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      Fine-mapping of 150 breast cancer risk regions identifies 191 likely target genes

      research-article

      1 , 2 , 3 , 4 , 5 , 6 , 6 , 1 , 6 , 6 , 6 , 7 , 4 , 8 , 8 , 6 , 1 , 1 , 5 , 3 , 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 16 , 17 , 6 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 27 , 35 , 15 , 36 , 37 , 38 , 39 , 40 , 6 , 41 , 42 , 43 , 44 , 45 , 46 , 18 , 46 , 47 , 48 , 49 , 50 , 51 , 52 , 53 , 54 , 55 , 56 , 27 , 57 , 58 , 59 , 60 , 61 , 62 , 63 , 64 , 65 , 66 , 36 , 67 , 68 , 69 , GEMO Study Collaborators 70 , 71 , 72 , EMBRACE Collaborators 6 , 73 , 74 , 75 , 50 , 76 , 31 , 77 , 78 , 57 , 79 , 80 , 81 , 82 , 83 , 84 , 85 , 37 , 86 , 8 , 87 , 8 , 8 , 88 , 89 , 90 , 91 , 92 , 93 , 77 , 94 , 95 , 96 , 97 , 98 , 99 , 100 , 101 , 102 , 103 , 104 , 105 , 6 , 77 , 106 , 107 , 58 , 108 , 64 , 109 , 110 , 64 , 111 , 84 , 112 , 113 , 12 , 114 , 115 , 116 , 117 , 29 , 118 , 119 , 120 , 31 , 121 , 122 , 123 , 124 , 125 , 126 , 77 , 127 , 128 , 1 , 129 , 130 , 131 , 132 , 133 , 77 , 1 , 134 , 135 , 37 , 136 , 134 , 134 , 84 , 137 , 128 , 138 , 139 , 140 , KConFab Investigators 60 , 61 , HEBON Investigators 141 , ABCTB Investigators 142 , 143 , 144 , 134 , 145 , 31 , 146 , 61 , 147 , 148 , 149 , 150 , 151 , 98 , 152 , 153 , 154 , 154 , 155 , 156 , 157 , 154 , 158 , 159 , 160 , 74 , 161 , 30 , 162 , 163 , 164 , 165 , 166 , 167 , 129 , 130 , 131 , 168 , 169 , 170 , 171 , 172 , 7 , 103 , 173 , 174 , 125 , 6 , 159 , 160 , 71 , 72 , 175 , 176 , 177 , 44 , 45 , 27 , 178 , 179 , 119 , 31 , 84 , 112 , 89 , 90 , 84 , 129 , 130 , 131 , 128 , 24 , 127 , 180 , 107 , 181 , 182 , 183 , 184 , 111 , 1 , 6 , 185 , 70 , 71 , 72 , 186 , 187 , 161 , 9 , 110 , 178 , 179 , 188 , 189 , 190 , 163 , 191 , 192 , 85 , 83 , 163 , 99 , 193 , 194 , 195 , 196 , 197 , 198 , 199 , 200 , 201 , 28 , 29 , 202 , 198 , 155 , 156 , 157 , 37 , 5 , 203 , 204 , 205 , 206 , 24 , 143 , 207 , 86 , 145 , 31 , 22 , 91 , 162 , 208 , 209 , 210 , 211 , 212 , 213 , 214 , 197 , 215 , 216 , 197 , 217 , 193 , 218 , 217 , 219 , 28 , 220 , 221 , 222 , 223 , 32 , 84 , 224 , 123 , 124 , 55 , 225 , 152 , 18 , 226 , 37 , 195 , 227 , 228 , 229 , 230 , 134 , 1 , 231 , 232 , 233 , 27 , 234 , 235 , 236 , 113 , 237 , 238 , 239 , 5 , 84 , 240 , 70 , 241 , 242 , 243 , 152 , 244 , 3 , 4 , 245 , 246 , 92 , 219 , 247 , 248 , 249 , 129 , 250 , 251 , 252 , 253 , 254 , 255 , 256 , 257 , 102 , 258 , 259 , 260 , 261 , 262 , 48 , 128 , 263 , 264 , 122 , 265 , 266 , 267 , 268 , 269 , 136 , 270 , 271 , 272 , 196 , 197 , 136 , 6 , 123 , 124 , 273 , 235 , 180 , 99 , 209 , 210 , 126 , 274 , 125 , 167 , 18 , 46 , 27 , 3 , 4 , 1 , 6 , 154 , 184 , 168 , 275 , 74 , 276 , 84 , 112 , 113 , 277 , 278 , 5 , 5 , 6 , 5 , 8 , 1 , 6 , 3 , 4 , * , 1 , *

      Nature genetics

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          There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

          Abstract

          Genome-wide association studies have identified breast cancer risk variants in over 150 genomic regions, but the mechanisms underlying risk remain largely unknown. These regions were explored by combining association analysis with in silico genomic feature annotations. We defined 205 independent risk-associated signals with the set of credible causal variants (CCVs) in each one. In parallel, we used a Bayesian approach (PAINTOR) that combines genetic association, linkage disequilibrium, and enriched genomic features to determine variants with high posterior probabilities of being causal. Potentially causal variants were significantly over-represented in active gene regulatory regions and transcription factor binding sites. We applied our INQUSIT pipeline for prioritizing genes as targets of those potentially causal variants, using gene expression (eQTL), chromatin interaction and functional annotations. Known cancer drivers, transcription factors and genes in the developmental, apoptosis, immune system and DNA integrity checkpoint gene ontology pathways, were over-represented among the highest confidence target genes.

