Rare germline copy number variants (CNVs) and breast cancer risk
|Author:||Dennis, Joe1; Tyrer, Jonathan P.2; Walker, Logan C.3;|
1Univ Cambridge, Ctr Canc Genet Epidemiol, Dept Publ Hlth & Primary Care, Cambridge, England.
2Univ Cambridge, Ctr Canc Genet Epidemiol, Dept Oncol, Cambridge, England.
3Univ Otago, Dept Pathol & Biomed Sci, Christchurch, New Zealand.
4Cyprus Inst Neurol & Genet, Biostat Unit, Nicosia, Cyprus.
5Cyprus Sch Mol Med, Cyprus Inst Neurol & Genet, Nicosia, Cyprus.
6NCI, Div Canc Epidemiol & Genet, US Dept HHS, NIH, Bethesda, MD 20892 USA.
7Mt Sinai Hosp, Fred A Litwin Ctr Canc Genet, Lunenfeld Tanenbaum Res Inst, Toronto, ON, Canada.
8Univ Toronto, Dept Mol Genet, Toronto, ON, Canada.
9Univ Calif Irvine, Dept Med, Genet Epidemiol Res Inst, Irvine, CA 92717 USA.
10NN Alexandrov Res Inst Oncol & Med Radiol, Minsk, BELARUS.
11German Canc Res Ctr, Div Clin Epidemiol & Aging Res, Heidelberg, Germany.
12Queens Univ, Dept Publ Hlth Sci, Kingston, ON, Canada.
13Queens Univ, Canc Res Inst, Kingston, ON, Canada.
14Friedrich Alexander Univ Erlangen Nuremberg FAU, Univ Hosp Erlangen, Comprehens Canc Ctr Erlangen EMN, Dept Gynecol & Obstet, Erlangen, Germany.
15German Canc Res Ctr, Div Canc Epidemiol, Heidelberg, Germany.
16Biomed Network Rare Dis CIBERER, Madrid, Spain.
17Spanish Natl Canc Res Ctr CNIO, Human Canc Genet Programme, Madrid, Spain.
18Russian Acad Sci, Inst Biochem & Genet, Ufa Fed Res Ctr, Ufa, Russia.
19Hannover Med Sch, Dept Radiat Oncol, Hannover, Germany.
20Hannover Med Sch, Gynaecol Res Unit, Hannover, Germany.
21Copenhagen Univ Hosp, Herlev & Gentofte Hosp, Copenhagen Gen Populat Study, Herlev, Denmark.
22Copenhagen Univ Hosp, Herlev & Gentofte Hosp, Dept Clin Biochem, Herlev, Denmark.
23Univ Copenhagen, Fac Hlth & Med Sci, Copenhagen, Denmark.
24German Canc Res Ctr, Div Prevent Oncol, Heidelberg, Germany.
25Natl Ctr Tumor Dis NCT, Heidelberg, Germany.
26German Canc Res Ctr, German Canc Consortium DKTK, Heidelberg, Germany.
27Inst Invest Sanitaria Galicia Sur IISGS, Oncol & Genet Unit, Xerencia Xest Integrada Vigo SERGAS, Vigo, Spain.
28Univ Med Ctr Hamburg Eppendorf, Univ Canc Ctr Hamburg UCCH, Canc Epidemiol Grp, Hamburg, Germany.
29QIMR Berghofer Med Res Inst, Dept Genet & Computat Biol, Brisbane, Qld, Australia.
30Univ Sydney, Westmead Inst Med Res, Sydney, NSW, Australia.
31Erasmus MC, Dept Clin Genet, Rotterdam, Netherlands.
32Mayo Clin, Dept Lab Med & Pathol, Rochester, MN USA.
33Univ Sheffield, Sheffield Inst Nucle Acids SInFoNiA, Dept Oncol & Metab, Sheffield, S Yorkshire, England.
34Univ Sheffield, Acad Unit Pathol, Dept Neurosci, Sheffield, S Yorkshire, England.
35Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden.
36Leiden Univ, Dept Pathol, Med Ctr, Leiden, Netherlands.
37Leiden Univ, Dept Human Genet, Med Ctr, Leiden, Netherlands.
38Int Agcy Res Canc IARC WHO, Nutr & Metab Sect, Lyon, France.
39Brigham & Womens Hosp, Dept Med, Channing Div Network Med, 75 Francis St, Boston, MA 02115 USA.
40Harvard Med Sch, Boston, MA 02115 USA.
41Harvard TH Chan Sch Publ Hlth, Dept Epidemiol, Boston, MA USA.
