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<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">Landscape of somatic mutations in 560 breast cancer whole genome sequences</title><author><name sortKey="Nik Zainal, Serena" sort="Nik Zainal, Serena" uniqKey="Nik Zainal S" first="Serena" last="Nik-Zainal">Serena Nik-Zainal</name><affiliation><nlm:aff id="A1">Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, UK</nlm:aff></affiliation><affiliation><nlm:aff id="A2">East Anglian Medical Genetics Service, Cambridge University Hospitals NHS Foundation Trust, Cambridge CB2 9NB, UK</nlm:aff></affiliation></author><author><name sortKey="Davies, Helen" sort="Davies, Helen" uniqKey="Davies H" first="Helen" last="Davies">Helen Davies</name><affiliation><nlm:aff id="A1">Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, UK</nlm:aff></affiliation></author><author><name sortKey="Staaf, Johan" sort="Staaf, Johan" uniqKey="Staaf J" first="Johan" last="Staaf">Johan Staaf</name><affiliation><nlm:aff id="A3">Division of Oncology and Pathology, Department of Clinical Sciences Lund, Lund University, Lund, Sweden</nlm:aff></affiliation></author><author><name sortKey="Ramakrishna, Manasa" sort="Ramakrishna, Manasa" uniqKey="Ramakrishna M" first="Manasa" last="Ramakrishna">Manasa Ramakrishna</name><affiliation><nlm:aff id="A1">Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, UK</nlm:aff></affiliation></author><author><name sortKey="Glodzik, Dominik" sort="Glodzik, Dominik" uniqKey="Glodzik D" first="Dominik" last="Glodzik">Dominik Glodzik</name><affiliation><nlm:aff id="A1">Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, UK</nlm:aff></affiliation></author><author><name sortKey="Zou, Xueqing" sort="Zou, Xueqing" uniqKey="Zou X" first="Xueqing" last="Zou">Xueqing Zou</name><affiliation><nlm:aff id="A1">Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, UK</nlm:aff></affiliation></author><author><name sortKey="Martincorena, Inigo" sort="Martincorena, Inigo" uniqKey="Martincorena I" first="Inigo" last="Martincorena">Inigo Martincorena</name><affiliation><nlm:aff id="A1">Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, UK</nlm:aff></affiliation></author><author><name sortKey="Alexandrov, Ludmil B" sort="Alexandrov, Ludmil B" uniqKey="Alexandrov L" first="Ludmil B." last="Alexandrov">Ludmil B. Alexandrov</name><affiliation><nlm:aff id="A1">Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, UK</nlm:aff></affiliation><affiliation><nlm:aff id="A4">Theoretical Biology and Biophysics (T-6), Los Alamos National Laboratory, Los Alamos, New Mexico, United States of America</nlm:aff></affiliation><affiliation><nlm:aff id="A5">Center for Nonlinear Studies, Los Alamos National Laboratory, Los Alamos, New Mexico, United States of America</nlm:aff></affiliation></author><author><name sortKey="Martin, Sancha" sort="Martin, Sancha" uniqKey="Martin S" first="Sancha" last="Martin">Sancha Martin</name><affiliation><nlm:aff id="A1">Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, UK</nlm:aff></affiliation></author><author><name sortKey="Wedge, David C" sort="Wedge, David C" uniqKey="Wedge D" first="David C." last="Wedge">David C. Wedge</name><affiliation><nlm:aff id="A1">Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, UK</nlm:aff></affiliation></author><author><name sortKey="Van Loo, Peter" sort="Van Loo, Peter" uniqKey="Van Loo P" first="Peter" last="Van Loo">Peter Van Loo</name><affiliation><nlm:aff id="A1">Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, UK</nlm:aff></affiliation><affiliation><nlm:aff id="A6">Department of Human Genetics, University of Leuven, B-3000 Leuven, Belgium</nlm:aff></affiliation></author><author><name sortKey="Ju, Young Seok" sort="Ju, Young Seok" uniqKey="Ju Y" first="Young Seok" last="Ju">Young Seok Ju</name><affiliation><nlm:aff id="A1">Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, UK</nlm:aff></affiliation></author><author><name sortKey="Smid, Marcel" sort="Smid, Marcel" uniqKey="Smid M" first="Marcel" last="Smid">Marcel Smid</name><affiliation><nlm:aff id="A7">Erasmus MC Cancer Institute and Cancer Genomics Netherlands, Erasmus University Medical Center, Department of Medical Oncology, Rotterdam, The Netherlands</nlm:aff></affiliation></author><author><name sortKey="Brinkman, Arie B" sort="Brinkman, Arie B" uniqKey="Brinkman A" first="Arie B" last="Brinkman">Arie B. Brinkman</name><affiliation><nlm:aff id="A8">Radboud University, Department of Molecular Biology, Faculties of Science and Medicine, Nijmegen, Netherlands</nlm:aff></affiliation></author><author><name sortKey="Morganella, Sandro" sort="Morganella, Sandro" uniqKey="Morganella S" first="Sandro" last="Morganella">Sandro Morganella</name><affiliation><nlm:aff id="A9">European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Trust Genome Campus,Hinxton, Cambridgeshire, CB10 1SD</nlm:aff></affiliation></author><author><name sortKey="Aure, Miriam R" sort="Aure, Miriam R" uniqKey="Aure M" first="Miriam R." last="Aure">Miriam R. Aure</name><affiliation><nlm:aff id="A10">Department of Cancer Genetics, Institute for Cancer Research, Oslo University Hospital The Norwegian Radiumhospital</nlm:aff></affiliation><affiliation><nlm:aff id="A11">K.G. Jebsen Centre for Breast Cancer Research, Institute for Clinical Medicine, University of Oslo, Oslo, Norway</nlm:aff></affiliation></author><author><name sortKey="Lingj Rde, Ole Christian" sort="Lingj Rde, Ole Christian" uniqKey="Lingj Rde O" first="Ole Christian" last="Lingj Rde">Ole Christian Lingj Rde</name><affiliation><nlm:aff id="A11">K.G. Jebsen Centre for Breast Cancer Research, Institute for Clinical Medicine, University of Oslo, Oslo, Norway</nlm:aff></affiliation><affiliation><nlm:aff id="A12">Department of Computer Science, University