, Norway. 34Oslo Univ Hosp Ulleva, Dept Canc, Div Surg, Sect Breast & Endocrine Surg, Oslo, Norway. 35Oslo Univ Hosp, Dept Radiol & Nucl Med, Oslo, Norway. 36Akershus Univ Hosp, Dept Pathol, Lorenskog, Norway. 37Oslo Univ Hosp, Inst Canc Res, Dept Tumor Biol, Oslo, Norway. 38Oslo Univ Hosp, Dept Oncol, Div Surg & Canc & Transplantat Med, Radiumhosp, Oslo, Norway. 39Oslo Univ Hosp, Dept Oncol, Natl Advisory Unit Late Effects Canc Treatment, Oslo, Norway. 40Akershus Univ Hosp, Dept Oncol, Lorenskog, Norway. 41Oslo Univ Hosp, Breast Canc Res Consortium, Oslo, Norway. 42Dr Margarete Fischer Bosch Inst Clin Pharmacol, Stuttgart, Germany. 43Univ Tubingen, Tubingen, Germany. 44German Canc Consortium DKTK, German Canc Res Ctr DKFZ, Heidelberg, Germany. 45German Canc Res Ctr, Div Prevent Oncol, Heidelberg, Germany. 46Natl Ctr Tumor Dis NCT, Heidelberg, Germany. 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Format: | article |
Version: | published version |
Access: | open |
Online Access: | PDF Full Text (PDF, 1 MB) |
Persistent link: | http://urn.fi/urn:nbn:fi-fe2019071022995 |
Language: | English |
Published: |
Springer Nature,
2019
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Publish Date: | 2019-07-10 |
Description: |
AbstractBackground: We examined the associations between germline variants and breast cancer mortality using a large meta-analysis of women of European ancestry. Methods: Meta-analyses included summary estimates based on Cox models of twelve datasets using ~10.4 million variants for 96,661 women with breast cancer and 7697 events (breast cancer-specific deaths). Oestrogen receptor (ER)-specific analyses were based on 64,171 ER-positive (4116) and 16,172 ER-negative (2125) patients. We evaluated the probability of a signal to be a true positive using the Bayesian false discovery probability (BFDP). Results: We did not find any variant associated with breast cancer-specific mortality at P < 5 × 10−8. For ER-positive disease, the most significantly associated variant was chr7:rs4717568 (BFDP = 7%, P = 1.28 × 10−7, hazard ratio [HR] = 0.88, 95% confidence interval [CI] = 0.84–0.92); the closest gene is AUTS2. For ER-negative disease, the most significant variant was chr7:rs67918676 (BFDP = 11%, P = 1.38 × 10−7, HR = 1.27, 95% CI = 1.16–1.39); located within a long intergenic non-coding RNA gene (AC004009.3), close to the HOXA gene cluster. Conclusions: We uncovered germline variants on chromosome 7 at BFDP < 15% close to genes for which there is biological evidence related to breast cancer outcome. However, the paucity of variants associated with mortality at genome-wide significance underpins the challenge in providing genetic-based individualised prognostic information for breast cancer patients. see all
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Series: |
British journal of cancer |
ISSN: | 0007-0920 |
ISSN-E: | 1532-1827 |
ISSN-L: | 0007-0920 |
Volume: | 120 |
Issue: | 6 |
Pages: | 647 - 657 |
DOI: | 10.1038/s41416-019-0393-x |
OADOI: | https://oadoi.org/10.1038/s41416-019-0393-x |
Type of Publication: |
A1 Journal article – refereed |
Field of Science: |
3122 Cancers |
Subjects: | |
Funding: |
BCAC is funded by Cancer Research UK [C1287/A16563 and C1287/A10118], the European Union’s Horizon 2020 Research and Innovation Programme (Grant numbers 634935 and 633784 for BRIDGES and B-CAST, respectively), and by the European Community's Seventh Framework Programme under grant agreement number 223175 (Grant number HEALTH-F2-2009-223175) (COGS). The EU Horizon 2020 Research and Innovation Programme funding source had no role in study design, data collection, data analysis, data interpretation or writing of the report. Genotyping of the OncoArray was funded by the NIH Grant U19 CA148065, and Cancer UK Grant C1287/A16563 and the PERSPECTIVE project supported by the Government of Canada through Genome Canada and the Canadian Institutes of Health Research (Grant GPH-129344) and, the Ministère de l’Économie, Science et Innovation du Québec through Genome Québec and the PSRSIIRI-701 grant, and the Quebec Breast Cancer Foundation. Funding for the iCOGS infrastructure came from: the European Community’s Seventh Framework Programme under grant agreement no. 223175 (HEALTH-F2-2009-223175) (COGS), Cancer Research UK (C1287/A10118, C1287/A10710, C12292/A11174, C1281/A12014, C5047/A8384, C5047/A15007, C5047/A10692 and 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, and Komen Foundation for the Cure, the Breast Cancer Research Foundation, and the