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          Most cited references50

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          Controlling the False Discovery Rate: A Practical and Powerful Approach to Multiple Testing

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            Gene Ontology: tool for the unification of biology

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              • Abstract: found
              • Article: not found

              A genome-wide association study identifies alleles in FGFR2 associated with risk of sporadic postmenopausal breast cancer.

              We conducted a genome-wide association study (GWAS) of breast cancer by genotyping 528,173 SNPs in 1,145 postmenopausal women of European ancestry with invasive breast cancer and 1,142 controls. We identified four SNPs in intron 2 of FGFR2 (which encodes a receptor tyrosine kinase and is amplified or overexpressed in some breast cancers) that were highly associated with breast cancer and confirmed this association in 1,776 affected individuals and 2,072 controls from three additional studies. Across the four studies, the association with all four SNPs was highly statistically significant (P(trend) for the most strongly associated SNP (rs1219648) = 1.1 x 10(-10); population attributable risk = 16%). Four SNPs at other loci most strongly associated with breast cancer in the initial GWAS were not associated in the replication studies. Our summary results from the GWAS are available online in a form that should speed the identification of additional risk loci.
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                Author and article information

                Journal
                9216904
                Nat Genet
                Nat. Genet.
                Nature genetics
                1061-4036
                1546-1718
                25 October 2019
                07 January 2020
                January 2020
                07 July 2020
                : 52
                : 1
                : 56-73
                Affiliations
                [1 ]Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Cambridge, CB1 8RN, UK
                [2 ]Centre de Bioinformatique, Biostatistique et Biologie Intégrative (C3BI), Institut Pasteur, Paris, France
                [3 ]Program in Genetic Epidemiology and Statistical Genetics, Harvard T.H. Chan School of Public Health, Boston, MA, 02115, USA
                [4 ]Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, 02115, USA
                [5 ]Department of Genetics and Computational Biology, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, 4006, Australia
                [6 ]Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, CB1 8RN, UK
                [7 ]Department of Electron Microscopy/Molecular Pathology and The Cyprus School of Molecular Medicine, The Cyprus Institute of Neurology & Genetics, Nicosia, 1683, Cyprus
                [8 ]Genomics Center, Centre Hospitalier Universitaire de Québec – Université Laval, Research Center, Québec City, QC, G1V 4G2, Canada
                [9 ]Immunology and Molecular Oncology Unit, Veneto Institute of Oncology IOV - IRCCS, Padua, 35128, Italy
                [10 ]Department of Clinical Genetics, Helsinki University Hospital, University of Helsinki, Helsinki, 00290, Finland
                [11 ]Human Genotyping-CEGEN Unit, Human Cancer Genetic Program, Spanish National Cancer Research Centre, Madrid, 28029, Spain
                [12 ]Fred A. Litwin Center for Cancer Genetics, Lunenfeld-Tanenbaum Research Institute of Mount Sinai Hospital, Toronto, ON, M5G 1X5, Canada
                [13 ]Department of Molecular Genetics, University of Toronto, Toronto, ON, M5S 1A8, Canada
                [14 ]Department of Epidemiology, Genetic Epidemiology Research Institute, University of California Irvine, Irvine, CA, 92617, USA
                [15 ]N.N. Alexandrov Research Institute of Oncology and Medical Radiology, Minsk, 223040, Belarus
                [16 ]Department of Pathology, Landspitali University Hospital, Reykjavik, 101, Iceland
                [17 ]BMC (Biomedical Centre), Faculty of Medicine, University of Iceland, Reykjavik, 101, Iceland
                [18 ]Division of Clinical Epidemiology and Aging Research, C070, German Cancer Research Center (DKFZ), Heidelberg, 69120, Germany
                [19 ]Department of Public Health Sciences, and Cancer Research Institute, Queen’s University, Kingston, ON, K7L 3N6, Canada
                [20 ]Department of Breast Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA
                [21 ]Institute of Human Genetics, Hannover Medical School, Hannover, 30625, Germany
                [22 ]Cancer Prevention Program, Fred Hutchinson Cancer Research Center, Seattle, WA, 98109, USA
                [23 ]Zilber School of Public Health, University of Wisconsin-Milwaukee, Milwaukee, WI, 53205, USA
                [24 ]Unit of Medical Genetics, Department of Medical Oncology and Hematology, Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, Milan, 20133, Italy
                [25 ]High Risk and Cancer Prevention Group, Vall d'Hebron Institute of Oncology, Barcelona, 08035, Spain