of Oslo, Oslo, Norway</nlm:aff></affiliation></author><author><name sortKey="Langer D, Anita" sort="Langer D, Anita" uniqKey="Langer D A" first="Anita" last="Langer D">Anita Langer D</name><affiliation><nlm:aff id="A10">Department of Cancer Genetics, Institute for Cancer Research, Oslo University Hospital The Norwegian Radiumhospital</nlm:aff></affiliation><affiliation><nlm:aff id="A11">K.G. Jebsen Centre for Breast Cancer Research, Institute for Clinical Medicine, University of Oslo, Oslo, Norway</nlm:aff></affiliation></author><author><name sortKey="Ringner, Markus" sort="Ringner, Markus" uniqKey="Ringner M" first="Markus" last="Ringnér">Markus Ringnér</name><affiliation><nlm:aff id="A3">Division of Oncology and Pathology, Department of Clinical Sciences Lund, Lund University, Lund, Sweden</nlm:aff></affiliation></author><author><name sortKey="Ahn, Sung Min" sort="Ahn, Sung Min" uniqKey="Ahn S" first="Sung-Min" last="Ahn">Sung-Min Ahn</name><affiliation><nlm:aff id="A13">Gachon Institute of Genome Medicine and Science, Gachon University Gil Medical Center, Incheon, South Korea</nlm:aff></affiliation></author><author><name sortKey="Boyault, Sandrine" sort="Boyault, Sandrine" uniqKey="Boyault S" first="Sandrine" last="Boyault">Sandrine Boyault</name><affiliation><nlm:aff id="A14">Translational Research Lab, Centre Léon Bérard, 28, rue Laënnec, 69373 Lyon Cedex 08, France</nlm:aff></affiliation></author><author><name sortKey="Brock, Jane E" sort="Brock, Jane E" uniqKey="Brock J" first="Jane E." last="Brock">Jane E. Brock</name><affiliation><nlm:aff id="A15">Department of Pathology, Brigham and Women’s Hospital, Boston, MA 02115 USA</nlm:aff></affiliation></author><author><name sortKey="Broeks, Annegien" sort="Broeks, Annegien" uniqKey="Broeks A" first="Annegien" last="Broeks">Annegien Broeks</name><affiliation><nlm:aff id="A16">The Netherlands Cancer Institute, 1066CX Amsterdam, The Netherlands</nlm:aff></affiliation></author><author><name sortKey="Butler, Adam" sort="Butler, Adam" uniqKey="Butler A" first="Adam" last="Butler">Adam Butler</name><affiliation><nlm:aff id="A1">Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, UK</nlm:aff></affiliation></author><author><name sortKey="Desmedt, Christine" sort="Desmedt, Christine" uniqKey="Desmedt C" first="Christine" last="Desmedt">Christine Desmedt</name><affiliation><nlm:aff id="A17">Breast Cancer Translational Research Laboratory, Université Libre de Bruxelles, Institut Jules Bordet, Bd de Waterloo 121, B-1000 Brussels, Belgium</nlm:aff></affiliation></author><author><name sortKey="Dirix, Luc" sort="Dirix, Luc" uniqKey="Dirix L" first="Luc" last="Dirix">Luc Dirix</name><affiliation><nlm:aff id="A18">Translational Cancer Research Unit, Center for Oncological Research, Faculty of Medicine and Health Sciences, University of Antwerp, Antwerp, Belgium</nlm:aff></affiliation></author><author><name sortKey="Dronov, Serge" sort="Dronov, Serge" uniqKey="Dronov S" first="Serge" last="Dronov">Serge Dronov</name><affiliation><nlm:aff id="A1">Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, UK</nlm:aff></affiliation></author><author><name sortKey="Fatima, Aquila" sort="Fatima, Aquila" uniqKey="Fatima A" first="Aquila" last="Fatima">Aquila Fatima</name><affiliation><nlm:aff id="A19">Dana-Farber Cancer Institute, Boston, MA 02215 USA</nlm:aff></affiliation></author><author><name sortKey="Foekens, John A" sort="Foekens, John A" uniqKey="Foekens J" first="John A." last="Foekens">John A. Foekens</name><affiliation><nlm:aff id="A7">Erasmus MC Cancer Institute and Cancer Genomics Netherlands, Erasmus University Medical Center, Department of Medical Oncology, Rotterdam, The Netherlands</nlm:aff></affiliation></author><author><name sortKey="Gerstung, Moritz" sort="Gerstung, Moritz" uniqKey="Gerstung M" first="Moritz" last="Gerstung">Moritz Gerstung</name><affiliation><nlm:aff id="A1">Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, UK</nlm:aff></affiliation></author><author><name sortKey="Hooijer, Gerrit Kj" sort="Hooijer, Gerrit Kj" uniqKey="Hooijer G" first="Gerrit Kj" last="Hooijer">Gerrit Kj Hooijer</name><affiliation><nlm:aff id="A20">Department of Pathology, Academic Medical Center, Meibergdreef 9, 1105 AZ Amsterdam, the Netherlands</nlm:aff></affiliation></author><author><name sortKey="Jang, Se Jin" sort="Jang, Se Jin" uniqKey="Jang S" first="Se Jin" last="Jang">Se Jin Jang</name><affiliation><nlm:aff id="A21">Department of Pathology, Asan Medical Center, College of Medicine, Ulsan University, South Korea</nlm:aff></affiliation></author><author><name sortKey="Jones, David R" sort="Jones, David R" uniqKey="Jones D" first="David R." last="Jones">David R. Jones</name><affiliation><nlm:aff id="A1">Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, UK</nlm:aff></affiliation></author><author><name sortKey="Kim, Hyung Yong" sort="Kim, Hyung Yong" uniqKey="Kim H" first="Hyung-Yong" last="Kim">Hyung-Yong Kim</name><affiliation><nlm:aff id="A22">Department of Pathology, College of Medicine, Hanyang University, Seoul, South Korea</nlm:aff></affiliation></author><author><name sortKey="King, Tari A" sort="King, Tari A" uniqKey="King T" first="Tari A." last="King">Tari A. King</name><affiliation><nlm:aff id="A23">Memorial Sloan Kettering Cancer Center, 1275 York Ave, New York, NY 10065, United States</nlm:aff></affiliation></author><author><name sortKey="Krishnamurthy, Savitri" sort="Krishnamurthy, Savitri" uniqKey="Krishnamurthy S" first="Savitri" last="Krishnamurthy">Savitri Krishnamurthy</name><affiliation><nlm:aff id="A24">Morgan Welch Inflammatory Breast Cancer Research Program and Clinic, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX 77030</nlm:aff></affiliation></author><author><name sortKey="Lee, Hee Jin" sort="Lee, Hee Jin" uniqKey="Lee