Ovarian Cancer Research Fund. The DRIVE Consortium was funded by U19 CA148065. ABCFS was supported by grant UM1 CA164920 from the National Cancer Institute (USA). The content of this manuscript does not necessarily reflect the views or policies of the National Cancer Institute or any of the collaborating centres in the in the Breast Cancer Family Registry (BCFR), nor does mention of trade names, commercial products, or organisations imply endorsement by the USA Government or the BCFR. The ABCFS was also supported by the National Health and Medical Research Council of Australia, the New South Wales Cancer Council, the Victorian Health Promotion Foundation (Australia) and the Victorian Breast Cancer Research Consortium. J.L.H. is a National Health and Medical Research Council (NHMRC) Senior Principal Research Fellow. M.C.S. is a NHMRC Senior Research Fellow. The ABCS study was supported by the Dutch Cancer Society [Grants NKI 2007-3839; 2009-4363 and2015-7632]. The ABCTB is generously supported by the National Health and Medical Research Council of Australia, The Cancer Institute NSW and the National Breast Cancer Foundation. The work of the BBCC was partly funded by ELAN-Fond of the University Hospital of Erlangen. The BBCS is funded by Cancer Research UK and Breast Cancer Now and acknowledges NHS funding to the NIHR Biomedical Research Centre, and the National Cancer Research Network (NCRN). For the BCFR-NY, BCFR-PA, BCFR-UT this work was supported by grant UM1 CA164920 from the National Cancer Institute. For BIGGS, ES is supported by NIHR Comprehensive Biomedical Research Centre, Guy’s & St. Thomas’ NHS Foundation Trust in partnership with King’s College London, United Kingdom. IT is supported by the Oxford Biomedical Research Centre. The BREOGAN is funded by Acción Estratégica de Salud del Instituto de Salud Carlos III FIS PI12/02125/Cofinanciado FEDER; Acción Estratégica de Salud del Instituto de Salud Carlos III FIS Intrasalud (PI13/01136); Programa Grupos Emergentes, Cancer Genetics Unit, Instituto de Investigacion Biomedica Galicia Sur. Xerencia de Xestion Integrada de Vigo-SERGAS, Instituto de Salud Carlos III, Spain; Grant 10CSA012E, Consellería de Industria Programa Sectorial de Investigación Aplicada, PEME I + D e I + D Suma del Plan Gallego de Investigación, Desarrollo e Innovación Tecnológica de la Consellería de Industria de la Xunta de Galicia, Spain; Grant EC11-192. Fomento de la Investigación Clínica Independiente, Ministerio de Sanidad, Servicios Sociales e Igualdad, Spain; and Grant FEDER-Innterconecta. Ministerio de Economia y Competitividad, Xunta de Galicia, Spain. The BSUCH study was supported by the Dietmar-Hopp Foundation, the Helmholtz Society and the German Cancer Research Center (DKFZ). CCGP is supported by funding from the University of Crete. The CECILE study was supported by Fondation de France, Institut National du Cancer (INCa), Ligue Nationale contre le Cancer, Agence Nationale de Sécurité Sanitaire, de l’Alimentation, de l’Environnement et du Travail (ANSES), Agence Nationale de la Recherche (ANR). The CGPS was supported by the Chief Physician Johan Boserup and Lise Boserup Fund, the Danish Medical Research Council, and Herlev and Gentofte Hospital. The CNIO-BCS was supported by the Instituto de Salud Carlos III, the Red Temática de Investigación Cooperativa en Cáncer and grants from the Asociación Española Contra el Cáncer and the Fondo de Investigación Sanitario (PI11/00923 and PI12/00070). The American Cancer Society funds the creation, maintenance, and updating of the CPS-II cohort. The CTS was initially supported by the California Breast Cancer Act of 1993 and the California Breast Cancer Research Fund (Contract 97-10500) and is currently funded through the National Institutes of Health (R01 CA77398, UM1 CA164917 and U01 CA199277). Collection of cancer incidence data was supported by the California Department of Public Health as part of the statewide cancer reporting programme mandated by California Health and Safety Code Section 103885. The University of Westminster curates the DietCompLyf database funded by Against Breast Cancer Registered Charity No. 1121258 and the NCRN. The coordination of EPIC is financially supported by the European Commission (DG-SANCO) and the International Agency for Research on Cancer. The national cohorts are supported by: Ligue Contre le Cancer, Institut Gustave Roussy, Mutuelle Générale de l’Education Nationale, Institut National de la Santé et de la Recherche Médicale (INSERM) (France); German Cancer