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Cancer genetics
Original research
Evaluation of European-based polygenic risk score for breast cancer in Ashkenazi Jewish women in Israel
  1. Hagai Levi1,2,
  2. Shai Carmi3,
  3. Saharon Rosset4,
  4. Rinat Yerushalmi5,6,
  5. Aviad Zick7,8,
  6. Tamar Yablonski-Peretz7,8,
  7. The BCAC Consortium,
  8. Qin Wang9,
  9. Manjeet K Bolla9,
  10. Joe Dennis9,
  11. Kyriaki Michailidou9,10,
  12. Michael Lush9,
  13. Thomas Ahearn11,
  14. Irene L Andrulis12,13,
  15. Hoda Anton-Culver14,
  16. Antonis C Antoniou9,
  17. Volker Arndt15,
  18. Annelie Augustinsson16,
  19. Päivi Auvinen17,18,19,
  20. Laura Beane Freeman11,
  21. Matthias Beckmann20,
  22. Sabine Behrens21,
  23. Marina Bermisheva22,
  24. Clara Bodelon23,
  25. Natalia V Bogdanova24,25,26,
  26. Stig E Bojesen27,28,29,
  27. Hermann Brenner15,30,31,
  28. Helen Byers32,
  29. Nicola Camp33,
  30. Jose Castelao34,
  31. Jenny Chang-Claude21,35,
  32. María-Dolores Chirlaque36,
  33. Wendy Chung37,
  34. Christine Clarke38,
  35. NBCS Collaborators39,40,41,42,43,44,45,46,47,48,49,50,
  36. Margriet J Collee51,
  37. Sarah Colonna33,
  38. CTS Consortium52,53,
  39. Fergus Couch54,
  40. Angela Cox55,
  41. Simon S Cross56,
  42. Kamila Czene57,
  43. Mary Daly58,
  44. Peter Devilee59,60,
  45. Thilo Dork25,
  46. Laure Dossus61,
  47. Diana M Eccles62,
  48. A. Heather Eliassen63,64,65,
  49. Mikael Eriksson57,
  50. Gareth Evans32,66,
  51. Peter Fasching20,
  52. Olivia Fletcher67,
  53. Henrik Flyger68,
  54. Lin Fritschi69,
  55. Marike Gabrielson57,
  56. Manuela Gago-Dominguez70,
  57. Montserrat García-Closas11,
  58. Jose Angel Garcia-Saenz71,
  59. Jeanine Genkinger72,73,
  60. Graham G Giles74,75,76,
  61. Mark Goldberg77,78,
  62. Pascal Guénel79,
  63. Per Hall57,80,
  64. Ute Hamann81,
  65. Wei He57,
  66. Peter Hillemanns25,
  67. Antoinette Hollestelle82,
  68. Reiner Hoppe83,84,
  69. John Hopper75,
  70. ABCTB Investigators85,
  71. Simona Jakovchevska86,
  72. Anna Jakubowska87,88,
  73. Helena Jernström16,
  74. Esther John89,90,
  75. Nichola Johnson67,
  76. Michael Jones91,
  77. Joseph Vijai92,93,
  78. Rudolf Kaaks21,
  79. Elza Khusnutdinova22,94,
  80. Cari Kitahara95,
  81. Stella Koutros11,
  82. Vessela Kristensen40,50,
  83. Allison W Kurian89,90,
  84. James Lacey52,53,
  85. Diether Lambrechts96,97,
  86. Loic Le Marchand98,
  87. Flavio Lejbkowicz99,
  88. Annika Lindblom100,101,
  89. Sibylle Loibl102,
  90. Adriana Lori23,
  91. Jan Lubinski87,
  92. Arto Mannermaa17,103,104,
  93. Mehdi Manoochehri81,
  94. Dimitrios Mavroudis105,
  95. Usha Menon106,
  96. AnnaMarie Mulligan107,108,
  97. Rachel Murphy109,110,
  98. Ines Nevelsteen111,
  99. William G Newman32,66,
  100. Nadia Obi112,
  101. Katie O'Brien113,
  102. Ken Offit92,93,
  103. Andrew Olshan114,
  104. Dijana Plaseska-Karanfilska86,
  105. Janet Olson115,
  106. Salvatore Panico116,
  107. Tjoung-Won Park-Simon25,
  108. Alpa Patel23,
  109. Paolo Peterlongo117,
  110. Brigitte Rack118,
  111. Paolo Radice119,
  112. Gad Rennert99,
  113. Valerie Rhenius120,
  114. Atocha Romero121,
  115. Emmanouil Saloustros122,
  116. Dale Sandler113,
  117. Marjanka K Schmidt123,124,125,
  118. Lukas Schwentner118,
  119. Mitul Shah120,
  120. Priyanka Sharma126,
  121. Jacques Simard127,
  122. Melissa Southey74,76,128,
  123. Jennifer Stone75,129,
  124. William J Tapper62,
  125. Jack Taylor113,130,
  126. Lauren Teras23,
  127. Amanda E Toland131,
  128. Melissa Troester114,
  129. Thérèse Truong79,
  130. Lizet E van der Kolk132,
  131. Clarice Weinberg133,
  132. Camilla Wendt134,
  133. Xiaohong Rose Yang11,
  134. Wei Zheng135,
  135. Argyrios Ziogas14,
  136. Alison M Dunning120,
  137. Paul Pharoah9,120,136,
  138. Douglas F Easton9,120,
  139. Shay Ben-Sachar6,137,
  140. Naama Elefant137,138,
  141. Ron Shamir1,
  142. Ran Elkon2
    1. 1 The Blavatnik School of Computer Science, Tel Aviv University, Tel Aviv, Israel
    2. 2 Department of Human Molecular Genetics and Biochemistry, Tel Aviv University, Tel Aviv, Israel
    3. 3 Braun School of Public Health and Community Medicine, The Hebrew University of Jerusalem, Jerusalem, Israel
    4. 4 Department of Statistics and Operations Research, Tel Aviv University, Tel Aviv, Israel
    5. 5 Institute of Oncology, Davidoff Cancer Center, Rabin Medical Center, Beilinson Hospital, Petah Tikva, Israel
    6. 6 Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel
    7. 7 Department of oncology, Hadassah Medical Center, Jerusalem, Israel