H" first="Hee Jin" last="Lee">Hee Jin Lee</name><affiliation><nlm:aff id="A21">Department of Pathology, Asan Medical Center, College of Medicine, Ulsan University, South Korea</nlm:aff></affiliation></author><author><name sortKey="Lee, Jeong Yeon" sort="Lee, Jeong Yeon" uniqKey="Lee J" first="Jeong-Yeon" last="Lee">Jeong-Yeon Lee</name><affiliation><nlm:aff id="A25">Institute for Bioengineering and Biopharmaceutical Research (IBBR), Hanyang University, Seoul, South Korea</nlm:aff></affiliation></author><author><name sortKey="Li, Yilong" sort="Li, Yilong" uniqKey="Li Y" first="Yilong" last="Li">Yilong Li</name><affiliation><nlm:aff id="A1">Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, UK</nlm:aff></affiliation></author><author><name sortKey="Mclaren, Stuart" sort="Mclaren, Stuart" uniqKey="Mclaren S" first="Stuart" last="Mclaren">Stuart Mclaren</name><affiliation><nlm:aff id="A1">Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, UK</nlm:aff></affiliation></author><author><name sortKey="Menzies, Andrew" sort="Menzies, Andrew" uniqKey="Menzies A" first="Andrew" last="Menzies">Andrew Menzies</name><affiliation><nlm:aff id="A1">Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, UK</nlm:aff></affiliation></author><author><name sortKey="Mustonen, Ville" sort="Mustonen, Ville" uniqKey="Mustonen V" first="Ville" last="Mustonen">Ville Mustonen</name><affiliation><nlm:aff id="A1">Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, UK</nlm:aff></affiliation></author><author><name sortKey="O Eara, Sarah" sort="O Eara, Sarah" uniqKey="O Eara S" first="Sarah" last="O Eara">Sarah O Eara</name><affiliation><nlm:aff id="A1">Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, UK</nlm:aff></affiliation></author><author><name sortKey="Pauporte, Iris" sort="Pauporte, Iris" uniqKey="Pauporte I" first="Iris" last="Pauporté">Iris Pauporté</name><affiliation><nlm:aff id="A26">Institut National du Cancer, Research Division, Clinical Research Department, 52 avenue Morizet, 92513 Boulogne-Billancourt, France</nlm:aff></affiliation></author><author><name sortKey="Pivot, Xavier" sort="Pivot, Xavier" uniqKey="Pivot X" first="Xavier" last="Pivot">Xavier Pivot</name><affiliation><nlm:aff id="A27">University Hospital of Minjoz, INSERM UMR 1098, Bd Fleming, Besançon 25000, France</nlm:aff></affiliation></author><author><name sortKey="Purdie, Colin A" sort="Purdie, Colin A" uniqKey="Purdie C" first="Colin A." last="Purdie">Colin A. Purdie</name><affiliation><nlm:aff id="A28">Pathology Department, Ninewells Hospital & Medical School, Dundee DD1 9SY, UK</nlm:aff></affiliation></author><author><name sortKey="Raine, Keiran" sort="Raine, Keiran" uniqKey="Raine K" first="Keiran" last="Raine">Keiran Raine</name><affiliation><nlm:aff id="A1">Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, UK</nlm:aff></affiliation></author><author><name sortKey="Ramakrishnan, Kamna" sort="Ramakrishnan, Kamna" uniqKey="Ramakrishnan K" first="Kamna" last="Ramakrishnan">Kamna Ramakrishnan</name><affiliation><nlm:aff id="A1">Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, UK</nlm:aff></affiliation></author><author><name sortKey="Rodriguez Gonzalez, F German" sort="Rodriguez Gonzalez, F German" uniqKey="Rodriguez Gonzalez F" first="F. Germán" last="Rodríguez-González">F. Germán Rodríguez-González</name><affiliation><nlm:aff id="A7">Erasmus MC Cancer Institute and Cancer Genomics Netherlands, Erasmus University Medical Center, Department of Medical Oncology, Rotterdam, The Netherlands</nlm:aff></affiliation></author><author><name sortKey="Romieu, Gilles" sort="Romieu, Gilles" uniqKey="Romieu G" first="Gilles" last="Romieu">Gilles Romieu</name><affiliation><nlm:aff id="A29">Oncologie Sénologie, ICM Institut Régional du Cancer, Montpellier, France</nlm:aff></affiliation></author><author><name sortKey="Sieuwerts, Anieta M" sort="Sieuwerts, Anieta M" uniqKey="Sieuwerts A" first="Anieta M." last="Sieuwerts">Anieta M. Sieuwerts</name><affiliation><nlm:aff id="A7">Erasmus MC Cancer Institute and Cancer Genomics Netherlands, Erasmus University Medical Center, Department of Medical Oncology, Rotterdam, The Netherlands</nlm:aff></affiliation></author><author><name sortKey="Simpson, Peter T" sort="Simpson, Peter T" uniqKey="Simpson P" first="Peter T" last="Simpson">Peter T. Simpson</name><affiliation><nlm:aff id="A30">The University of Queensland: UQ Centre for Clinical Research and School of Medicine, Brisbane, Australia</nlm:aff></affiliation></author><author><name sortKey="Shepherd, Rebecca" sort="Shepherd, Rebecca" uniqKey="Shepherd R" first="Rebecca" last="Shepherd">Rebecca Shepherd</name><affiliation><nlm:aff id="A1">Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, UK</nlm:aff></affiliation></author><author><name sortKey="Stebbings, Lucy" sort="Stebbings, Lucy" uniqKey="Stebbings L" first="Lucy" last="Stebbings">Lucy Stebbings</name><affiliation><nlm:aff id="A1">Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, UK</nlm:aff></affiliation></author><author><name sortKey="Stefansson, Olafur A" sort="Stefansson, Olafur A" uniqKey="Stefansson O" first="Olafur A" last="Stefansson">Olafur A. Stefansson</name><affiliation><nlm:aff id="A31">Cancer Research Laboratory, Faculty of Medicine, University of Iceland, 101 Reykjavik, Iceland</nlm:aff></affiliation></author><author><name sortKey="Teague, Jon" sort="Teague, Jon" uniqKey="Teague J" first="Jon" last="Teague">Jon Teague</name><affiliation><nlm:aff id="A1">Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, UK</nlm:aff></affiliation></author><author><name sortKey="Tommasi, Stefania" sort="Tommasi, Stefania" uniqKey="Tommasi S" first="Stefania" last="Tommasi">Stefania Tommasi</name><affiliation><nlm:aff id="A32">IRCCS Istituto Tumori “Giovanni Paolo