42Univ Manchester, Manchester Acad Hlth Sci Ctr, Fac Biol Med & Hlth, Sch Biol Sci,Div Evolut & Genom Sci, Manchester, Lancs, England.
43Manchester Univ NHS Fdn Trust, Manchester Acad Hlth Sci Ctr, Manchester Ctr Genom Med, North West Genom Lab Hub,St Marys Hosp, Manchester, Lancs, England.
44Univ Calif Los Angeles, David Geffen Sch Med, Dept Med, Div Hematol & Oncol, Los Angeles, CA 90095 USA.
45Univ Edinburgh, Usher Inst Populat Hlth Sci & Informat, Edinburgh, Midlothian, Scotland.
46Univ Edinburgh, Canc Res England Edinburgh Ctr, Edinburgh, Midlothian, Scotland.
47Inst Canc Res, Breast Canc Now Toby Robins Res Ctr, London, England.
48Copenhagen Univ Hosp, Herlev & Gentofte Hosp, Dept Breast Surg, Herlev, Denmark.
49Curtin Univ, Sch Publ Hlth, Perth, WA, Australia.
50Complejo Hosp Univ Santiago, Inst Invest Sanitaria Santiago de Compostela, SERGAS, Fdn Publ Galega Med Xen, Santiago De Compostela, Spain.
51Univ Calif San Diego, Moores Canc Ctr, La Jolla, CA 92093 USA.
52Canc Council Victoria, Canc Epidemiol Div, Melbourne, Vic, Australia.
53Univ Melbourne, Ctr Epidemiol & Biostat, Melbourne Sch Populat & Global Hlth, Melbourne, Vic, Australia.
54Monash Univ, Sch Clin Sci, Precis Med, Monash Hlth, Clayton, Vic, Australia.
55Univ Paris Saclay, Ctr Res Epidemiol & Populat Hlth CESP, INSERM, Team Exposome & Hered, Villejuif, France.
56Univ Cologne, Fac Med, Ctr Familial Breast & Ovarian Canc, Cologne, Germany.
57Univ Cologne, Univ Hosp Cologne, Cologne, Germany.
58Univ Cologne, Fac Med, Ctr Integrated Oncol CIO, Cologne, Germany.
59Univ Southern Calif, Keck Sch Med, Dept Prevent Med, Los Angeles, CA 90007 USA.
60Sodersjenglandhuset, Dept Oncol, Stockholm, Sweden.
61Erasmus MC Canc Inst, Dept Med Oncol, Rotterdam, Netherlands.
62Dr Margarete Fischer Bosch Inst Clin Pharmacol, Stuttgart, Germany.
63Univ Tubingen, Tubingen, Germany.
64Univ Manchester, Div Canc Sci, Manchester, Lancs, England.
65Pomeranian Med Univ, Dept Genet & Pathol, Szczecin, Poland.
66Pomeranian Med Univ, Independent Lab Mol Biol & Genet Diagnost, Szczecin, Poland.
67Stanford Univ, Dept Epidemiol & Populat Hlth, Sch Med, Stanford, CA 94305 USA.
68Stanford Univ, Stanford Canc Inst, Dept Med, Div Oncol,Sch Med, Stanford, CA 94305 USA.
69Inst Canc Res, Div Genet & Epidemiol, London, England.
70Antoni van Leeuwenhoek Hosp, Netherlands Canc Inst, Div Mol Pathol, Amsterdam, Netherlands.
71Bashkir State Univ, Dept Genet & Fundamental Med, Ufa, Russia.
72NCI, Radiat Epidemiol Branch, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA.
73Evangel Kliniken Bonn gGmbH, Johanniter Krankenhaus, Dept Internal Med, Bonn, Germany.
74Univ Eastern Finland, Translat Canc Res Area, Kuopio, Finland.
75Univ Eastern Finland, Inst Clin Med Pathol & Forens Med, Kuopio, Finland.
76Kuopio Univ Hosp, Biobank Eastern Finland, Kuopio, Finland.
77Harvard TH Chan Sch Publ Hlth, Program Genet Epidemiol & Stat Genet, Boston, MA USA.
78Oslo Univ Hosp, Dept Med Genet, Oslo, Norway.
79Univ Oslo, Oslo, Norway.
80Univ Oslo, Fac Med, Inst Clin Med, Oslo, Norway.
81Clin Hosp Acibadem Sistina, Dept Histopathol & Cytol, Skopje, North Macedonia.
82City Hope Natl Med Ctr, Dept Computat & Quantitat Med, Duarte, CA USA.