                [26 ]Department of Medical Oncology, University Hospital of Vall d'Hebron, Barcelona, 08035, Spain
                [27 ]Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, TN, 37232, USA
                [28 ]Centro de Investigación en Red de Enfermedades Raras (CIBERER), Madrid, 28029, Spain
                [29 ]Human Cancer Genetics Programme, Spanish National Cancer Research Centre (CNIO), Madrid, 28029, Spain
                [30 ]Institute of Biochemistry and Genetics, Ufa Federal Research Centre of the Russian Academy of Sciences, Ufa, 450054, Russia
                [31 ]Department of Genetics and Pathology, Pomeranian Medical University, Szczecin, 71-252, Poland
                [32 ]Cancer Genetics and Prevention Program, University of California San Francisco, San Francisco, CA, 94143-1714, USA
                [33 ]Department of Oncology, Helsinki University Hospital, University of Helsinki, Helsinki, 00290, Finland
                [34 ]Department of Oncology, Örebro University Hospital, Örebro, 70185, Sweden
                [35 ]International Epidemiology Institute, Rockville, MD, 20850, USA
                [36 ]Department of Radiation Oncology, Hannover Medical School, Hannover, 30625, Germany
                [37 ]Gynaecology Research Unit, Hannover Medical School, Hannover, 30625, Germany
                [38 ]Copenhagen General Population Study, Herlev and Gentofte Hospital, Copenhagen University Hospital, Herlev, 2730, Denmark
                [39 ]Department of Clinical Biochemistry, Herlev and Gentofte Hospital, Copenhagen University Hospital, Herlev, 2730, Denmark
                [40 ]Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, 2200, Denmark
                [41 ]Division of Cancer Prevention and Genetics, IEO, European Institute of Oncology IRCCS, Milan, 20141, Italy
                [42 ]Department of Oncology, Lund University and Skåne University Hospital, Lund, 222 41, Sweden
                [43 ]Institute of Medical Genetics and Applied Genomics, University of Tübingen, Tübingen, 72074, Germany
                [44 ]Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology, Stuttgart, 70376, Germany
                [45 ]iFIT-Cluster of Excellence, University of Tuebingen, Tuebingen, 72074, Germany
                [46 ]German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, 69120, Germany
                [47 ]Division of Preventive Oncology, German Cancer Research Center (DKFZ) and National Center for Tumor Diseases (NCT), Heidelberg, 69120, Germany
                [48 ]Institute of Human Genetics, Pontificia Universidad Javeriana, Bogota, Colombia
                [49 ]Medical Faculty, Universidad de La Sabana, Bogota, Colombia
                [50 ]Sheffield Institute for Nucleic Acids (SInFoNiA), Department of Oncology and Metabolism, University of Sheffield, Sheffield, S10 2TN, UK
                [51 ]Genome Sciences Centre, BC Cancer Agency, Vancouver, BC, V5Z 1L3, Canada
                [52 ]Department of Biomedical Physiology and Kinesiology, Simon Fraser University, Burnaby, BC, V5A 1S6, Canada
                [53 ]Institute for Prevention and Occupational Medicine of the German Social Accident Insurance, Institute of the Ruhr University Bochum (IPA), Bochum, 44789, Germany
                [54 ]Molecular Epidemiology Group, C080, German Cancer Research Center (DKFZ), Heidelberg, 69120, Germany
                [55 ]Molecular Biology of Breast Cancer, University Womens Clinic Heidelberg, University of Heidelberg, Heidelberg, 69120, Germany
                [56 ]Department of Medicine, Huntsman Cancer Institute, Salt Lake City, UT, 84112, USA
                [57 ]Molecular Oncology Laboratory, CIBERONC, Hospital Clinico San Carlos, IdISSC (Instituto de Investigación Sanitaria del Hospital Clínico San Carlos), Madrid, 28040, Spain
                [58 ]SOD Genetica Molecolare, University Hospital, Pisa, Italy
                [59 ]Department of Internal Medicine, Huntsman Cancer Institute, Salt Lake City, UT, 84112, USA
                [60 ]Research Department, Peter MacCallum Cancer Center, Melbourne, Victoria, 3000, Australia
                [61 ]Sir Peter MacCallum Department of Oncology, The University of Melbourne, Melbourne, Victoria, 3000, Australia
                [62 ]Genomic Epidemiology Group, German Cancer Research Center (DKFZ), Heidelberg, 69120, Germany
                [63 ]Cancer Research UK Cambridge Research Institute, Li Ka Shing Centre, University of Cambridge, Cambridge, UK
                [64 ]Behavioral and Epidemiology Research Group, American Cancer Society, Atlanta, GA, 30303, USA
                [65 ]Oncology and Genetics Unit, Instituto de Investigacion Sanitaria Galicia Sur (IISGS), Xerencia de Xestion Integrada de Vigo-SERGAS, Vigo, 36312, Spain
                [66 ]CRCHU de Québec-Université Laval, axe oncologie, Québec, QC, G1S 4L8, Canada
                [67 ]Departments of Pediatrics and Medicine, Columbia University, New York, NY, 10032, USA
                [68 ]Centre for Medical Genetics, Ghent University, Gent, 9000, Belgium
                [69 ]Westmead Institute for Medical Research, University of Sydney, Sydney, New South Wales, 2145, Australia
                [70 ]Department of Tumour Biology, INSERM U830, Paris, 75005, France