II”, Bari, Italy</nlm:aff></affiliation></author><author><name sortKey="Treilleux, Isabelle" sort="Treilleux, Isabelle" uniqKey="Treilleux I" first="Isabelle" last="Treilleux">Isabelle Treilleux</name><affiliation><nlm:aff id="A33">Department of Pathology, Centre Léon Bérard, 28 rue Laënnec, 69373 Lyon Cédex 08, France</nlm:aff></affiliation></author><author><name sortKey="Van Den Eynden, Gert G" sort="Van Den Eynden, Gert G" uniqKey="Van Den Eynden G" first="Gert G." last="Van Den Eynden">Gert G. Van Den Eynden</name><affiliation><nlm:aff id="A18">Translational Cancer Research Unit, Center for Oncological Research, Faculty of Medicine and Health Sciences, University of Antwerp, Antwerp, Belgium</nlm:aff></affiliation><affiliation><nlm:aff id="A34">Department of Pathology, GZA Hospitals Sint-Augustinus, Antwerp, Belgium</nlm:aff></affiliation></author><author><name sortKey="Vermeulen, Peter" sort="Vermeulen, Peter" uniqKey="Vermeulen P" first="Peter" last="Vermeulen">Peter Vermeulen</name><affiliation><nlm:aff id="A18">Translational Cancer Research Unit, Center for Oncological Research, Faculty of Medicine and Health Sciences, University of Antwerp, Antwerp, Belgium</nlm:aff></affiliation><affiliation><nlm:aff id="A34">Department of Pathology, GZA Hospitals Sint-Augustinus, Antwerp, Belgium</nlm:aff></affiliation></author><author><name sortKey="Vincent Salomon, Anne" sort="Vincent Salomon, Anne" uniqKey="Vincent Salomon A" first="Anne" last="Vincent-Salomon">Anne Vincent-Salomon</name><affiliation><nlm:aff id="A35">Institut Curie, Department of Pathology and INSERM U934, 26 rue d’Ulm, 75248 Paris Cedex 05, France</nlm:aff></affiliation></author><author><name sortKey="Yates, Lucy" sort="Yates, Lucy" uniqKey="Yates L" first="Lucy" last="Yates">Lucy Yates</name><affiliation><nlm:aff id="A1">Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, UK</nlm:aff></affiliation></author><author><name sortKey="Caldas, Carlos" sort="Caldas, Carlos" uniqKey="Caldas C" first="Carlos" last="Caldas">Carlos Caldas</name><affiliation><nlm:aff id="A36">Cancer Research UK Cambridge Institute, University of Cambridge, Li Ka Shing Centre, Robinson Way, Cambridge CB2 0RE, United Kingdom</nlm:aff></affiliation></author><author><name sortKey="Van Veer, Laura" sort="Van Veer, Laura" uniqKey="Van Veer L" first="Laura" last="Van Veer">Laura Van Veer</name><affiliation><nlm:aff id="A16">The Netherlands Cancer Institute, 1066CX Amsterdam, The Netherlands</nlm:aff></affiliation></author><author><name sortKey="Tutt, Andrew" sort="Tutt, Andrew" uniqKey="Tutt A" first="Andrew" last="Tutt">Andrew Tutt</name><affiliation><nlm:aff id="A37">Breast Cancer Now Toby Research Unit, King’s College London</nlm:aff></affiliation><affiliation><nlm:aff id="A38">Breast Cancer Now Toby Robin’s Research Centre, Institute of Cancer Research, London</nlm:aff></affiliation></author><author><name sortKey="Knappskog, Stian" sort="Knappskog, Stian" uniqKey="Knappskog S" first="Stian" last="Knappskog">Stian Knappskog</name><affiliation><nlm:aff id="A39">Department of Clinical Science, University of Bergen, 5020 Bergen, Norway</nlm:aff></affiliation><affiliation><nlm:aff id="A40">Department of Oncology, Haukeland University Hospital, 5021 Bergen, Norway</nlm:aff></affiliation></author><author><name sortKey="Tan, Benita Kiat Tee" sort="Tan, Benita Kiat Tee" uniqKey="Tan B" first="Benita Kiat Tee" last="Tan">Benita Kiat Tee Tan</name><affiliation><nlm:aff id="A41">National Cancer Centre Singapore, 11 Hospital Drive, Singapore 169610</nlm:aff></affiliation><affiliation><nlm:aff id="A42">Singapore General Hospital, Outram Road, Singapore 169608</nlm:aff></affiliation></author><author><name sortKey="Jonkers, Jos" sort="Jonkers, Jos" uniqKey="Jonkers J" first="Jos" last="Jonkers">Jos Jonkers</name><affiliation><nlm:aff id="A16">The Netherlands Cancer Institute, 1066CX Amsterdam, The Netherlands</nlm:aff></affiliation></author><author><name sortKey="Borg, Ke" sort="Borg, Ke" uniqKey="Borg " first=" Ke" last="Borg"> Ke Borg</name><affiliation><nlm:aff id="A3">Division of Oncology and Pathology, Department of Clinical Sciences Lund, Lund University, Lund, Sweden</nlm:aff></affiliation></author><author><name sortKey="Ueno, Naoto T" sort="Ueno, Naoto T" uniqKey="Ueno N" first="Naoto T" last="Ueno">Naoto T. Ueno</name><affiliation><nlm:aff id="A24">Morgan Welch Inflammatory Breast Cancer Research Program and Clinic, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX 77030</nlm:aff></affiliation></author><author><name sortKey="Sotiriou, Christos" sort="Sotiriou, Christos" uniqKey="Sotiriou C" first="Christos" last="Sotiriou">Christos Sotiriou</name><affiliation><nlm:aff id="A17">Breast Cancer Translational Research Laboratory, Université Libre de Bruxelles, Institut Jules Bordet, Bd de Waterloo 121, B-1000 Brussels, Belgium</nlm:aff></affiliation></author><author><name sortKey="Viari, Alain" sort="Viari, Alain" uniqKey="Viari A" first="Alain" last="Viari">Alain Viari</name><affiliation><nlm:aff id="A43">Equipe Erable, INRIA Grenoble-Rhône-Alpes, 655, Av. de l’Europe, 38330 Montbonnot-Saint Martin, France</nlm:aff></affiliation><affiliation><nlm:aff id="A44">Synergie Lyon Cancer, Centre Léon Bérard, 28 rue Laënnec, Lyon Cedex 08, France</nlm:aff></affiliation></author><author><name sortKey="Futreal, P Andrew" sort="Futreal, P Andrew" uniqKey="Futreal P" first="P. Andrew" last="Futreal">P. Andrew Futreal</name><affiliation><nlm:aff id="A1">Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, UK</nlm:aff></affiliation><affiliation><nlm:aff id="A45">Department of Genomic Medicine, UT MD Anderson Cancer Center, Houston, TX, 77230</nlm:aff></affiliation></author><author><name sortKey="Campbell, Peter J" sort="Campbell, Peter J" uniqKey="Campbell P" first="Peter J" last="Campbell">Peter