Aid, German Cancer Research Center (DKFZ), Federal Ministry of Education and Research (BMBF) (Germany); the Hellenic Health Foundation, the Stavros Niarchos Foundation (Greece); Associazione Italiana per la Ricerca sul Cancro-AIRC-Italy and 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 to Granada, PI13/01162 to EPIC-Murcia, Regional Governments of Andalucía, Asturias, Basque Country, Murcia and Navarra, ISCIII RETIC (RD06/0020) (Spain); Cancer Research UK (14136 to EPIC-Norfolk; C570/A16491 and C8221/A19170 to EPIC-Oxford), Medical Research Council (1000143 to EPIC-Norfolk, MR/M012190/1 to EPIC-Oxford) (United Kingdom). The ESTHER study was supported by a grant from the Baden Württemberg Ministry of Science, Research and Arts. Additional cases were recruited in the context of the VERDI study, which was supported by a grant from the German Cancer Aid (Deutsche Krebshilfe). FHRISK is funded from NIHR grant PGfAR 0707-10031. The GC-HBOC is supported by the German Cancer Aid (Grant no. 110837, coordinator: Rita K. Schmutzler, Cologne). This work was also funded by the European Regional Development Fund and Free State of Saxony, Germany (LIFE—Leipzig Research Centre for Civilisation Diseases, project numbers 713-241202, 713-241202, 14505/2470 and 14575/2470). The GENICA was funded by the Federal Ministry of Education and Research (BMBF) Germany grants 01KW9975/5, 01KW9976/8, 01KW9977/0 and 01KW0114, the Robert Bosch Foundation, Stuttgart, Deutsches Krebsforschungszentrum (DKFZ), Heidelberg, the Institute for Prevention and Occupational Medicine of the German Social Accident Insurance, Institute of the Ruhr University Bochum (IPA), Bochum, as well as the Department of Internal Medicine, Evangelische Kliniken Bonn gGmbH, Johanniter Krankenhaus, Bonn, Germany. The GESBC was supported by the Deutsche Krebshilfe e. V. [70492] and the German Cancer Research Centre (DKFZ). The HABCS study was supported by the Claudia von Schilling Foundation for Breast Cancer Research, by the Lower Saxonian Cancer Society, and by the Rudolf Bartling Foundation. The HEBCS was financially supported by the Helsinki University Central Hospital Research Fund, Academy of Finland (266528), the Finnish Cancer Society, and the Sigrid Juselius Foundation. The HUBCS was supported by a grant from the German Federal Ministry of Research and Education (RUS08/017), and by the Russian Foundation for Basic Research and the Federal Agency for Scientific Organisations for support the Bioresource collections and RFBR grants 14-04-97088, 17-29-06014 and 17-44-020498. Financial support for KARBAC was provided through the regional agreement on medical training and clinical research (ALF) between Stockholm County Council and Karolinska Institutet, the Swedish Cancer Society, The Gustav V. Jubilee foundation and Bert von Kantzows foundation. The KARMA study was supported by Märit and Hans Rausings Initiative Against Breast Cancer. The KBCP was financially supported by the special Government Funding (EVO) of Kuopio University Hospital grants, Cancer Fund of North Savo, the Finnish Cancer Organisations, and by the strategic funding of the University of Eastern Finland. 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. LMBC is supported by the ‘Stichting tegen Kanker’. The MARIE study was supported by the Deutsche Krebshilfe e.V. [70-2892-BR I, 106332, 108253, 108419, 110826 and110828], the Hamburg Cancer Society, the German Cancer Research Centre (DKFZ) and the Federal Ministry of Education and Research (BMBF) Germany [01KH0402]. MBCSG is supported by grants from the Italian Association for Cancer Research (AIRC) and by funds from the 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”). The MCBCS was supported by the NIH grants CA192393, CA116167 and CA176785 an NIH Specialised Programme of Research Excellence (SPORE) in Breast Cancer [CA116201], and the Breast Cancer Research Foundation and a generous gift from the David F. and Margaret T. Grohne Family Foundation. MCCS cohort recruitment was funded by VicHealth and Cancer Council Victoria. The MCCS was further supported by Australian NHMRC grants 209057 and 396414, and by infrastructure provided by Cancer Council Victoria. Cases and their vital status were ascertained through the Victorian Cancer Registry (VCR) and the Australian Institute of Health and Welfare (AIHW), including the National Death Index and the Australian Cancer Database. The MEC was supported by NIH grants CA63464, CA54281, CA098758, CA132839 and CA164973. The MISS study is supported