    8. 8 Hebrew University of Jerusalem, Jerusalem, Israel
    9. 9 Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK
    10. 10 Biostatistics Unit, The Cyprus Institute of Neurology & Genetics, Nicosia, Cyprus
    11. 11 Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
    12. 12 Fred A. Litwin Center for Cancer Genetics, Lunenfeld-Tanenbaum Research Institute of Mount Sinai Hospital, Toronto, Ontario, Canada
    13. 13 Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada
    14. 14 Department of Medicine, Genetic Epidemiology Research Institute, University of California Irvine, Irvine, CA, USA
    15. 15 Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany
    16. 16 Oncology, Department of Clinical Sciences in Lund, Lund University, Lund, Sweden
    17. 17 Translational Cancer Research Area, University of Eastern Finland, Kuopio, Finland
    18. 18 Institute of Clinical Medicine, Oncology, University of Eastern Finland, Kuopio, Finland
    19. 19 Department of Oncology, Cancer Center, Kuopio University Hospital, Kuopio, Finland
    20. 20 Department of Gynecology and Obstetrics, Comprehensive Cancer Center Erlangen-EMN, Friedrich-Alexander University Erlangen-Nuremberg, Erlangen, Germany
    21. 21 Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany
    22. 22 Institute of Biochemistry and Genetics, Ufa Federal Research Centre of the Russian Academy of Sciences, Ufa, Russia
    23. 23 Department of Population Science, American Cancer Society, Atlanta, GA, USA
    24. 24 Department of Radiation Oncology, Hannover Medical School, Hannover, Germany
    25. 25 Gynaecology Research Unit, Hannover Medical School, Hamburg, Germany
    26. 26 N.N. Alexandrov Research Institute of Oncology and Medical Radiology, Minsk, Belarus
    27. 27 Copenhagen General Population Study, Herlev and Gentofte Hospital, Copenhagen University Hospital, Herlev, Denmark
    28. 28 Department of Clinical Biochemistry, Herlev and Gentofte Hospital, Copenhagen University Hospital, Herlev, Denmark
    29. 29 Faculty of Health and Medical Sciences, Copenhagen, Denmark
    30. 30 German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany
    31. 31 Division of Preventive Oncology, German Cancer Research Center (DKFZ) and National Center for Tumor Diseases (NCT), Heidelberg, Germany
    32. 32 North West Genomics Laboratory Hub, Manchester Centre for Genomic Medicine, St Mary’s Hospital, Manchester University NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester, UK
    33. 33 Department of Internal Medicine and Huntsman Cancer Institute, University of Utah, Salt lake city, UT, USA
    34. 34 Oncology and Genetics Unit, Instituto de Investigación Sanitaria Galicia Sur (IISGS), Xerencia de Xestion Integrada de Vigo-SERGAS, Vigo, Spain
    35. 35 Cancer Epidemiology Group, University Cancer Center Hamburg (UCCH), University Medical Center Hamburg-Eppendorf, Hamburg, Germany
    36. 36 CIBER of Epidemiology and Public Health (CIBERESP), Madrid, Spain
    37. 37 Departments of Pediatrics and Medicine, Columbia University, New York, NY, USA
    38. 38 Westmead Institute for Medical Research, University of Sydney, Sydney, New South Wales, Australia
    39. 39 Department of Cancer Genetics, Institute for Cancer Research, Oslo University Hospital-Radiumhospitalet, Oslo, Norway
    40. 40 Institute of Clinical Medicine, Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway
    41. 41 Department of Research, Vestre Viken Hospital, Drammen, Norway
    42. 42 Section for Breast- and Endocrine Surgery, Department of Cancer, Division of Surgery, Cancer and Transplantation Medicine, Oslo University Hospital, Oslo, Norway
    43. 43 Department of Radiology and Nuclear Medicine, Oslo University Hospital, Oslo, Norway
    44. 44 Department of Pathology, Akershus University Hospital, Lorenskog, Norway
    45. 45 Department of Tumor Biology, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway
    46. 46 Department of Oncology, Division of Surgery, Cancer and Transplantation Medicine, Oslo University Hospital-Radiumhospitalet, Oslo, Norway
    47. 47 National Advisory Unit on Late Effects after Cancer Treatment, Oslo University Hospital, Oslo, Norway
    48. 48 Department of Oncology, Akershus University Hospital, Lorenskog, Norway
    49. 49 Oslo Breast Cancer Research Consortium, Oslo University Hospital, Oslo, Norway
    50. 50 Department of Medical Genetics, Oslo University Hospital and University of Oslo, Oslo, Norway
    51. 51 Department of Clinical Genetics, Erasmus Medical Center, Rotterdam, Netherlands
    52. 52 Department of Computational and Quantitative Medicine, City of Hope, Duarte, CA, USA