                [71 ]Institut Curie, Paris, 75005, France
                [72 ]Mines ParisTech, Fontainebleau, 77305, France
                [73 ]Department of Clinical Genetics, Erasmus University Medical Center, Rotterdam, 3015 CN, The Netherlands
                [74 ]Division of Molecular Pathology, The Netherlands Cancer Institute - Antoni van Leeuwenhoek Hospital, Amsterdam, 1066 CX, The Netherlands
                [75 ]Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, 55905, USA
                [76 ]Academic Unit of Pathology, Department of Neuroscience, University of Sheffield, Sheffield, S10 2TN, UK
                [77 ]Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, 171 65, Sweden
                [78 ]Department of Clinical Genetics, Fox Chase Cancer Center, Philadelphia, PA, 19111, USA
                [79 ]Department of Pathology, Leiden University Medical Center, Leiden, 2333 ZA, The Netherlands
                [80 ]Department of Human Genetics, Leiden University Medical Center, Leiden, 2333 ZA, The Netherlands
                [81 ]Oncogenetics Group, Vall dHebron Institute of Oncology (VHIO), Barcelona, 8035, Spain
                [82 ]Clinical and Molecular Genetics Area, University Hospital Vall dHebron, Barcelona, 8035, Spain
                [83 ]Department of Population Sciences, Beckman Research Institute of City of Hope, Duarte, CA, 91010, USA
                [84 ]Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, Victoria, 3010, Australia
                [85 ]Basser Center for BRCA, Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA, 19066, USA
                [86 ]Department of Non-Communicable Disease Epidemiology, London School of Hygiene and Tropical Medicine, London, WC1E 7HT, UK
                [87 ]Département de Médecine Moléculaire, Faculté de Médecine, Centre Hospitalier Universitaire de Québec Research Center, Laval University, Québec City, QC, G1V 0A6, Canada
                [88 ]Cáncer Hereditario, Instituto de Biología y Genética Molecular, IBGM, Universidad de Valladolid, Centro Superior de Investigaciones Científicas, UVA-CSIC, Valladolid, 47003, Spain
                [89 ]Southampton Clinical Trials Unit, Faculty of Medicine, University of Southampton, Southampton, SO17 1BJ, UK
                [90 ]Cancer Sciences Academic Unit, Faculty of Medicine, University of Southampton, Southampton, SO17 1BJ, UK
                [91 ]School of Life Sciences, University of Westminster, London, W1B 2HW, UK
                [92 ]Faculty of Medicine, University of Southampton, Southampton, SO17 1BJ, UK
                [93 ]Institute for Medical Informatics, Statistics and Epidemiology, University of Leipzig, Leipzig, 04107, Germany
                [94 ]Genomic Medicine, Division of Evolution and Genomic Sciences, The University of Manchester, Manchester Academic Health Science Centre, Manchester Universities Foundation Trust, St. Mary’s Hospital, Manchester, M13 9WL, UK
                [95 ]Genomic Medicine, North West Genomics hub, Manchester Academic Health Science Centre, Manchester Universities Foundation Trust, St. Mary’s Hospital, Manchester, M13 9WL, UK
                [96 ]David Geffen School of Medicine, Department of Medicine Division of Hematology and Oncology, University of California at Los Angeles, Los Angeles, CA, 90095, USA
                [97 ]Department of Gynecology and Obstetrics, Comprehensive Cancer Center ER-EMN, University Hospital Erlangen, Friedrich-Alexander-University Erlangen-Nuremberg, Erlangen, 91054, Germany
                [98 ]The Breast Cancer Now Toby Robins Research Centre, The Institute of Cancer Research, London, SW7 3RP, UK
                [99 ]Leuven Multidisciplinary Breast Center, Department of Oncology, Leuven Cancer Institute, University Hospitals Leuven, Leuven, 3000, Belgium
                [100 ]Department of Breast Surgery, Herlev and Gentofte Hospital, Copenhagen University Hospital, Herlev, 2730, Denmark
                [101 ]Department of Cancer Epidemiology and Genetics, Masaryk Memorial Cancer Institute, Brno, 65653, Czech Republic
                [102 ]Program in Cancer Genetics, Departments of Human Genetics and Oncology, McGill University, Montréal, QC, H4A 3J1, Canada
                [103 ]The Susanne Levy Gertner Oncogenetics Unit, Chaim Sheba Medical Center, Ramat Gan, 52621, Israel
                [104 ]Sackler Faculty of Medicine, Tel Aviv University, Ramat Aviv, 69978, Israel
                [105 ]School of Public Health, Curtin University, Perth, Western Australia, 6102, Australia
                [106 ]Genomic Medicine Group, Galician Foundation of Genomic Medicine, Instituto de Investigación Sanitaria de Santiago de Compostela (IDIS), Complejo Hospitalario Universitario de Santiago, SERGAS, Santiago de Compostela, 15706, Spain
                [107 ]Moores Cancer Center, University of California San Diego, La Jolla, CA, 92037, USA
                [108 ]Schools of Medicine and Public Health, Division of Cancer Prevention & Control Research, Jonsson Comprehensive Cancer Centre, UCLA, Los Angeles, CA, 90096-6900, USA
                [109 ]Cancer Risk and Prevention Clinic, Dana-Farber Cancer Institute, Boston, MA, 02215, USA