J. Campbell</name><affiliation><nlm:aff id="A1">Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, UK</nlm:aff></affiliation></author><author><name sortKey="Span, Paul N" sort="Span, Paul N" uniqKey="Span P" first="Paul N." last="Span">Paul N. Span</name><affiliation><nlm:aff id="A46">Department of Radiation Oncology, and department of Laboratory Medicine, Radboud university medical center, Nijmegen, the Netherlands</nlm:aff></affiliation></author><author><name sortKey="Van Laere, Steven" sort="Van Laere, Steven" uniqKey="Van Laere S" first="Steven" last="Van Laere">Steven Van Laere</name><affiliation><nlm:aff id="A18">Translational Cancer Research Unit, Center for Oncological Research, Faculty of Medicine and Health Sciences, University of Antwerp, Antwerp, Belgium</nlm:aff></affiliation></author><author><name sortKey="Lakhani, Sunil R" sort="Lakhani, Sunil R" uniqKey="Lakhani S" first="Sunil R" last="Lakhani">Sunil R. Lakhani</name><affiliation><nlm:aff id="A30">The University of Queensland: UQ Centre for Clinical Research and School of Medicine, Brisbane, Australia</nlm:aff></affiliation><affiliation><nlm:aff id="A47">Pathology Queensland, The Royal Brisbane and Women’s Hospital, Brisbane, Australia</nlm:aff></affiliation></author><author><name sortKey="Eyfjord, Jorunn E" sort="Eyfjord, Jorunn E" uniqKey="Eyfjord J" first="Jorunn E." last="Eyfjord">Jorunn E. Eyfjord</name><affiliation><nlm:aff id="A31">Cancer Research Laboratory, Faculty of Medicine, University of Iceland, 101 Reykjavik, Iceland</nlm:aff></affiliation></author><author><name sortKey="Thompson, Alastair M" sort="Thompson, Alastair M" uniqKey="Thompson A" first="Alastair M." last="Thompson">Alastair M. Thompson</name><affiliation><nlm:aff id="A24">Morgan Welch Inflammatory Breast Cancer Research Program and Clinic, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX 77030</nlm:aff></affiliation><affiliation><nlm:aff id="A48">Department of Surgical Oncology, University of Texas MD Anderson Cancer Center, 1400 Pressler Street,Houston, Texas 77030</nlm:aff></affiliation></author><author><name sortKey="Birney, Ewan" sort="Birney, Ewan" uniqKey="Birney E" first="Ewan" last="Birney">Ewan Birney</name><affiliation><nlm:aff id="A9">European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Trust Genome Campus,Hinxton, Cambridgeshire, CB10 1SD</nlm:aff></affiliation></author><author><name sortKey="Stunnenberg, Hendrik G" sort="Stunnenberg, Hendrik G" uniqKey="Stunnenberg H" first="Hendrik G" last="Stunnenberg">Hendrik G. Stunnenberg</name><affiliation><nlm:aff id="A8">Radboud University, Department of Molecular Biology, Faculties of Science and Medicine, Nijmegen, Netherlands</nlm:aff></affiliation></author><author><name sortKey="Van De Vijver, Marc J" sort="Van De Vijver, Marc J" uniqKey="Van De Vijver M" first="Marc J" last="Van De Vijver">Marc J. Van De Vijver</name><affiliation><nlm:aff id="A20">Department of Pathology, Academic Medical Center, Meibergdreef 9, 1105 AZ Amsterdam, the Netherlands</nlm:aff></affiliation></author><author><name sortKey="Martens, John W M" sort="Martens, John W M" uniqKey="Martens J" first="John W. M." last="Martens">John W. M. Martens</name><affiliation><nlm:aff id="A7">Erasmus MC Cancer Institute and Cancer Genomics Netherlands, Erasmus University Medical Center, Department of Medical Oncology, Rotterdam, The Netherlands</nlm:aff></affiliation></author><author><name sortKey="B Rresen Dale, Anne Lise" sort="B Rresen Dale, Anne Lise" uniqKey="B Rresen Dale A" first="Anne-Lise" last="B Rresen-Dale">Anne-Lise B Rresen-Dale</name><affiliation><nlm:aff id="A10">Department of Cancer Genetics, Institute for Cancer Research, Oslo University Hospital The Norwegian Radiumhospital</nlm:aff></affiliation><affiliation><nlm:aff id="A11">K.G. Jebsen Centre for Breast Cancer Research, Institute for Clinical Medicine, University of Oslo, Oslo, Norway</nlm:aff></affiliation></author><author><name sortKey="Richardson, Andrea L" sort="Richardson, Andrea L" uniqKey="Richardson A" first="Andrea L." last="Richardson">Andrea L. Richardson</name><affiliation><nlm:aff id="A15">Department of Pathology, Brigham and Women’s Hospital, Boston, MA 02115 USA</nlm:aff></affiliation><affiliation><nlm:aff id="A19">Dana-Farber Cancer Institute, Boston, MA 02215 USA</nlm:aff></affiliation></author><author><name sortKey="Kong, Gu" sort="Kong, Gu" uniqKey="Kong G" first="Gu" last="Kong">Gu Kong</name><affiliation><nlm:aff id="A22">Department of Pathology, College of Medicine, Hanyang University, Seoul, South Korea</nlm:aff></affiliation></author><author><name sortKey="Thomas, Gilles" sort="Thomas, Gilles" uniqKey="Thomas G" first="Gilles" last="Thomas">Gilles Thomas</name><affiliation><nlm:aff id="A44">Synergie Lyon Cancer, Centre Léon Bérard, 28 rue Laënnec, Lyon Cedex 08, France</nlm:aff></affiliation></author><author><name sortKey="Stratton, Michael R" sort="Stratton, Michael R" uniqKey="Stratton M" first="Michael R." last="Stratton">Michael R. Stratton</name><affiliation><nlm:aff id="A1">Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, UK</nlm:aff></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PMC</idno><idno type="pmid">27135926</idno><idno type="pmc">4910866</idno><idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4910866</idno><idno type="RBID">PMC:4910866</idno><idno type="doi">10.1038/nature17676</idno><date when="2016">2016</date><idno type="wicri:Area/Pmc/Corpus">002D71</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">002D71</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">Landscape of somatic mutations in 560 breast cancer whole genome sequences</title><author><name sortKey="Nik Zainal, Serena" sort="Nik Zainal, Serena" uniqKey="Nik Zainal S" first="Serena" last="Nik-Zainal">Serena