    53. 53 City of Hope Comprehensive Cancer Center, City of Hope, Duarte, CA, USA
    54. 54 Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA
    55. 55 Department of Oncology and Metabolism, Sheffield Institute for Nucleic Acids (SInFoNiA), University of Sheffield, Sheffield, UK
    56. 56 Academic Unit of Pathology, Department of Neuroscience, University of Sheffield, Sheffield, UK
    57. 57 Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden
    58. 58 Department of Clinical Genetics, Fox Chase Cancer Center, Philadelphia, PA, USA
    59. 59 Department of Pathology, Leiden University Medical Center, Leiden, Netherlands
    60. 60 Department of Human Genetics, Leiden University Medical, Leiden, Netherlands
    61. 61 Nutrition and Metabolism Section, International Agency for Research on Cancer (IARC-WHO), Lyon, France
    62. 62 Cancer Sciences, Faculty of Medicine, University of Southampton, Southampton, UK
    63. 63 Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA
    64. 64 Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA
    65. 65 Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA
    66. 66 Division of Evolution and Genomic Sciences, School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester Academic Health Science Centre, Manchester, UK
    67. 67 The Breast Cancer Now Toby Robins Research Centre, The Institute of Cancer Research, London, UK
    68. 68 Department of Breast Surgery, Herlev and Gentofte Hospital, Copenhagen University Hospital, Herlev, Denmark
    69. 69 School of Population Health, Curtin University, Perth, Western Australia, Australia
    70. 70 Genomic Medicine Group, International Cancer Genetics and Epidemiology Group, Fundación Pública Galega de Medicina Xenómica, Instituto de Investigación Sanitaria de Santiago de Compostela (IDIS), Complejo Hospitalario Universitario de Santiago, SERGAS, Santiago de Compostela, Spain
    71. 71 Medical Oncology, Hospital Clinico San Carlos, Madrid, Spain, USA
    72. 72 Department of Epidemiology, Mailman School of Public Health, Columbia University, New York, NY, USA
    73. 73 Herbert Irving Comprehensive Cancer Center, New York, New York, USA
    74. 74 Cancer Epidemiology Centre, Cancer Council Victoria, Melbourne, Victoria, Australia
    75. 75 Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, Victoria, Australia
    76. 76 Precision Medicine, School of Clinical Sciences at Monash Health, Monash University, Clayton, Victoria, Australia
    77. 77 Department of Medicine, McGill University, Montreal, Quebec, Canada
    78. 78 Division of Clinical Epidemiology, Royal Victoria Hospital, McGill University, Montreal, QU, Canada
    79. 79 Team 'Exposome and Heredity', CESP, Gustave Roussy, INSERM, University Paris-Saclay, UVSQ, Villejuif, France
    80. 80 Department of Oncology, Södersjukhuset, Stockholm, Sweden
    81. 81 Molecular Genetics of Breast Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany
    82. 82 Medical Oncology, Erasmus Medical Center, Rotterdam, Netherlands
    83. 83 Dr Margarete Fischer Bosch Institute of Clinical Pharmacology, Stuttgart, Germany
    84. 84 University of Tübingen, Tubingen, Germany
    85. 85 Australian Breast Cancer Tissue Bank, Westmead Institute for Medical Research, University of Sydney, Sydney, New South Wales, Australia
    86. 86 Research Centre for Genetic Engineering and Biotechnology 'Georgi D. Efremov', Skopje, North Macedonia
    87. 87 Department of Genetics and Pathology, Pomeranian Medical University, Szczecin, Poland
    88. 88 Independent Laboratory of Molecular Biology and Genetic Diagnostics, Pomeranian Medical University, Szczecin, Poland
    89. 89 Department of Epidemiology and Population Health, Stanford University School of Medicine, Stanford, CA, USA
    90. 90 Department of Medicine, Division of Oncology, Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA, USA
    91. 91 Division of Genetics and Epidemiology, The Institute of Cancer Research, Sutton, UK
    92. 92 Clinical Genetics Research Lab, Department of Cancer Biology and Genetics, Memorial Sloan Kettering Cancer Center, New York, NY, USA
    93. 93 Clinical Genetics Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA
    94. 94 Department of Genetics and Fundamental Medicine, Bashkir State University, Ufa, Russia
    95. 95 Radiation Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, USA
    96. 96 Laboratory for Translational Genetics, Department of Human Genetics, KU Leuven, Leuven, Belgium
    97. 97 VIB Center for Cancer Biology, VIB, Leuven, Belgium