                [110 ]Medical Oncology Department, Hospital Clínico San Carlos, Instituto de Investigación Sanitaria San Carlos (IdISSC), Centro Investigación Biomédica en Red de Cáncer (CIBERONC), Madrid, 28040, Spain
                [111 ]Department of Medical Oncology, University Hospital of Heraklion, Heraklion, 711 10, Greece
                [112 ]Cancer Epidemiology Division, Cancer Council Victoria, Melbourne, Victoria, 3004, Australia
                [113 ]Precision Medicine, School of Clinical Sciences at Monash Health, Monash University, Clayton, Victoria, 3168, Australia
                [114 ]Department of Pathology and Laboratory Medicine, Kansas University Medical Center, Kansas City, KS, 66160, USA
                [115 ]Department of Medicine, McGill University, Montréal, QC, H4A 3J1, Canada
                [116 ]Division of Clinical Epidemiology, Royal Victoria Hospital, McGill University, Montréal, QC, H4A 3J1, Canada
                [117 ]Department of Dermatology, Huntsman Cancer Institute, University of Utah School of Medicine, Salt Lake City, UT, 84112, USA
                [118 ]UO Anatomia Patologica Ospedale di Circolo, ASST Settelaghi, Varese, Italy
                [119 ]Clinical Genetics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, 20850-9772, USA
                [120 ]Department of Surgery, Oulu University Hospital, University of Oulu, Oulu, 90220, Finland
                [121 ]Centre de Recherche du Centre Hospitalier de Université de Montréal (CHUM), Université de Montréal, Montréal, QC, H2X 0A9, Canada
                [122 ]Cancer & Environment Group, Center for Research in Epidemiology and Population Health (CESP), INSERM, University Paris-Sud, University Paris-Saclay, Villejuif, 94805, France
                [123 ]Center for Hereditary Breast and Ovarian Cancer, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, 50937, Germany
                [124 ]Center for Integrated Oncology (CIO), Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, 50937, Germany
                [125 ]Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, 90033, USA
                [126 ]Institute of Environmental Medicine, Karolinska Institutet, Stockholm, 171 77, Sweden
                [127 ]Department of Oncology, Södersjukhuset, Stockholm, 118 83, Sweden
                [128 ]Molecular Genetics of Breast Cancer, German Cancer Research Center (DKFZ), Heidelberg, 69120, Germany
                [129 ]Translational Cancer Research Area, University of Eastern Finland, Kuopio, 70210, Finland
                [130 ]Institute of Clinical Medicine, Pathology and Forensic Medicine, University of Eastern Finland, Kuopio, 70210, Finland
                [131 ]Imaging Center, Department of Clinical Pathology, Kuopio University Hospital, Kuopio, 70210, Finland
                [132 ]Saw Swee Hock School of Public Health, National University of Singapore, Singapore, 119077, Singapore
                [133 ]Department of Surgery, National University Health System, Singapore, 119228, Singapore
                [134 ]Department of Medical Oncology, Family Cancer Clinic, Erasmus MC Cancer Institute, Rotterdam, 3015 CN, The Netherlands
                [135 ]School of Population and Global Health, The University of Western Australia, Perth, Western Australia, 6009, Australia
                [136 ]Family Cancer Clinic, The Netherlands Cancer Institute - Antoni van Leeuwenhoek hospital, Amsterdam, 1066 CX, The Netherlands
                [137 ]Division of Cancer Sciences, University of Manchester, Manchester, M13 9PL, UK
                [138 ]Center for Medical Genetics, NorthShore University HealthSystem, Evanston, IL, 60201, USA
                [139 ]The University of Chicago Pritzker School of Medicine, Chicago, IL, 60637, USA
                [140 ]N.N. Petrov Institute of Oncology, St. Petersburg, 197758, Russia
                [141 ]The Hereditary Breast and Ovarian Cancer Research Group Netherlands (HEBON), Coordinating center: The Netherlands Cancer Institute, Amsterdam, 1066 CX, The Netherlands
                [142 ]Australian Breast Cancer Tissue Bank, Westmead Institute for Medical Research, University of Sydney, Sydney, New South Wales, 2145, Australia
                [143 ]Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC, 20007, USA
                [144 ]Division of Epidemiology, Center for Public Health Sciences, National Cancer Center, Tokyo, 104-0045, Japan
                [145 ]Research Centre for Genetic Engineering and Biotechnology 'Georgi D. Efremov', Macedonian Academy of Sciences and Arts, Skopje, 1000, Republic of North Macedonia
                [146 ]Independent Laboratory of Molecular Biology and Genetic Diagnostics, Pomeranian Medical University, Szczecin, 71-252, Poland
                [147 ]Parkville Familial Cancer Centre, Peter MacCallum Cancer Center, Melbourne, Victoria, 3000, Australia
                [148 ]Hematology, oncology and transfusion medicine center, Dept. of Molecular and Regenerative Medicine, Vilnius University Hospital Santariskiu Clinics, Vilnius, Lithuania
                [149 ]State Research Institute Centre for Innovative Medicine, Vilnius, Lithuania
                [150 ]Department of Medicine, Division of Hematology/Oncology, UPMC Hillman Cancer Center; University of Pittsburgh School of Medicine, Pittsburgh, PA 15232, USA