83City Hope Natl Med Ctr, City Hope Comprehens Canc Ctr, Duarte, CA USA.
84VIB Ctr Canc Biol, Leuven, Belgium.
85Univ Leuven, Dept Human Genet, Lab Translat Genet, Leuven, Belgium.
86Mayo Clin, Dept Hlth Sci Res, Rochester, MN USA.
87Fdn IRCCS Ist Nazl Tumori Milano, Dept Med Oncol & Hematol, Unit Med Genet, Milan, Italy.
88Karolinska Inst, Dept Clin Sci & Educ, Sodersjenglandhuset, Stockholm, Sweden.
89Univ Hosp Heraklion, Dept Med Oncol, Iraklion, Greece.
90Univ Helsinki, Helsinki Univ Hosp, Dept Obstet & Gynecol, Helsinki, Finland.
91Univ British Columbia, Sch Populat & Publ Hlth, Vancouver, BC, Canada.
92BC Canc, Canc Control Res, Vancouver, BC, Canada.
93Lund Univ, Dept Canc Epidemiol, Clin Sci, Lund, Sweden.
94Univ N Carolina, Lineberger Comprehens Canc Ctr, Dept Genet, Chapel Hill, NC 27515 USA.
95IFOM FIRC Inst Mol Oncol, Genome Diagnost Program, Milan, Italy.
96MASA, Res Ctr Genet Engn & Biotechnol Georgi D Efremov, Skopje, North Macedonia.
97Univ Oulu, Bioctr Oulu, Canc & Translat Med Res Unit, Lab Canc Genet & Tumor Biol, Oulu, Finland.
98Northern Finland Lab Ctr Oulu, Lab Canc Genet & Tumor Biol, Oulu, Finland.
99Carmel Hosp, Clalit Natl Canc Control Ctr, Haifa, Israel.
100Technion Fac Med, Haifa, Israel.
101Univ Hosp Larissa, Dept Oncol, Larisa, Greece.
102NIEHS, Epidemiol Branch, NIH, Res Triangle Pk, NC 27709 USA.
103Kings Coll London, Comprehens Canc Ctr, Sch Canc & Pharmaceut Sci, Guys Campus, London, England.
104Antoni van Leeuwenhoek Hosp, Netherlands Canc Inst, Div Psychosocial Res & Epidemiol, Amsterdam, Netherlands.
105Univ Cologne, Fac Med, Ctr Mol Med Cologne CMMC, Cologne, Germany.
106Univ Hosp Leuven, Dept Surg Oncol, Leuven, Belgium.
107Univ Laval, Genom Ctr, Res Ctr, Ctr Hosp Univ Quebec, Quebec City, PQ, Canada.
108Univ Melbourne, Dept Clin Pathol, Melbourne, Vic, Australia.
109Inst Canc Res, Div Breast Canc Res, London, England.
110Weill Cornell Med, Dept Populat Hlth Sci, New York, NY USA.
111NIEHS, Epigenet & Stem Cell Biol Lab, NIH, POB 12233, Res Triangle Pk, NC 27709 USA.
112Amer Canc Soc, Dept Populat Sci, Atlanta, GA 30329 USA.
113Columbia Univ, Mailman Sch Publ Hlth, Dept Epidemiol, New York, NY USA.
114Univ N Carolina, Gillings Sch Global Publ Hlth, Dept Epidemiol, Chapel Hill, NC 27515 USA.
115Univ N Carolina, UNC Lineberger Comprehens Canc Ctr, Chapel Hill, NC 27515 USA.
116Mayo Clin, Div Epidemiol, Dept Quantitat Hlth Sci, Rochester, MN USA.
117Karolinska Inst, Inst Environm Med, Stockholm, Sweden.
118Uppsala Univ, Dept Surg Sci, Uppsala, Sweden.
119Vanderbilt Univ, Sch Med, Vanderbilt Ingram Canc Ctr, Div Epidemiol,Dept Med,Vanderbilt Epidemiol Ctr, Nashville, TN 37212 USA.