    98. 98 Epidemiology Program, University of Hawaii Cancer Center, Honolulu, HI, USA
    99. 99 Clalit National Cancer Control Center, Carmel Medical Center and Technion Faculty of Medicine, Haifa, Israel
    100. 100 Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden
    101. 101 Department of Clinical Genetics, Karolinska University Hospital, Stockholm, Sweden
    102. 102 German Breast Group, GmbH, Neu Isenburg, Germany
    103. 103 Institute of Clinical Medicine, Pathology and Forensic Medicine, University of Eastern Finland, Kuopio, Finland
    104. 104 Biobank of Eastern Finland, Kuopio University Hospital, Kuopio, Finland
    105. 105 Department of Medical Oncology, University Hospital of Heraklion, Heraklion, Greece
    106. 106 MRC Clinical Trials Unit, Institute of Clinical Trials and Methodology, University College, London, UK
    107. 107 Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada
    108. 108 Laboratory Medicine Program, University Health Network, Toronto, Ontario, Canada
    109. 109 School of Population and Public Health, University of British Columbia, Vancouver, BC, Canada
    110. 110 Cancer Control Research, BC Cancer Agency, Vancouver, BC, Canada
    111. 111 Leuven Multidisciplinary Breast Center, Department of Oncology, Leuven Cancer Institute, University Hospitals Leuven, Leuven, Belgium
    112. 112 Institute for Medical Biometry and Epidemiology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
    113. 113 Epidemiology Branch, National Institute of Environmental Health Sciences, NIH, Research Triangle Park, NC, USA
    114. 114 Department of Epidemiology, Gillings School of Global Public Health and UNC Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
    115. 115 Department of Quantitative Health Sciences, Division of Epidemiology, Mayo Clinic, Rochester, MN, USA
    116. 116 Dipertimento Di Medicina Clinca e Chirurgia, Federico II University, Naples, Italy
    117. 117 Genome Diagnostics Program, IFOM ETS - the AIRC Institute of Molecular Oncology, Milan, Italy
    118. 118 Department of Gynaecology and Obstetrics, University Hospital Ulm, Ulm, Germany
    119. 119 Unit of Molecular Bases of Genetic Risk and Genetic Testing, Department of Research, Fondazione IRCCS Istituto Nazionale dei Tumori (INT), Milan, Italy
    120. 120 Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Cambridge, UK
    121. 121 Laboratorio de Oncología Molecular, Hospital Clínico San Carlos, Madrid, Spain
    122. 122 Department of Oncology, University Hospital of Larissa, Larissa, Greece
    123. 123 Division of Molecular Pathology, The Netherlands Cancer Institute, Amsterdam, Netherlands
    124. 124 Division of Psychosocial Research and Epidemiology, The Netherlands Cancer Institute - Antoni van Leeuwenhoek hospital, Amsterdam, Netherlands
    125. 125 Department of Clinical Genetics, Leiden University Medical Center, Leiden, Netherlands
    126. 126 Department of Internal Medicine, Division of Medical Oncology, University of Kansas Medical Center, Westwood, KS, USA
    127. 127 Genomics Center, Molecular Medicine, Université Laval, Quebec, Quebec, Canada
    128. 128 Department of Clinical Pathology, The University of Melbourne, Melbourne, Victoria, Australia
    129. 129 Genetic Epidemiology Group, School of Population and Global Health, University of Western Australia, Perth, Western Australia, Australia
    130. 130 Epigenetic and Stem Cell Biology Laboratory, National Institute of Environmental Health Sciences, NIH, Research Triangle Park, NC, USA
    131. 131 Department of Cancer Biology and Genetics, The Ohio State University, Columbus, OH, USA
    132. 132 Family Cancer Clinic, The Netherlands Cancer Institute, Amsterdam, Netherlands
    133. 133 Biostatistics and Computational Biology Branch, National Institute of Environmental Health Sciences, NIH, Research Triangle Park, NC, USA
    134. 134 Department of Clinical Science and Education, Karolinska Institutet, Stockholm, Sweden
    135. 135 Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, TN, USA
    136. 136 Department of Computational Biomedicine, Cedars-Sinai Medical Center, West Hollywood, CA, USA
    137. 137 Clalit Research Institute, Clalit Health Services, Ramat Gan, Israel
    138. 138 Department of Genetics, Hadassah Medical Center, Jerusalem, Israel
    1. Correspondence to Prof. Ran Elkon, Department of Human Molecular Genetics and Biochemistry, Tel Aviv University, Tel Aviv, Israel; ranel{at}tauex.tau.ac.il; Prof. Ron Shamir; rshamir{at}tau.ac.il; Dr. Naama Elefant; naamael1{at}clalit.org.il