Nik-Zainal</name><affiliation><nlm:aff id="A1">Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, UK</nlm:aff></affiliation><affiliation><nlm:aff id="A2">East Anglian Medical Genetics Service, Cambridge University Hospitals NHS Foundation Trust, Cambridge CB2 9NB, UK</nlm:aff></affiliation></author><author><name sortKey="Davies, Helen" sort="Davies, Helen" uniqKey="Davies H" first="Helen" last="Davies">Helen Davies</name><affiliation><nlm:aff id="A1">Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, UK</nlm:aff></affiliation></author><author><name sortKey="Staaf, Johan" sort="Staaf, Johan" uniqKey="Staaf J" first="Johan" last="Staaf">Johan Staaf</name><affiliation><nlm:aff id="A3">Division of Oncology and Pathology, Department of Clinical Sciences Lund, Lund University, Lund, Sweden</nlm:aff></affiliation></author><author><name sortKey="Ramakrishna, Manasa" sort="Ramakrishna, Manasa" uniqKey="Ramakrishna M" first="Manasa" last="Ramakrishna">Manasa Ramakrishna</name><affiliation><nlm:aff id="A1">Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, UK</nlm:aff></affiliation></author><author><name sortKey="Glodzik, Dominik" sort="Glodzik, Dominik" uniqKey="Glodzik D" first="Dominik" last="Glodzik">Dominik Glodzik</name><affiliation><nlm:aff id="A1">Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, UK</nlm:aff></affiliation></author><author><name sortKey="Zou, Xueqing" sort="Zou, Xueqing" uniqKey="Zou X" first="Xueqing" last="Zou">Xueqing Zou</name><affiliation><nlm:aff id="A1">Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, UK</nlm:aff></affiliation></author><author><name sortKey="Martincorena, Inigo" sort="Martincorena, Inigo" uniqKey="Martincorena I" first="Inigo" last="Martincorena">Inigo Martincorena</name><affiliation><nlm:aff id="A1">Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, UK</nlm:aff></affiliation></author><author><name sortKey="Alexandrov, Ludmil B" sort="Alexandrov, Ludmil B" uniqKey="Alexandrov L" first="Ludmil B." last="Alexandrov">Ludmil B. Alexandrov</name><affiliation><nlm:aff id="A1">Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, UK</nlm:aff></affiliation><affiliation><nlm:aff id="A4">Theoretical Biology and Biophysics (T-6), Los Alamos National Laboratory, Los Alamos, New Mexico, United States of America</nlm:aff></affiliation><affiliation><nlm:aff id="A5">Center for Nonlinear Studies, Los Alamos National Laboratory, Los Alamos, New Mexico, United States of America</nlm:aff></affiliation></author><author><name sortKey="Martin, Sancha" sort="Martin, Sancha" uniqKey="Martin S" first="Sancha" last="Martin">Sancha Martin</name><affiliation><nlm:aff id="A1">Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, UK</nlm:aff></affiliation></author><author><name sortKey="Wedge, David C" sort="Wedge, David C" uniqKey="Wedge D" first="David C." last="Wedge">David C. Wedge</name><affiliation><nlm:aff id="A1">Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, UK</nlm:aff></affiliation></author><author><name sortKey="Van Loo, Peter" sort="Van Loo, Peter" uniqKey="Van Loo P" first="Peter" last="Van Loo">Peter Van Loo</name><affiliation><nlm:aff id="A1">Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, UK</nlm:aff></affiliation><affiliation><nlm:aff id="A6">Department of Human Genetics, University of Leuven, B-3000 Leuven, Belgium</nlm:aff></affiliation></author><author><name sortKey="Ju, Young Seok" sort="Ju, Young Seok" uniqKey="Ju Y" first="Young Seok" last="Ju">Young Seok Ju</name><affiliation><nlm:aff id="A1">Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, UK</nlm:aff></affiliation></author><author><name sortKey="Smid, Marcel" sort="Smid, Marcel" uniqKey="Smid M" first="Marcel" last="Smid">Marcel Smid</name><affiliation><nlm:aff id="A7">Erasmus MC Cancer Institute and Cancer Genomics Netherlands, Erasmus University Medical Center, Department of Medical Oncology, Rotterdam, The Netherlands</nlm:aff></affiliation></author><author><name sortKey="Brinkman, Arie B" sort="Brinkman, Arie B" uniqKey="Brinkman A" first="Arie B" last="Brinkman">Arie B. Brinkman</name><affiliation><nlm:aff id="A8">Radboud University, Department of Molecular Biology, Faculties of Science and Medicine, Nijmegen, Netherlands</nlm:aff></affiliation></author><author><name sortKey="Morganella, Sandro" sort="Morganella, Sandro" uniqKey="Morganella S" first="Sandro" last="Morganella">Sandro Morganella</name><affiliation><nlm:aff id="A9">European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Trust Genome Campus,Hinxton, Cambridgeshire, CB10 1SD</nlm:aff></affiliation></author><author><name sortKey="Aure, Miriam R" sort="Aure, Miriam R" uniqKey="Aure M" first="Miriam R." last="Aure">Miriam R. Aure</name><affiliation><nlm:aff id="A10">Department of Cancer Genetics, Institute for Cancer Research, Oslo University Hospital The Norwegian Radiumhospital</nlm:aff></affiliation><affiliation><nlm:aff id="A11">K.G. Jebsen Centre for Breast Cancer Research, Institute for Clinical Medicine, University of Oslo, Oslo, Norway</nlm:aff></affiliation></author><author><name sortKey="Lingj Rde, Ole Christian" sort="Lingj Rde, Ole Christian" uniqKey="Lingj Rde O" first="Ole Christian" last="Lingj Rde">Ole Christian Lingj Rde</name><affiliation><nlm:aff id="A11">K.G. Jebsen Centre for Breast Cancer Research, Institute for Clinical Medicine, University of Oslo, Oslo, Norway</nlm:aff></affiliation><affiliation><nlm:aff id="A12">Department of Computer Science, University of Oslo, Oslo, Norway</nlm:aff></affiliation></author><author><name sortKey="Langer D, Anita" sort="Langer D, Anita" uniqKey="Langer D A" first="Anita" last="Langer D">Anita Langer D</name><affiliation><nlm:aff id="A10">Department of Cancer Genetics, Institute for Cancer Research, Oslo University Hospital The Norwegian