by funding from ERC-2011-294576 Advanced grant, Swedish Cancer Society, Swedish Research Council, Local hospital funds, Berta Kamprad Foundation, Gunnar Nilsson. The MMHS study was supported by NIH grants CA97396, CA128931, CA116201, CA140286 and CA177150. The work of MTLGEBCS was supported by the Quebec Breast Cancer Foundation, the Canadian Institutes of Health Research for the “CIHR Team in Familial Risks of Breast Cancer” programme—Grant # CRN-87521 and the Ministry of Economic Development, Innovation and Export Trade—grant # PSR-SIIRI-701. The NBCS has received funding from the K.G. Jebsen Centre for Breast Cancer Research; the Research Council of Norway grant 193387/V50 (to A.-L. Børresen-Dale and V.N. Kristensen) and grant 193387/H10 (to A.-L. Børresen-Dale and V.N. Kristensen), South Eastern Norway Health Authority (Grant 39346 to A.-L. Børresen-Dale) and the Norwegian Cancer Society (to A.-L. Børresen-Dale and V.N. Kristensen). The NC-BCFR and OFBCR were supported by grant UM1 CA164920 from the National Cancer Institute (USA). The NCBCS was funded by Komen Foundation, the National Cancer Institute (P50 CA058223, U54 CA156733 and U01 CA179715), and the North Carolina University Cancer Research Fund. The NHS was supported by NIH grants P01 CA87969, UM1 CA186107 and U19 CA148065. The NHS2 was supported by NIH grants UM1 CA176726 and U19 CA148065. The OBCS was supported by research grants from the Finnish Cancer Foundation, the Academy of Finland (Grant numbers 250083 and 122715, and Centre of Excellence grant number 251314), the Finnish Cancer Foundation, the Sigrid Juselius Foundation, the University of Oulu, the University of Oulu Support Foundation and the special Governmental EVO funds for Oulu University Hospital-based research activities. The ORIGO study was supported by the Dutch Cancer Society (RUL 1997-1505) and the Biobanking and Biomolecular Resources Research Infrastructure (BBMRI-NL CP16). The PBCS was funded by Intramural Research Funds of the National Cancer Institute, Department of Health and Human Services, USA. Genotyping for PLCO was supported by the Intramural Research Programme of the National Institutes of Health, NCI, Division of Cancer Epidemiology and Genetics. The PLCO is supported by the Intramural Research Programme of the Division of Cancer Epidemiology and Genetics and supported by contracts from the Division of Cancer Prevention, National Cancer Institute, National Institutes of Health. The POSH study is funded by Cancer Research UK (Grants C1275/A11699, C1275/C22524, C1275/A19187 and C1275/A15956, and Breast Cancer Campaign grant numbers 2010PR62 and 2013PR044. PROCAS is funded from NIHR grant PGfAR 0707-10031. The RBCS was funded by the Dutch Cancer Society (DDHK 2004-3124 and DDHK 2009-4318). The SASBAC study was supported by funding from the Agency for Science, Technology and Research of Singapore (A*STAR), the US National Institute of Health (NIH) and the Susan G. Komen Breast Cancer Foundation. The SBCS was supported by Sheffield Experimental Cancer Medicine Centre and Breast Cancer Now Tissue Bank. SEARCH is funded by Cancer Research UK [C490/A10124 and C490/A16561] and supported by the UK National Institute for Health Research Biomedical Research Centre at the University of Cambridge. The University of Cambridge has received salary support for PDPP from the NHS in the East of England through the Clinical Academic Reserve. SKKDKFZS is supported by the DKFZ. The SMC is funded by the Swedish Cancer Foundation. The SZBCS was supported by Grant PBZ_KBN_122/P05/2004. The UCIBCS component of this research was supported by the NIH [CA58860, CA92044] and the Lon V Smith Foundation [LVS39420]. The UKBGS is funded by Breast Cancer Now and the Institute of Cancer Research (ICR), London. ICR acknowledges NHS funding to the NIHR Biomedical Research Centre. The USRT Study was funded by Intramural Research Funds of the National Cancer Institute, Department of Health and Human Services, USA. The WHI programme is funded by the National Heart, Lung, and Blood Institute, the US National Institutes of Health and the US Department of Health and Human Services (HHSN268201100046C, HHSN268201100001C, HHSN268201100002C, HHSN268201100003C, HHSN268201100004C and HHSN271201100004C). This work was also funded by NCI U19 CA148065-01. |
Academy of Finland Grant Number: |
251314 122715 |
Detailed Information: |
251314 (Academy of Finland Funding decision) 122715 (Academy of Finland Funding decision) |
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