    Abstract

    Background Polygenic risk score (PRS), calculated based on genome-wide association studies (GWASs), can improve breast cancer (BC) risk assessment. To date, most BC GWASs have been performed in individuals of European (EUR) ancestry, and the generalisation of EUR-based PRS to other populations is a major challenge. In this study, we examined the performance of EUR-based BC PRS models in Ashkenazi Jewish (AJ) women.

    Methods We generated PRSs based on data on EUR women from the Breast Cancer Association Consortium (BCAC). We tested the performance of the PRSs in a cohort of 2161 AJ women from Israel (1437 cases and 724 controls) from BCAC (BCAC cohort from Israel (BCAC-IL)). In addition, we tested the performance of these EUR-based BC PRSs, as well as the established 313-SNP EUR BC PRS, in an independent cohort of 181 AJ women from Hadassah Medical Center (HMC) in Israel.

    Results In the BCAC-IL cohort, the highest OR per 1 SD was 1.56 (±0.09). The OR for AJ women at the top 10% of the PRS distribution compared with the middle quintile was 2.10 (±0.24). In the HMC cohort, the OR per 1 SD of the EUR-based PRS that performed best in the BCAC-IL cohort was 1.58±0.27. The OR per 1 SD of the commonly used 313-SNP BC PRS was 1.64 (±0.28).

    Conclusions Extant EUR GWAS data can be used for generating PRSs that identify AJ women with markedly elevated risk of BC and therefore hold promise for improving BC risk assessment in AJ women.

    • Genomics
    • Polymorphism, Genetic

    Data availability statement

    Data are available upon reasonable request. The Breast Cancer Association Consortium (BCAC) data are available upon request from Cambridge University (see the BCAC website: https://bcac.ccge.medschl.cam.ac.uk/bcacdata/).The Hadassah Medical Center data are available from the corresponding author upon a reasonable request.

    https://creativecommons.org/licenses/by/4.0/

    This is an open access article distributed in accordance with the Creative Commons Attribution 4.0 Unported (CC BY 4.0) license, which permits others to copy, redistribute, remix, transform and build upon this work for any purpose, provided the original work is properly cited, a link to the licence is given, and indication of whether changes were made. See: https://creativecommons.org/licenses/by/4.0/.

    http://dx.doi.org/10.1136/jmg-2023-109185

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      Data availability statement

      Data are available upon reasonable request. The Breast Cancer Association Consortium (BCAC) data are available upon request from Cambridge University (see the BCAC website: https://bcac.ccge.medschl.cam.ac.uk/bcacdata/).The Hadassah Medical Center data are available from the corresponding author upon a reasonable request.

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      Footnotes

      • Twitter @KyrMichailidou

      • Collaborators Members of the Breast Cancer Association Consortium (BCAC) Consortium who have contributed the genotypoe data of the BCAC cohort analysed in our study: QW, MKB, JD, KM, ML, TUA, ILA, HAC, ACA, VA, AA, PA, LBF, MWB, SB, MB, CB, NVB, SEB, HBr, HBy, NJC, JEC, JCC, M-DC, WKC, CLC, JMC, SVC, FJC, AC, SSC, KC, MBD, PD, TD, LD, DME, AHE, ME, DGE, PAF, OF, HF, LF, MG, MGD, MGC, JGS, JG, GGG, MSG, PG, PH, UH, WH, PH, AH, RH, JLH, SJ, AJ, HJ, EMJ, NJ, MEJ, VJ, RK, EKK, CMK, SK, VNK, AWK, JVL, DL, LLM, FL, AL, SL, AL, JL, AM, MM, DM, UM, AMM, RAM, IN, WGN, NO, KOB, KO, AFO, JEO, SP, TWPS, AVP, PP, DPK, BR, PR, GD, VR, AR, ES, DPS, MKS, LS, MS, PS, JS, MCS, JS, WJT, JAT, LRT, AET, MAT, TT, LEK, CRW, CW, XRY, WZ, AZ, AMD, PDPP, DFE.