|Online Access:||PDF Full Text (PDF, 1.6 MB)|
|Persistent link:|| http://urn.fi/urn:nbn:fi-fe2022081255161
|Publish Date:|| 2022-08-12
Germline copy number variants (CNVs) are pervasive in the human genome but potential disease associations with rare CNVs have not been comprehensively assessed in large datasets. We analysed rare CNVs in genes and non-coding regions for 86,788 breast cancer cases and 76,122 controls of European ancestry with genome-wide array data. Gene burden tests detected the strongest association for deletions in BRCA1 (P = 3.7E-18). Nine other genes were associated with a p-value < 0.01 including known susceptibility genes CHEK2 (P = 0.0008), ATM (P = 0.002) and BRCA2 (P = 0.008). Outside the known genes we detected associations with p-values < 0.001 for either overall or subtype-specific breast cancer at nine deletion regions and four duplication regions. Three of the deletion regions were in established common susceptibility loci. To the best of our knowledge, this is the first genome-wide analysis of rare CNVs in a large breast cancer case-control dataset. We detected associations with exonic deletions in established breast cancer susceptibility genes. We also detected suggestive associations with non-coding CNVs in known and novel loci with large effects sizes. Larger sample sizes will be required to reach robust levels of statistical significance.
|Type of Publication:||
A1 Journal article – refereed
|Field of Science:||
Joe Dennis is supported by the CanRisk Cancer Research UK programme grant: PPRPGM-Nov20\100002 and by the Confluence project which is funded with intramural funds from the National Cancer Institute Intramural Research Programme, National Institutes of Health. Logan Walker is supported by a Rutherford Discovery Fellowship (Royal Society of NewP Zealand). We thank all the individuals who took part in these studies and all the researchers, clinicians, technicians, and administrative staff who have enabled this work to be carried out. The COGS study would not have been possible without the contributions of the following Andrew Berchuck (OCAC), Rosalind A. Eeles, Ali Amin Al Olama, Zsofia Kote-Jarai, Sara Benlloch (PRACTICAL), Antonis Antoniou, Lesley McGuffog and Ken Offit (CIMBA), Andrew Lee, and Ed Dicks, Craig Luccarini and the staff of the Centre for Genetic Epidemiology Laboratory, the staff of the CNIO genotyping unit, Jacques Simard and Daniel C. Tessier, Francois Bacot, Daniel Vincent, Sylvie LaBoissiere and Frederic Robidoux and the staff of the McGill University and Genome Quebec Innovation Centre, Sune F. Nielsen, Borge G. Nordestgaard, and the staff of the Copenhagen DNA laboratory, and Julie M. Cunningham, Sharon A. Windebank, Christopher A. Hilker, Jeffrey Meyer and the staff of Mayo Clinic Genotyping Core Facility. ABCFS thank Maggie Angelakos, Judi Maskiell, Gillian Dite. ABCS thanks the Blood bank Sanquin, The Netherlands. ABCTB Investigators: Christine Clarke, Deborah Marsh, Rodney Scott, Robert Baxter, Desmond Yip, Jane Carpenter, Alison Davis, Nirmala Pathmanathan, Peter Simpson, J. Dinny Graham, Mythily Sachchithananthan. Samples are made available to researchers on a non-exclusive basis. BBCS thanks Eileen Williams, Elaine Ryder-Mills, Kara Sargus. BCEES thanks Allyson Thomson, Christobel Saunders, Terry Slevin, BreastScreen Western Australia, Elizabeth Wylie, Rachel Lloyd. The BCINIS study would not have been possible without the contributions of Dr. K. Landsman, Dr. N. Gronich, Dr. A. Flugelman, Dr. W. Saliba, Dr. F. Lejbkowicz, Dr. E. Liani, Dr. I. Cohen, Dr. S. Kalet, Dr. V. Friedman, Dr. O. Barnet of the NICCC in Haifa, and all the contributing family medicine, surgery, pathology, and oncology teams in all medical institutes in Northern Israel. BIGGS thanks Niall McInerney, Gabrielle Colleran, Andrew Rowan, Angela Jones. The BREOGAN study would not have been possible without the contributions of the following: Angel Carracedo, Victor Munoz Garzon, Alejandro Novo Dominguez, Maria Elena Martinez, Sara Miranda Ponte, Carmen Redondo Marey, Maite Pena Fernandez, Manuel Enguix Castelo, Maria Torres, Manuel Calaza (BREOGAN), Jose Antunez, Maximo Fraga and the staff of the Department of Pathology and Biobank of the University Hospital Complex of Santiago-CHUS, Instituto de Investigacion Sanitaria de Santiago, IDIS, Xerencia de Xestion Integrada de Santiago-SERGAS; Joaquin Gonzalez-Carrero and the staff of the Department of Pathology and Biobank of University Hospital Complex of Vigo, Instituto de Investigacion Biomedica Galicia Sur, SERGAS, Vigo, Spain. CBCS thanks study participants, co-investigators, collaborators, and staff of the Canadian Breast Cancer Study, and project coordinators Agnes Lai and Celine Morissette. CCGP thanks Styliani Apostolaki, Anna Margiolaki, Georgios