                [151 ]Department of Medicine, Division of Oncology, Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA, 94304, USA
                [152 ]Division of Genetics and Epidemiology, The Institute of Cancer Research, London, SM2 5NG, UK
                [153 ]Department of Oncology, Tampere University Hospital, Tampere University and Tampere Cancer Center, Tampere, 33521, Finland
                [154 ]Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, 69120, Germany
                [155 ]Department of Preventive Medicine, Seoul National University College of Medicine, Seoul, 03080, Korea
                [156 ]Department of Biomedical Sciences, Seoul National University Graduate School, Seoul, 03080, Korea
                [157 ]Cancer Research Institute, Seoul National University, Seoul, 03080, Korea
                [158 ]Faculty of Medicine, University of Heidelberg, Heidelberg, 69120, Germany
                [159 ]David Geffen School of Medicine, Department of Obstetrics and Gynecology, University of California at Los Angeles, Los Angeles, CA, 90095, USA
                [160 ]Women's Cancer Program at the Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, 90048, USA
                [161 ]Surgery, School of Medicine, National University of Ireland, Galway, H91TK33, Ireland
                [162 ]Department of Genetics and Fundamental Medicine, Bashkir State Medical University, Ufa, 450000, Russia
                [163 ]Department of Obstetrics and Gynecology, Helsinki University Hospital, University of Helsinki, Helsinki, 00290, Finland
                [164 ]Familial Cancer Service, Weatmead Hospital, Wentworthville, New South Wales, 2145, Australia
                [165 ]Radiation Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, 20892, USA
                [166 ]Department of Internal Medicine, Evangelische Kliniken Bonn gGmbH, Johanniter Krankenhaus, Bonn, 53177, Germany
                [167 ]Molecular Diagnostics Laboratory, INRASTES, National Centre for Scientific Research 'Demokritos', Athens, 15310, Greece
                [168 ]Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Department of Health and Human Services, Bethesda, MD, 20850, USA
                [169 ]Department of Histopathology and Cytology, Clinical Hospital Acibadem Sistina, Skopje, 1000, Republic of North Macedonia
                [170 ]Hong Kong Hereditary Breast Cancer Family Registry, Cancer Genetics Centre, Happy Valley, Hong Kong
                [171 ]Department of Surgery, The University of Hong Kong, Pok Fu Lam, Hong Kong
                [172 ]Department of Surgery, Hong Kong Sanatorium and Hospital, Happy Valley, Hong Kong
                [173 ]VIB Center for Cancer Biology, VIB, Leuven, 3001, Belgium
                [174 ]Laboratory for Translational Genetics, Department of Human Genetics, University of Leuven, Leuven, 3000, Belgium
                [175 ]Genetic Epidemiology of Cancer team, Inserm U900, Paris, 75005, France
                [176 ]Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, 171 76, Sweden
                [177 ]Department of Clinical Genetics, Karolinska University Hospital, Stockholm, 171 76, Sweden
                [178 ]Division of Health Sciences, Warwick Medical School, University of Warwick, Coventry, CV4 7AL, UK
                [179 ]Institute of Population Health, University of Manchester, Manchester, M13 9PL, UK
                [180 ]Department of Clinical Science and Education, Södersjukhuset, Karolinska Institutet, Stockholm, 118 83, Sweden
                [181 ]Department of Family Medicine and Public Health, University of California San Diego, La Jolla, CA, 92093, USA
                [182 ]Division of Cancer Epidemiology and Prevention, Aichi Cancer Center Research Institute, Nagoya, 464-8681, Japan
                [183 ]Division of Cancer Epidemiology, Nagoya University Graduate School of Medicine, Nagoya, 466-8550, Japan
                [184 ]Cancer Epidemiology Group, University Cancer Center Hamburg (UCCH), University Medical Center Hamburg-Eppendorf, Hamburg, 20246, Germany
                [185 ]Anatomical Pathology, The Alfred Hospital, Melbourne, Victoria, 3004, Australia
                [186 ]Department of Gynecology and Obstetrics, University of Munich, Campus Großhadern, Munich, 81377, Germany
                [187 ]NRG Oncology, Statistics and Data Management Center, Roswell Park Cancer Institute, Buffalo, NY, 14263, USA
                [188 ]Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, M5S 1A8, Canada
                [189 ]Laboratory Medicine Program, University Health Network, Toronto, ON, M5G 2C4, Canada
                [190 ]Radiation Oncology, Hospital Meixoeiro-XXI de Vigo, Vigo, 36214, Spain
                [191 ]Women's College Research Institute, University of Toronto, Toronto, ON, M5S 1A8, Canada
                [192 ]Department of Biochemistry and Molecular Medicine, University of California Davis, Davis, CA, 95817, USA
                [193 ]Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital, Copenhagen, DK-2100, Denmark
                [194 ]Latvian Biomedical Research and Study Centre, Riga, Latvia
                [195 ]Department of Health Sciences Research, Mayo Clinic, Rochester, MN, 55905, USA