      • Contributors RE and RS conceived the project. HL designed, developed and performed the analysis under the supervision of RE and RS. SC, SR, NE and SBS were consulted on the analyses. NE, SBS, RY, AZ and TYP collected and provided the HMC data. The rest of the authors are part of Breast Cancer Association Consortium (BCAC), which contributed the BCAC dataset. All authors wrote the manuscript and approved the final manuscript. Guarantor: RE.

      • Funding This study was supported in part by grants from the Israeli Science Foundation (number 3165/19, within the Israel Precision Medicine Partnership program; number 2206/22 to RS, and number 407/17 to SC), from the Tel Aviv University Center for AI and Data Science (TAD) to RE and RS, by a joint program grant from the Cancer Biology Research Center, Djerassi Oncology Center, Edmond J. Safra Center for Bioinformatics and TAD to RE, and by the Koret-UC Berkeley-Tel Aviv University Initiative in Computational Biology and Bioinformatics to RE and RS. HL was supported in part by a fellowship from the Edmond J. Safra Center for Bioinformatics at Tel Aviv University. The Breast Cancer Association Consortium (BCAC) is funded by the Confluence project, which is funded with intramural funds from the National Cancer Institute Intramural Research Program, National Institutes of Health. Additional funding for BCAC is provided by Cancer Research UK grant: PPRPGM-Nov20\100002, the European Union's Horizon 2020 Research and Innovation Programme (grant numbers 634935 and 633784 for BRIDGES and B-CAST, respectively), and the PERSPECTIVE I&I project, funded by the government of Canada through Genome Canada and the Canadian Institutes of Health Research, the Ministère de l’Économie et de l'Innovation du Québec through Genome Québec, 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. 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 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 iCOGS came from the European Community's Seventh Framework Programme (under grant agreement number 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 BRIDGES panel sequencing was supported by the European Union Horizon 2020 research and innovation program BRIDGES (grant number, 634935) and the Wellcome Trust (v203477/Z/16/Z).The Australian Breast Cancer Family Study (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 centers 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. JLH is a National Health and Medical Research Council (NHMRC) Senior Principal Research Fellow. MCS is an NHMRC senior research fellow. The ABCS study was supported by the Dutch Cancer Society (grants NKI 2007-3839 and 2009 4363) and an institutional grant of the Dutch Cancer Society and of the Dutch Ministry of Health, Welfare and Sport. The Australian Breast Cancer Tissue Bank 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 program 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 BCFR-NY, BCFR-PA, BCFR-UT 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 centers in the BCFR, nor does mention of trade names, commercial products, or organizations 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. BOCS is supported by funds from Cancer Research UK (C8620/A8372/A15106) and the Institute of Cancer Research (UK). BOCS acknowledges NHS funding to the Royal Marsden / Institute of Cancer Research NIHR Specialist Cancer Biomedical Research Centre. The Breast Oncology GAlician Network is funded by Acción Estratégica de Salud del Instituto de Salud Carlos III FIS PI12/02125/Cofinanciado and FEDER PI17/00918/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). CBCS is funded by the Canadian Cancer Society (grant # 313404) and the CIHR. CCGP is supported by funding from the University of Crete. The CECILE study was supported by Fondation de France, Institut National du Cancer, Ligue Nationale contre le Cancer, Agence Nationale de Sécurité Sanitaire, de l'Alimentation, de l'Environnement et du Travail and Agence Nationale de la Recherche. 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). COLBCCC is supported by the DKFZ, Heidelberg, Germany. DT was in part supported by a postdoctoral fellowship from the Alexander von Humboldt Foundation. The American Cancer Society funds the creation, maintenance, and updating of the CPS-II cohort. The California Teachers Study (CTS) and the research reported in this publication were supported by the National Cancer Institute of the National Institutes of Health (under award numbers U01-CA199277, P30-CA033572, P30-CA023100, UM1-CA164917 and R01-CA077398). 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 CTS was supported by the California Department of Public Health pursuant to California Health and Safety Code Section 103885; Centers for Disease Control and Prevention’s National Program of Cancer Registries (under cooperative agreement 5NU58DP006344); the National Cancer Institute’s Surveillance, Epidemiology and End Results Program (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 Centers for Disease Control and Prevention or their Contractors and Subcontractors, or the Regents of the University of California or any of its programmes. 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 (France); German Cancer Aid, 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, Netherlands Cancer Registry, LK Research Funds, Dutch Prevention Funds, Dutch ZON (Zorg Onderzoek Nederland), World Cancer Research Fund, 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) (UK). 