Radiumhospital</nlm:aff></affiliation><affiliation><nlm:aff id="A11">K.G. Jebsen Centre for Breast Cancer Research, Institute for Clinical Medicine, University of Oslo, Oslo, Norway</nlm:aff></affiliation></author><author><name sortKey="Ringner, Markus" sort="Ringner, Markus" uniqKey="Ringner M" first="Markus" last="Ringnér">Markus Ringnér</name><affiliation><nlm:aff id="A3">Division of Oncology and Pathology, Department of Clinical Sciences Lund, Lund University, Lund, Sweden</nlm:aff></affiliation></author><author><name sortKey="Ahn, Sung Min" sort="Ahn, Sung Min" uniqKey="Ahn S" first="Sung-Min" last="Ahn">Sung-Min Ahn</name><affiliation><nlm:aff id="A13">Gachon Institute of Genome Medicine and Science, Gachon University Gil Medical Center, Incheon, South Korea</nlm:aff></affiliation></author><author><name sortKey="Boyault, Sandrine" sort="Boyault, Sandrine" uniqKey="Boyault S" first="Sandrine" last="Boyault">Sandrine Boyault</name><affiliation><nlm:aff id="A14">Translational Research Lab, Centre Léon Bérard, 28, rue Laënnec, 69373 Lyon Cedex 08, France</nlm:aff></affiliation></author><author><name sortKey="Brock, Jane E" sort="Brock, Jane E" uniqKey="Brock J" first="Jane E." last="Brock">Jane E. Brock</name><affiliation><nlm:aff id="A15">Department of Pathology, Brigham and Women’s Hospital, Boston, MA 02115 USA</nlm:aff></affiliation></author><author><name sortKey="Broeks, Annegien" sort="Broeks, Annegien" uniqKey="Broeks A" first="Annegien" last="Broeks">Annegien Broeks</name><affiliation><nlm:aff id="A16">The Netherlands Cancer Institute, 1066CX Amsterdam, The Netherlands</nlm:aff></affiliation></author><author><name sortKey="Butler, Adam" sort="Butler, Adam" uniqKey="Butler A" first="Adam" last="Butler">Adam Butler</name><affiliation><nlm:aff id="A1">Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, UK</nlm:aff></affiliation></author><author><name sortKey="Desmedt, Christine" sort="Desmedt, Christine" uniqKey="Desmedt C" first="Christine" last="Desmedt">Christine Desmedt</name><affiliation><nlm:aff id="A17">Breast Cancer Translational Research Laboratory, Université Libre de Bruxelles, Institut Jules Bordet, Bd de Waterloo 121, B-1000 Brussels, Belgium</nlm:aff></affiliation></author><author><name sortKey="Dirix, Luc" sort="Dirix, Luc" uniqKey="Dirix L" first="Luc" last="Dirix">Luc Dirix</name><affiliation><nlm:aff id="A18">Translational Cancer Research Unit, Center for Oncological Research, Faculty of Medicine and Health Sciences, University of Antwerp, Antwerp, Belgium</nlm:aff></affiliation></author><author><name sortKey="Dronov, Serge" sort="Dronov, Serge" uniqKey="Dronov S" first="Serge" last="Dronov">Serge Dronov</name><affiliation><nlm:aff id="A1">Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, UK</nlm:aff></affiliation></author><author><name sortKey="Fatima, Aquila" sort="Fatima, Aquila" uniqKey="Fatima A" first="Aquila" last="Fatima">Aquila Fatima</name><affiliation><nlm:aff id="A19">Dana-Farber Cancer Institute, Boston, MA 02215 USA</nlm:aff></affiliation></author><author><name sortKey="Foekens, John A" sort="Foekens, John A" uniqKey="Foekens J" first="John A." last="Foekens">John A. Foekens</name><affiliation><nlm:aff id="A7">Erasmus MC Cancer Institute and Cancer Genomics Netherlands, Erasmus University Medical Center, Department of Medical Oncology, Rotterdam, The Netherlands</nlm:aff></affiliation></author><author><name sortKey="Gerstung, Moritz" sort="Gerstung, Moritz" uniqKey="Gerstung M" first="Moritz" last="Gerstung">Moritz Gerstung</name><affiliation><nlm:aff id="A1">Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, UK</nlm:aff></affiliation></author><author><name sortKey="Hooijer, Gerrit Kj" sort="Hooijer, Gerrit Kj" uniqKey="Hooijer G" first="Gerrit Kj" last="Hooijer">Gerrit Kj Hooijer</name><affiliation><nlm:aff id="A20">Department of Pathology, Academic Medical Center, Meibergdreef 9, 1105 AZ Amsterdam, the Netherlands</nlm:aff></affiliation></author><author><name sortKey="Jang, Se Jin" sort="Jang, Se Jin" uniqKey="Jang S" first="Se Jin" last="Jang">Se Jin Jang</name><affiliation><nlm:aff id="A21">Department of Pathology, Asan Medical Center, College of Medicine, Ulsan University, South Korea</nlm:aff></affiliation></author><author><name sortKey="Jones, David R" sort="Jones, David R" uniqKey="Jones D" first="David R." last="Jones">David R. Jones</name><affiliation><nlm:aff id="A1">Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, UK</nlm:aff></affiliation></author><author><name sortKey="Kim, Hyung Yong" sort="Kim, Hyung Yong" uniqKey="Kim H" first="Hyung-Yong" last="Kim">Hyung-Yong Kim</name><affiliation><nlm:aff id="A22">Department of Pathology, College of Medicine, Hanyang University, Seoul, South Korea</nlm:aff></affiliation></author><author><name sortKey="King, Tari A" sort="King, Tari A" uniqKey="King T" first="Tari A." last="King">Tari A. King</name><affiliation><nlm:aff id="A23">Memorial Sloan Kettering Cancer Center, 1275 York Ave, New York, NY 10065, United States</nlm:aff></affiliation></author><author><name sortKey="Krishnamurthy, Savitri" sort="Krishnamurthy, Savitri" uniqKey="Krishnamurthy S" first="Savitri" last="Krishnamurthy">Savitri Krishnamurthy</name><affiliation><nlm:aff id="A24">Morgan Welch Inflammatory Breast Cancer Research Program and Clinic, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX 77030</nlm:aff></affiliation></author><author><name sortKey="Lee, Hee Jin" sort="Lee, Hee Jin" uniqKey="Lee H" first="Hee Jin" last="Lee">Hee Jin Lee</name><affiliation><nlm:aff id="A21">Department of Pathology, Asan Medical Center, College of Medicine, Ulsan University, South Korea</nlm:aff></affiliation></author><author><name sortKey="Lee, Jeong Yeon" sort="Lee, Jeong Yeon" uniqKey="Lee J" first="Jeong-Yeon" last="Lee">Jeong-Yeon