Nintos, Maria Perraki, Georgia Saloustrou, Georgia Sevastaki, Konstantinos Pompodakis. CGPS thanks staff and participants of the Copenhagen General Population Study.; For the excellent technical assistance: Dorthe Uldall Andersen, Maria Birna Arnadottir, Anne Bank, Dorthe Kjeldgard Hansen. The Danish Cancer Biobank is acknowledged for providing infrastructure for the collection of blood samples for the cases. CNIO-BCS thanks Guillermo Pita, Charo Alonso, Nuria Alvarez, Pilar Zamora, Primitiva Menendez, the Human Genotyping-CEGEN Unit Study Management Group for their invaluable contributions to this research. They also acknowledge the contribution to this study from central cancer registries supported through the Centres for Disease Control and Prevention National Programme of Cancer Registries, as well as cancer registries supported by the National Cancer Institute Surveillance Epidemiology and End Results programme. The authors would like to thank the California Teachers Study Steering Committee that is responsible for the formation and maintenance of the Study within which this research was conducted. A full list of California Teachers Study team members is available at https://www.calteachersstudy.org/team.ESTHER thanks Hartwig Ziegler, Sonja Wolf, Volker Hermann, Christa Stegmaier, Katja Butterbach. FHRISK thanks NIHR for funding and the Manchester NIHR Biomedical Research Centre (IS-BRC-1215-20007). GC-HBOC thanks Stefanie Engert, Heide Hellebrand, Sandra Krober and LIFE -Leipzig Research Centre for Civilisation Diseases (Markus Loeffler, Joachim Thiery, Matthias Nuchter, Ronny Baber). The GENICA Network: Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology, Stuttgart, and University of Tubingen, Germany [Hiltrud Brauch, RH, Wing-Yee Lo], German Cancer Consortium (DKTK) and German Cancer Reseach Centre (DKFZ), Partner Site Tubingen, 72074 Tubingen, Germany [Hiltrud Brauch], gefordert durch die Deutsche Forschungsgemeinschaft (DFG) im Rahmen der Exzellenzstrategie des Bundes und der Lander -EXC 2180 -390900677 [Hiltrud Brauch], Department of Internal Medicine, Evangelische Kliniken Bonn gGmbH, Johanniter Krankenhaus, Bonn, Germany [YDK, Christian Baisch], Institute of Pathology, University of Bonn, Germany [Hans-Peter Fischer], Molecular Genetics of Breast Cancer, Deutsches Krebsforschungszentrum (DKFZ), Heidelberg, Germany [Ute Hamann], Institute for Prevention and Occupational Medicine of the German Social Accident Insurance, Institute of the Ruhr University Bochum (IPA), Bochum, Germany [Thomas Bruning, Beate Pesch, Sylvia Rabstein, Anne Lotz]; and Institute of Occupational Medicine and Maritime Medicine, University Medical Centre Hamburg-Eppendorf, Germany [Volker Harth]. HEBCS thanks Johanna Kiiski, Carl Blomqvist, Kristiina Aittomaki, Kirsimari Aaltonen, Karl von Smitten, Irja Erkkila. HMBCS thanks Peter Hillemanns, Hans Christiansen and Johann H. Karstens. HUBCS thanks Shamil Gantsev. ICICLE thanks Kelly Kohut, Michele Caneppele, Maria Troy. KARMA and SASBAC thank the Swedish Medical Research Counsel. KBCP thanks Eija Myohanen. kConFab/AOCS 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 Foundation, Cancer Australia, and the National Institute of Health who contribute to kConFab. LMBC thanks Gilian Peuteman, Thomas Van Brussel, EvyVanderheyden and Kathleen Corthouts. MABCS thanks Milena Jakimovska (RCGEB "Georgi D.; Efremov"), Snezhana Smichkoska, Emilija Lazarova (University Clinic of Radiotherapy and Oncology), Mitko Karadjozov (Adzibadem-Sistina Hospital), Andrej Arsovski and Liljana Stojanovska (Re-Medika Hospital) for their contributions and commitment to this study. MARIE thanks Petra Seibold, Dieter Flesch-Janys, Judith Heinz, Nadia Obi, Alina Vrieling, Sabine Behrens, Ursula Eilber, Muhabbet Celik, Til Olchers and Stefan Nickels. MBCSG (Milan Breast Cancer Study Group): Paolo Radice, Bernard Peissel, Jacopo Azzollini, Erica Rosina, Daniela Zaffaroni, Bernardo Bonanni, Irene Feroce, Mariarosaria Calvello, Aliana Guerrieri Gonzaga, Monica Marabelli, Davide Bondavalli and the personnel of the Cogentech Cancer Genetic Test Laboratory. The MCCS was made possible by the contribution of many people, including the original investigators, the teams that recruited the participants and continue working on followup, and the many thousands of Melbourne residents who continue to participate in the study. We thank the coordinators, the research staff, and especially the MMHS participants for their continued collaboration on research studies in breast cancer. The following are NBCS Collaborators: Anne-Lise Borresen-Dale (Prof. Em.), Kristine K. Sahlberg (PhD), Lars Ottestad Holmen (MD), Toril Sauer (MD), Vilde Haakensen (MD), Olav Engebraten Kristin V. Reinertsen (MD), Aslaug Helland (MD), Margit Riis (MD), Jurgen Geisler (MD), OSBREAC