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 and PROCAS are funded from NIHR (grant PGfAR 0707-10031). DGE, AH and WGN were supported by the NIHR Manchester Biomedical Research Centre (IS-BRC-1215-20007). The GC-HBOC (German Consortium of Hereditary Breast and Ovarian Cancer) was supported by the German Cancer Aid (grant numbers 110837 and 70114178, coordinator: Rita K Schmutzler, Cologne) and the Federal Ministry of Education and Research, Germany (grant number 01GY1901). This work was also funded by the European Regional Development Fund and Free State of Saxony, Germany (LIFE - Leipzig Research Centre for Civilization Diseases, project numbers 713-241202, 713-241202, 14505/2470 and 14575/2470). The GENICA was funded by the BMBF Germany grants 01KW9975/5, 01KW9976/8, 01KW9977/0 and 01KW0114, the Robert Bosch Foundation, Stuttgart, DKFZ, Heidelberg, the Institute for Prevention and Occupational Medicine of the German Social Accident Insurance, Institute of the Ruhr University Bochum, Bochum, as well as the Department of Internal Medicine, Johanniter GmbH Bonn, Johanniter Krankenhaus, Bonn, Germany. Generation Scotland received core support from the Chief Scientist Office of the Scottish Government Health Directorates (CZD/16/6) and the Scottish Funding Council (HR03006). Genotyping of the GS:SFHS samples was carried out by the Genetics Core Laboratory at the Edinburgh Clinical Research Facility, University of Edinburgh, Scotland, and was funded by the Medical Research Council UK and the Wellcome Trust (Wellcome Trust Strategic Award, 'Stratifying Resilience and Depression Longitudinally', reference 104036/Z/14/Z). Funding for identification of cases and contribution to BCAC was provided in part by the Wellcome Trust Seed Award, 'Temporal trends in incidence and mortality of molecular subtypes of breast cancer to inform public health, policy and prevention' (reference 207800/Z/17/Z). The GEPARSIXTO study was conducted by the German Breast Group GmbH. The GESBC was supported by the Deutsche Krebshilfe e. V. (70492) and the DKFZ. GLACIER was supported by Breast Cancer Now, CRUK and Biomedical Research Centre at Guy’s and St Thomas’ NHS Foundation Trust and King’s College London. The HABCS study was supported by German Research Foundation (DFG Do761/15-1), 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 Sigrid Juselius Foundation and the Cancer Foundation Finland. The HEBON study is supported by the Dutch Cancer Society (grants NKI1998-1854, NKI2004-3088 and NKI2007-3756), the Netherlands Organisation of Scientific Research (grant NWO 91109024), the Pink Ribbon (grants 110005 and 2014-187.WO76), the BBMRI (grant NWO 184.021.007/CP46) and the Transcan (grant JTC 2012 Cancer 12-054). The HMBCS was supported by the German Research Foundation (DFG Do761/15-1), a grant from the Friends of Hannover Medical School and by the Rudolf Bartling Foundation. The HUBCS was supported by German Research Foundation (DFG Do761/15-1), a grant from the German Federal Ministry of Research and Education (RUS08/017). BM was supported by the Russian Foundation for Basic Research (grants 17-44-020498 and 17-29-06014). DP was supported by the Russian Foundation for Basic Research (grant 18-29-09129). EK was supported by the mega grant from the Government of Russian Federation (2020-220-08-2197), and the study was performed as part of the assignment of the Ministry of Science and Higher Education of the Russian Federation (№АААА-А16-116020350032-1). ICICLE was supported by Breast Cancer Now, CRUK and Biomedical Research Centre at Guy’s and St Thomas’ NHS Foundation Trust and King’s College London. 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 (VTR) of Kuopio University Hospital grants, Cancer Fund of North Savo, the Finnish Cancer Organizations, 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 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 NHMRC (400413, 400281 and 199600). GCT and PW were supported by the NHMRC. RB was a Cancer Institute NSW Clinical Research Fellow. LMBC was supported by the 'Stichting tegen Kanker'. DL was 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 and 110828), the Hamburg Cancer Society, the German Cancer Research Center (DKFZ) and the BMBF Germany (01KH0402). MBCSG was supported by grants from the AIRC. The MCBCS was supported by the NIH (grants R35CA253187, R01CA192393, R01CA116167 and R01CA176785), an NIH Specialized Program 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 the 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 was supported by funding from ERC-2011-294576 Advanced grant, Swedish Cancer Society CAN 2018/675, Swedish Research Council, local hospital funds, Berta Kamprad Foundation FBKS 2021-19, Gunnar Nilsson. MSKCC is supported by grants from the Breast Cancer Research Foundation and Robert and Kate Niehaus Clinical Cancer Genetics Initiative. 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 number CRN-87521) and the Ministry of Economic Development, Innovation and Export Trade (grant number 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-LB-D and VNK, and grant 193387/H10 to A-LB-D and VNK), South Eastern Norway Health Authority (grant 39346 to A-LB-D) and the Norwegian Cancer Society (to A-LB-D and VNK). 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 BCFR and Ontario Familial Breast Cancer Registry were supported by grant U01CA164920 from the USA National Cancer Institute of the National Institutes of Health. The content of this article does not necessarily reflect the views or policies of the National Cancer Institute or any of the collaborating centers in the BCFR, nor does mention of trade names, commercial products or 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 and U01 CA179715) and the North Carolina University Cancer Research Fund. The NGOBCS was supported by the National Cancer Center Research and Development Fund (Japan). 