                [196 ]Clinical Genetics Research Lab, Department of Cancer Biology and Genetics, Memorial Sloan Kettering Cancer Center, New York, NY, 10065, USA
                [197 ]Clinical Genetics Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, 10065, USA
                [198 ]Department of Molecular Genetics, National Institute of Oncology, Budapest, 1122, Hungary
                [199 ]Center for Clinical Cancer Genetics, The University of Chicago, Chicago, IL, 60637, USA
                [200 ]Department of Cancer Epidemiology, Clinical Sciences, Lund University, Lund, 222 42, Sweden
                [201 ]Centre for Cancer Research and Cell Biology, Queen's University Belfast, Belfast, Ireland, BT7 1NN, UK
                [202 ]University of New Mexico Health Sciences Center, University of New Mexico, Albuquerque, NM, 87131, USA
                [203 ]Cancer Research UK Clinical Trials Unit, Institute of Cancer Sciences, University of Glasgow, Glasgow, G12 0YN, UK
                [204 ]Molecular Diagnostics, Aalborg University Hospital, Aalborg, 9000, Denmark
                [205 ]Clinical Cancer Research Center, Aalborg University Hospital, Aalborg, 9000, Denmark
                [206 ]Department of Clinical Medicine, Aalborg University, Aalborg, 9000, Denmark
                [207 ]Genome Diagnostics Program, IFOM - the FIRC (Italian Foundation for Cancer Research) Institute of Molecular Oncology, Milan, 20139, Italy
                [208 ]Translational Research Laboratory, IDIBELL (Bellvitge Biomedical Research Institute),Catalan Institute of Oncology, CIBERONC, Barcelona, 08908, Spain
                [209 ]Laboratory of Cancer Genetics and Tumor Biology, Cancer and Translational Medicine Research Unit, Biocenter Oulu, University of Oulu, Oulu, 90570, Finland
                [210 ]Laboratory of Cancer Genetics and Tumor Biology, Northern Finland Laboratory Centre Oulu, Oulu, 90570, Finland
                [211 ]Unit of Molecular Bases of Genetic Risk and Genetic Testing, Department of Research, Fondazione IRCCS Istituto Nazionale dei Tumori (INT), Milan, 20133, Italy
                [212 ]School of Women's and Children's Health, Faculty of Medicine, University of NSW Sydney, Sydney, New South Wales, 2052, Australia
                [213 ]The Kinghorn Cancer Centre, Garvan Institute of Medical Research, Sydney, New South Wales, 2010, Australia
                [214 ]Clinical Genetics, Karolinska Institutet, Stockholm, 171 76, Sweden
                [215 ]Clalit National Cancer Control Center, Carmel Medical Center and Technion Faculty of Medicine, Haifa, 35254, Israel
                [216 ]Chronic Disease Epidemiology, Yale School of Public Health, New Haven, CT, 06510, USA
                [217 ]Medical Oncology Department, Hospital Universitario Puerta de Hierro, Madrid, 28222, Spain
                [218 ]Department of Oncology, University Hospital of Larissa, Larissa, 411 10, Greece
                [219 ]Epidemiology Branch, National Institute of Environmental Health Sciences, NIH, Research Triangle Park, NC, 27709, USA
                [220 ]Fundación Pública Galega Medicina Xenómica, Santiago De Compostela, 15706, Spain
                [221 ]Instituto de Investigación Sanitaria de Santiago de Compostela, Santiago De Compostela, 15706, Spain
                [222 ]School of Medicine, University of Western Australia, Perth, Western Australia, Australia
                [223 ]Research Oncology, Guy’s Hospital, King's College London, London, SE1 9RT, UK
                [224 ]Faculty of Information Technology, Monash University, Melbourne, Victoria, 3800, Australia
                [225 ]National Center for Tumor Diseases, University Hospital and German Cancer Research Center, Heidelberg, 69120, Germany
                [226 ]Network Aging Research, University of Heidelberg, Heidelberg, 69115, Germany
                [227 ]Division of Molecular Medicine, Pathology North, John Hunter Hospital, Newcastle, New South Wales, 2305, Australia
                [228 ]Discipline of Medical Genetics, School of Biomedical Sciences and Pharmacy, Faculty of Health, University of Newcastle, Callaghan, New South Wales, 2308, Australia
                [229 ]Hunter Medical Research Institute, John Hunter Hospital, Newcastle, New South Wales, 2305, Australia
                [230 ]Clinical Cancer Genetics Program, Division of Human Genetics, Department of Internal Medicine, The Comprehensive Cancer Center, The Ohio State University, Columbus, OH, 43210, USA
                [231 ]Department of Internal Medicine, Division of Medical Oncology, University of Kansas Medical Center, Westwood, KS, 66205, USA
                [232 ]Institute of Biomedical Sciences, Academia Sinica, Taipei, 115, Taiwan
                [233 ]School of Public Health, China Medical University, Taichung, Taiwan
                [234 ]Dept of OB/GYN and Comprehensive Cancer Center, Medical University of Vienna, Vienna, 1090, Austria
                [235 ]Clinical Cancer Genomics, City of Hope, Duarte, CA, 91010, USA
                [236 ]Ss. Cyril and Methodius University in Skopje, Medical Faculty, University Clinic of Radiotherapy and Oncology, Skopje, 1000, Republic of North Macedonia