and Grethe I. Grenaker Alnaes (MSc). NBHS and SBCGS thank study participants and research staff for their contributions and commitment to the studies. For NHS and NHS2 the study protocol was approved by the institutional review boards of the Brigham and Women's Hospital and Harvard T.H. Chan School of Public Health, and those of participating registries as required. We would like to thank the participants and staff of the NHS and NHS2 for their valuable contributions, as well as the following state cancer registries for their help: A.L., A.Z., A.R., C.A., C.O., C.T., D.E., F.L., G.A., I.D., I.L., I.N., I.A., K.Y., L.A., M.E., M.D., M.A., M.I., N.E., N.H., N.J., N.Y., N.C., N.D., O.H., O.K., O.R., P.A., R.I., S.C., T.N., T.X., V.A., W.A., and W.Y. The authors assume full responsibility for analyses and interpretation of these data. OBCS thanks Arja Jukkola-Vuorinen, Mervi Grip, Saila Kauppila, Meeri Otsukka, Leena Keskitalo and Kari Mononen for their contributions to this study. The OFBCR thanks Teresa Selander, Nayana Weerasooriya, and Steve Gallinger. ORIGO thanks E. Krol-Warmerdam, and J. Blom for patient accrual, administering questionnaires, and managing clinical information. The LUMC survival data were retrieved from the Leiden hospital-based cancer registry system (ONCDOC) with the help of Dr. J. Molenaar. PBCS thanks Louise Brinton, Mark Sherman, Neonila Szeszenia-Dabrowska, Beata Peplonska, Witold Zatonski, Pei Chao, Michael Stagner. The ethical approval for the POSH study is MREC/00/6/69, UKCRN ID: 1137. We thank the staff in the Experimental Cancer Medicine Centre (ECMC) supported Faculty of Medicine Tissue Bank and the Faculty of Medicine DNA Banking resource. The RBCS thanks Jannet Blom, Saskia Pelders, Wendy J.C. Prager -van der Smissen, and the Erasmus MC Family Cancer Clinic. SBCS thanks Sue Higham, Helen Cramp, Dan Connley, Ian Brock, Sabapathy Balasubramanian, and Malcolm W.R. Reed. We thank the SEARCH and EPIC teams. SZBCS thanks Ewa Putresza.; UCIBCS thanks Irene Masunaka. UKBGS thanks Breast Cancer Now and the Institute of Cancer Research for support and funding of the Generations Study, and the study participants, study staff, and the doctors, nurses and other health care providers and health information sources who have contributed to the study. We acknowledge NHS funding to the Royal Marsden/ICR NIHR Biomedical Research Centre. BCAC is funded by the European Union's Horizon 2020 Research and Innovation Programme and the PERSPECTIVE I&I project, funded by the Government of Canada through Genome Canada and the Canadian Institutes of Health Research, the Ministere de l'Economie et de l'Innovation du Quebec through Genome Quebec, the Quebec Breast Cancer Foundation. 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. Additional funding for BCAC is provided via the Confluence project which is funded with intramural funds from the National Cancer Institute Intramural Research Programme, National Institutes of Health. Genotyping of the OncoArray was funded by the NIH Grant U19 CA148065, and Cancer Research 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 Ministere de l'Economie, Science et Innovation du Quebec through Genome Quebec and the PSRSIIRI-701 grant, and the Quebec Breast Cancer Foundation. Funding for iCOGS came from: the European Community's Seventh Framework Programme under grant agreement n degrees 223175 C1287/A10710, C12292/A11174, C1281/A12014, C5047/A8384, C5047/A15007, C5047/A10692, C8197/A16565), the National Institutes of Health CA148065, and 1U19 CA148112-the GAME-ON initiative), the Department of Defence (W81XWH-10-10341), the Canadian Institutes of Health Research Foundation for the Cure, the Breast Cancer Research Foundation, and the Ovarian Cancer Research Fund. The DRIVE Consortium was funded by U19 CA148065. The Australian Breast Cancer Family Study (ABCFS) was supported by grant UM1 CA164920 from the National Cancer Institute views or policies of the National Cancer Institute or any of the collaborating centres 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]. The Australian Breast Cancer Tissue Bank (ABCTB) was supported by the National Health and Medical Research Council of Australia, The Cancer Institute NSW and the National Breast Cancer Foundation.; The AHS study is supported by the intramural research programme of the National Institutes of Health, the National Cancer Institute (grant number Z01-CP010119), and the National Institute of Environmental Health Sciences (grant number Z01-ES049030). 