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). OBCS was supported by research grants from the Finnish Cancer Foundation, the Academy of Finland (grant numbers 250083 and 122715, and Center of Excellence grant number 251314), the Sigrid Juselius Foundation, the University of Oulu general as well as strategic funding, the University of Oulu Support Foundation and the special Governmental VTR funds towards 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 Program of the National Institutes of Health, NCI, Division of Cancer Epidemiology and Genetics. The PLCO is supported by the Intramural Research Program 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 (2010PR62 and 2013PR044). The RBCS was funded by the Dutch Cancer Society (DDHK 2004-3124 and DDHK 2009-4318). The SBCGS was supported primarily by NIH (grants R01CA64277, R01CA148667, UMCA182910 and R37CA70867). Biological sample preparation was conducted the Survey and Biospecimen Shared Resource, which is supported by P30 CA68485. The scientific development and funding of this project were, in part, supported by the Genetic Associations and Mechanisms in Oncology Network U19 CA148065. The SBCS was supported by Sheffield Experimental Cancer Medicine Centre and Breast Cancer Now Tissue Bank. The SCCS is supported by a grant from the National Institutes of Health (R01 CA092447). Data on SCCS cancer cases used in this publication were provided by the Alabama Statewide Cancer Registry; Kentucky Cancer Registry, Lexington, Kentucky; Tennessee Department of Health, Office of Cancer Surveillance; Florida Cancer Data System; North Carolina Central Cancer Registry, North Carolina Division of Public Health; Georgia Comprehensive Cancer Registry; Louisiana Tumor Registry; Mississippi Cancer Registry; South Carolina Central Cancer Registry; Virginia Department of Health, Virginia Cancer Registry; Arkansas Department of Health, Cancer Registry, 4815 W. Markham, Little Rock, AR 72205. The Arkansas Central Cancer Registry is fully funded by a grant from National Program of Cancer Registries, Centers for Disease Control and Prevention (CDC). Data on SCCS cancer cases from Mississippi were collected by the Mississippi Cancer Registry which participates in the National Program of Cancer Registries (NPCR) of the CDC. The contents of this publication are solely the responsibility of the authors and do not necessarily represent the official views of the CDC or the Mississippi Cancer Registry. 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. SEBCS was supported by the BRL (Basic Research Laboratory) program through the National Research Foundation of Korea funded by the Ministry of Education, Science and Technology (2012-0000347). The Sister Study (SISTER) is supported by the Intramural Research Program of the NIH, National Institute of Environmental Health Sciences (Z01-ES044005 and Z01-ES049033). The Two Sister Study (2SISTER) was supported by the Intramural Research Program of the NIH, National Institute of Environmental Health Sciences (Z01-ES044005 and Z01-ES102245), and, also by a grant from Susan G. Komen for the Cure, grant FAS0703856. SKKDKFZS is supported by the DKFZ. 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 EnvironmentalResearch (SIMPLER). The SZBCS was supported by Grant PBZ_KBN_122/P05/2004 and the program 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 SPORE in Breast Cancer (CA116201), a grant from the Breast Cancer Research Foundation, a generous gift from the David F. and Margaret T. Grohne Family Foundation. UBCS was supported by funding from National Cancer Institute (NCI) grant R01 CA163353 (to N.J. Camp) and the Women’s Cancer Center at the Huntsman Cancer Institute (HCI). Data collection for UBCS was supported by the Utah Population Database (UPDB) and Utah Cancer Registry (UCR). The UPDB is supported by HCI (including Huntsman Cancer Foundation, HCF), the University of Utah, and NCI grant P30 CA2014. The UCR is funded by the NCI's SEER Program, Contract No. HHSN261201800016I, the US Center for Disease Control and Prevention's National Program of Cancer Registries (cooperative agreement number NU58DP006320), the University of Utah and HCF. The UCIBCS component of this research was supported by the NIH (CA58860 and 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 (The Oak Foundation) and supported by the National Institute for Health Research University College London Hospitals Biomedical Research Centre. The US3SS study was supported by Massachusetts (KME, R01CA47305), Wisconsin (PAN, R01 CA47147) and New Hampshire (LT-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.

      • Competing interests BCAC conflict of interest: MWB conducts research funded by Amgen, Novartis and Pfizer. PAF conducts research funded by Amgen, Novartis and Pfizer. He received Honoraria from Roche, Novartis and Pfizer. JV is one ofthe inventors of diagnosis and treatment of ERCC3-mutant cancer. AWK has a research funding for his institution from Myriad Genetics for an unrelated project (funding dates 2017–2019). UM has research collaborations with Mercy BioAnalytics, RNA Guardian, Dana Farber and iLOF (Intelligent Lab on Fiber). RAM is a consultant for Pharmavite.

      • Provenance and peer review Not commissioned; externally peer reviewed.

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