                [237 ]Department of Clinical Pathology, The University of Melbourne, Melbourne, Victoria, 3010, Australia
                [238 ]Population Oncology, BC Cancer, Vancouver, BC, V5Z 1G1, Canada
                [239 ]School of Population and Public Health, University of British Columbia, Vancouver, BC, V6T 1Z4, Canada
                [240 ]The Curtin UWA Centre for Genetic Origins of Health and Disease, Curtin University and University of Western Australia, Perth, Western Australia, 6000, Australia
                [241 ]Service de Génétique, Institut Curie, Paris, 75005, France
                [242 ]Université Paris Descartes, Paris, 75006, France
                [243 ]Institute of Human Genetics, University Hospital Heidelberg, Heidelberg, 69120, Germany
                [244 ]Division of Breast Cancer Research, The Institute of Cancer Research, London, SW7 3RP, UK
                [245 ]Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, 02115, USA
                [246 ]Dept of OB/GYN, Medical University of Vienna, Vienna, 1090, Austria
                [247 ]Epigenetic and Stem Cell Biology Laboratory, National Institute of Environmental Health Sciences, NIH, Research Triangle Park, NC, 27709, USA
                [248 ]Department of Genetics, Portuguese Oncology Institute, Porto, 4220-072, Portugal
                [249 ]Biomedical Sciences Institute (ICBAS), University of Porto, Porto, 4050-013, Portugal
                [250 ]Cancer Center, Kuopio University Hospital, Kuopio, 70210, Finland
                [251 ]Institute of Clinical Medicine, Oncology, University of Eastern Finland, Kuopio, 70210, Finland
                [252 ]Breast Cancer Research Programme, Cancer Research Malaysia, Subang Jaya, Selangor, 47500, Malaysia
                [253 ]Department of Surgery, Faculty of Medicine, University Malaya, Kuala Lumpur, 50603, Malaysia
                [254 ]Department of Epidemiology, Mailman School of Public Health, Columbia University, New York, NY, 10032, USA
                [255 ]Hereditary Cancer Program, ONCOBELL-IDIBELL-IDIBGI-IGTP, Catalan Institute of Oncology, CIBERONC, Barcelona, Spain
                [256 ]Department of Clinical Genetics, Odense University Hospital, Odence C, 5000, Denmark
                [257 ]Department of Medicine, Magee-Womens Hospital, University of Pittsburgh School of Medicine, Pittsburgh, PA, 15213, USA
                [258 ]Department of Medical Genetics, University of Cambridge, Cambridge, CB2 0QQ, UK
                [259 ]Department of Cancer Biology and Genetics, The Ohio State University, Columbus, OH, 43210, USA
                [260 ]Department of Surgery, Leiden University Medical Center, Leiden, 2333 ZA, The Netherlands
                [261 ]Institute of Cancer and Genomic Sciences, University of Birmingham, Birmingham, B15 2TT, UK
                [262 ]Wellcome Trust Centre for Human Genetics and Oxford NIHR Biomedical Research Centre, University of Oxford, Oxford, OX3 7BN, UK
                [263 ]Center for Population Health Research, National Institute of Public Health, Cuernavaca, Morelos, 62100, Mexico
                [264 ]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
                [265 ]Department of Medical Oncology, Beth Israel Deaconess Medical Center, Boston, MA, 02215, USA
                [266 ]Department of Pathology, University Hospital of Heraklion, Heraklion, 711 10, Greece
                [267 ]Frauenklinik der Stadtklinik Baden-Baden, Baden-Baden, 76532, Germany
                [268 ]Department of Health Science Research, Division of Epidemiology, Mayo Clinic, Rochester, MN, 55905, USA
                [269 ]Department of Clinical Genetics, Leiden University Medical Center, Leiden, 2333 ZA, The Netherlands
                [270 ]Department of Genetics, University of Pretoria, Arcadia, 0007, South Africa
                [271 ]Fundación Pública galega Medicina Xenómica-SERGAS, Grupo de Medicina Xenómica-USC, CIBERER, IDIS, Santiago de Compostela, Spain
                [272 ]Division of Functional onco-genomics and genetics, Centro di Riferimento Oncologico di Aviano (CRO), IRCCS, Aviano, 33081, Italy
                [273 ]Biostatistics and Computational Biology Branch, National Institute of Environmental Health Sciences, NIH, Research Triangle Park, NC, 27709, USA
                [274 ]Department of Surgical Sciences, Uppsala University, Uppsala, 751 05, Sweden
                [275 ]Division of Genetics and Epidemiology, Institute of Cancer Research, London, SM2 5NG, UK
                [276 ]Division of Psychosocial Research and Epidemiology, The Netherlands Cancer Institute - Antoni van Leeuwenhoek hospital, Amsterdam, 1066 CX, The Netherlands
                [277 ]Department of Cancer Genetics, Institute for Cancer Research, Oslo University Hospital-Radiumhospitalet, Oslo, 0379, Norway
                [278 ]Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, 0450, Norway
                Author notes
                [280]

                Senior author.

                Article
                EMS84721
                10.1038/s41588-019-0537-1
                6974400
                31911677
                b63b902b-e598-4752-a3a7-741acd5cae6e

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