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). The BCEES was funded by the National Health and Medical Research Council, Australia and the Cancer Council Western Australia and acknowledges funding from the National Breast Cancer Foundation (JS). For the BCFRNY this work was supported by grant UM1 CA164920 from the 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 centres in the Breast Cancer Family Registry (BCFR), nor does mention of trade names, commercial products, or organisations imply endorsement by the US Government or the BCFR. The BCINIS study is supported in part by the Breast Cancer Research Foundation (BCRF). 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 BREast Oncology GAlician Network (BREOGAN) is funded by Accion Estrategica de Salud del Instituto de Salud Carlos III (ISCIII) FIS PI12/02125/Cofinanciado FEDER, and ISCIII/PI17/00918/Cofinanciado FEDER; Accion Estrategica 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, 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; Grant EC11-192. Fomento de la Investigacion Clinica 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 Centre (DKFZ). CBCS is funded by the Canadian Cancer Society (grant #313404) and the Canadian Institutes of Health Research. 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 Securite Sanitaire, de l'Alimentation, de l'Environnement et du Travail 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 Tematica de Investigacion Cooperativa en Cancer and grants from the Asociacion Espanola Contra el Cancer and the Fondo de Investigacion Sanitario creation, maintenance, and updating of the CPS-II cohort.; The California Teachers Study and the research reported in this publication were supported by the National Cancer Institute of the National Institutes of Health under award number U01-CA199277; P30-CA033572; P30-CA023100; UM1-CA164917; and R01CA077398. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Cancer Institute or the National Institutes of Health. The collection of cancer incidence data used in the California Teachers Study was supported by the California Department of Public Health pursuant to California Health and Safety Code Section 103885; Centres for Disease Control and Prevention's National Programme of Cancer Registries, under cooperative agreement 5NU58DP006344; the National Cancer Institute's Surveillance, Epidemiology and End Results Programme under contract HHSN261201800032I awarded to the University of California, San Francisco, contract HHSN261201800015I awarded to the University of Southern California, and contract HHSN261201800009I awarded to the Public Health Institute. The opinions, findings, and conclusions expressed herein are those of the author(s) and do not necessarily reflect the official views of the State of California, Department of Public Health, the National Cancer Institute, the National Institutes of Health, the Centres for Disease Control and Prevention or their Contractors and Subcontractors, or the Regents of the University of California, or any of its programmes. The coordination of EPIC is financially supported by the European Commission (DGSANCO) and the International Agency for Research on Cancer. Where authors are identified as personnel of the International Agency for Research on Cancer/World Health Organization, the authors alone are responsible for the views expressed in this article and they do not necessarily represent the decisions, policy or views of the International Agency for Research on Cancer/World Health Organization. The national cohorts are supported by: 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, German Cancer Research Centre (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 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 Andalucia, Asturias, Basque Country, Murcia and Navarra, ISCIII RETIC (RD06/0020) 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 Wurttemberg 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 (German Consortium of Hereditary Breast and Ovarian Cancer) 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, 713241202, 14505/2470, 14575/2470). The GENICA was funded by the Federal Ministry of Education and Research the Robert Bosch Foundation, Stuttgart, Deutsches Krebsforschungszentrum 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.  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 Hospital Research Fund, the Finnish Cancer Society, and the Sigrid Juselius Foundation. The HMBCS was supported by a grant from the Friends of Hannover Medical School and by the Rudolf Bartling Foundation. The HUBCS was supported by a grant from the German Federal Ministry of Research and Education (RUS08/017), B.M. was supported by grant 17-44-020498, 17-29-06014 of the Russian Foundation for Basic Research, D.P. was supported by grant 18-29-09129 of the Russian Foundation for Basic Research, E.K. was supported by the programme for supporting the bioresource collections.007-030164/2, and the study was performed as part of the assignment of the Ministry of Science and Higher Education of the Russian Federation (.....-.16116020350032-1). 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 Marit and Hans Rausings Initiative Against Breast Cancer. The KBCP was financially supported by the special Government Funding (VTR) 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. Financial support for the AOCS was provided by the United States Army Medical Research and Materiel Command [DAMD17-01-1-0729], Cancer Council Victoria, Queensland Cancer Fund, Cancer Council New South Wales, Cancer Council South Australia, The Cancer Foundation of Western Australia, Cancer Council Tasmania and the National Health and Medical Research Council of Australia (NHMRC; 400413, 400281, 199600). G.C.T. and P.W. are supported by the NHMRC. RB was a Cancer Institute NSW Clinical Research Fellow. LMBC is supported by the `Stichting tegen Kanker'. D.L. is supported by the FWO. The MABCS study is funded by the Research Centre for Genetic Engineering and Biotechnology "Georgi D. Efremov", MASA. The MARIE study was supported by the Deutsche Krebshilfe e.V.; [70-2892-BR I, 106332, 108253, 108419, 110826, 110828], the Hamburg Cancer Society, the German Cancer Research Centre (DKFZ), and the Federal Ministry of Education and Research (BMBF) Germany [01KH0402]. The MASTOS study was supported by "Cyprus Research Promotion Foundation" grants 0104/13 and 0104/17, and the Cyprus Institute of Neurology and Genetics. MBCSG is supported by grants from the Italian Association for Cancer Research (AIRC). The MCBCS was supported by the NIH grants R35CA253187, R01CA192393, R01CA116167, R01CA176785 a NIH Specialised Programme of Research Excellence (SPORE) in Breast Cancer [P50CA116201], and the Breast Cancer Research Foundation. The Melbourne Collaborative Cohort Study (MCCS) cohort recruitment was funded by VicHealth and Cancer Council Victoria. The MCCS was further augmented by Australian National Health and Medical Research Council grants 209057, 396414, and 1074383 and by infrastructure provided by Cancer Council Victoria. Cases and their vital status were ascertained through the Victorian Cancer Registry and the Australian Institute of Health and Welfare, 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 for Breast Cancer Research; the Research Council of Norway grant 193387/V50 (to A-L Borresen-Dale and V.N. Kristensen) and grant 193387/H10 (to A.-L. Borresen-Dale and V.N. Kristensen), South Eastern Norway Health Authority (grant 39346 to A-L Borresen-Dale) and the Norwegian Cancer Society (to A-L Borresen-Dale and V.N. Kristensen). The NBHS was supported by NIH grant R01CA100374. Biological sample preparation was conducted by the Survey and Biospecimen Shared Resource, which is supported by P30 CA68485. The Northern California Breast Cancer Family Registry (NC-BCFR) and Ontario Familial Breast Cancer Registry Institute of the National Institutes of Health. 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 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 Carolina Breast Cancer Study (NCBCS) was funded by Komen Foundation, the National Cancer Institute (P50 CA058223, U54 CA156733, 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 number 250083, 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 RBCS was funded by the Dutch Cancer Society (DDHK 2004-3124, 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, 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. The Sister Study (SISTER) is supported by the Intramural Research Programme of the NIH, National Institute of Environmental Health Sciences (Z01-ES044005 and Z01-ES049033). The SMC is funded by the Swedish Cancer Foundation and the Swedish Research Council (VR 2017-00644) grant for the Swedish Infrastructure for Medical Population-based Life-course Environmental Research (SIMPLER). The SZBCS was supported by Grant PBZ_KBN_122/P05/2004 and the programme of the Minister of Science and Higher Education under the name "Regional Initiative of Excellence" in 2019-2022 project number 002/RID/2018/19 amount of financing 12,000,000 PLN. The TNBCC was supported by: a Specialised Programme of Research Excellence (SPORE) in Breast Cancer generous gift from the David F. and Margaret T. Grohne Family Foundation. 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 UKOPS study was funded by The Eve Appeal Research University College London Hospitals Biomedical Research Centre. The US3SS study was supported by Massachusetts (K.M.E., R01CA47305), Wisconsin (P.A.N., R01 CA47147) and New Hampshire (L.T.-E., R01CA69664) centres, and Intramural Research Funds of the National Cancer Institute, Department of Health and Human Services, USA. The USRT Study was funded by Intramural Research Funds of the National Cancer Institute, Department of Health and Human Services, USA.
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