Lee</name><affiliation><nlm:aff id="A25">Institute for Bioengineering and Biopharmaceutical Research (IBBR), Hanyang University, Seoul, South Korea</nlm:aff></affiliation></author><author><name sortKey="Li, Yilong" sort="Li, Yilong" uniqKey="Li Y" first="Yilong" last="Li">Yilong Li</name><affiliation><nlm:aff id="A1">Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, UK</nlm:aff></affiliation></author><author><name sortKey="Mclaren, Stuart" sort="Mclaren, Stuart" uniqKey="Mclaren S" first="Stuart" last="Mclaren">Stuart Mclaren</name><affiliation><nlm:aff id="A1">Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, UK</nlm:aff></affiliation></author><author><name sortKey="Menzies, Andrew" sort="Menzies, Andrew" uniqKey="Menzies A" first="Andrew" last="Menzies">Andrew Menzies</name><affiliation><nlm:aff id="A1">Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, UK</nlm:aff></affiliation></author><author><name sortKey="Mustonen, Ville" sort="Mustonen, Ville" uniqKey="Mustonen V" first="Ville" last="Mustonen">Ville Mustonen</name><affiliation><nlm:aff id="A1">Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, UK</nlm:aff></affiliation></author><author><name sortKey="O Eara, Sarah" sort="O Eara, Sarah" uniqKey="O Eara S" first="Sarah" last="O Eara">Sarah O Eara</name><affiliation><nlm:aff id="A1">Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, UK</nlm:aff></affiliation></author><author><name sortKey="Pauporte, Iris" sort="Pauporte, Iris" uniqKey="Pauporte I" first="Iris" last="Pauporté">Iris Pauporté</name><affiliation><nlm:aff id="A26">Institut National du Cancer, Research Division, Clinical Research Department, 52 avenue Morizet, 92513 Boulogne-Billancourt, France</nlm:aff></affiliation></author><author><name sortKey="Pivot, Xavier" sort="Pivot, Xavier" uniqKey="Pivot X" first="Xavier" last="Pivot">Xavier Pivot</name><affiliation><nlm:aff id="A27">University Hospital of Minjoz, INSERM UMR 1098, Bd Fleming, Besançon 25000, France</nlm:aff></affiliation></author><author><name sortKey="Purdie, Colin A" sort="Purdie, Colin A" uniqKey="Purdie C" first="Colin A." last="Purdie">Colin A. Purdie</name><affiliation><nlm:aff id="A28">Pathology Department, Ninewells Hospital & Medical School, Dundee DD1 9SY, UK</nlm:aff></affiliation></author><author><name sortKey="Raine, Keiran" sort="Raine, Keiran" uniqKey="Raine K" first="Keiran" last="Raine">Keiran Raine</name><affiliation><nlm:aff id="A1">Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, UK</nlm:aff></affiliation></author><author><name sortKey="Ramakrishnan, Kamna" sort="Ramakrishnan, Kamna" uniqKey="Ramakrishnan K" first="Kamna" last="Ramakrishnan">Kamna Ramakrishnan</name><affiliation><nlm:aff id="A1">Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, UK</nlm:aff></affiliation></author><author><name sortKey="Rodriguez Gonzalez, F German" sort="Rodriguez Gonzalez, F German" uniqKey="Rodriguez Gonzalez F" first="F. Germán" last="Rodríguez-González">F. Germán Rodríguez-González</name><affiliation><nlm:aff id="A7">Erasmus MC Cancer Institute and Cancer Genomics Netherlands, Erasmus University Medical Center, Department of Medical Oncology, Rotterdam, The Netherlands</nlm:aff></affiliation></author><author><name sortKey="Romieu, Gilles" sort="Romieu, Gilles" uniqKey="Romieu G" first="Gilles" last="Romieu">Gilles Romieu</name><affiliation><nlm:aff id="A29">Oncologie Sénologie, ICM Institut Régional du Cancer, Montpellier, France</nlm:aff></affiliation></author><author><name sortKey="Sieuwerts, Anieta M" sort="Sieuwerts, Anieta M" uniqKey="Sieuwerts A" first="Anieta M." last="Sieuwerts">Anieta M. Sieuwerts</name><affiliation><nlm:aff id="A7">Erasmus MC Cancer Institute and Cancer Genomics Netherlands, Erasmus University Medical Center, Department of Medical Oncology, Rotterdam, The Netherlands</nlm:aff></affiliation></author><author><name sortKey="Simpson, Peter T" sort="Simpson, Peter T" uniqKey="Simpson P" first="Peter T" last="Simpson">Peter T. Simpson</name><affiliation><nlm:aff id="A30">The University of Queensland: UQ Centre for Clinical Research and School of Medicine, Brisbane, Australia</nlm:aff></affiliation></author><author><name sortKey="Shepherd, Rebecca" sort="Shepherd, Rebecca" uniqKey="Shepherd R" first="Rebecca" last="Shepherd">Rebecca Shepherd</name><affiliation><nlm:aff id="A1">Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, UK</nlm:aff></affiliation></author><author><name sortKey="Stebbings, Lucy" sort="Stebbings, Lucy" uniqKey="Stebbings L" first="Lucy" last="Stebbings">Lucy Stebbings</name><affiliation><nlm:aff id="A1">Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, UK</nlm:aff></affiliation></author><author><name sortKey="Stefansson, Olafur A" sort="Stefansson, Olafur A" uniqKey="Stefansson O" first="Olafur A" last="Stefansson">Olafur A. Stefansson</name><affiliation><nlm:aff id="A31">Cancer Research Laboratory, Faculty of Medicine, University of Iceland, 101 Reykjavik, Iceland</nlm:aff></affiliation></author><author><name sortKey="Teague, Jon" sort="Teague, Jon" uniqKey="Teague J" first="Jon" last="Teague">Jon Teague</name><affiliation><nlm:aff id="A1">Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, UK</nlm:aff></affiliation></author><author><name sortKey="Tommasi, Stefania" sort="Tommasi, Stefania" uniqKey="Tommasi S" first="Stefania" last="Tommasi">Stefania Tommasi</name><affiliation><nlm:aff id="A32">IRCCS Istituto Tumori “Giovanni Paolo II”, Bari, Italy</nlm:aff></affiliation></author><author><name sortKey="Treilleux, Isabelle" sort="Treilleux, Isabelle" uniqKey="Treilleux I" first="Isabelle" last="Treilleux">Isabelle Treilleux</name><affiliation><nlm:aff id="A33">Department of Pathology, Centre Léon Bérard, 28 rue Laënnec, 69373 Lyon Cédex 08, France</nlm:aff></affiliation></author><author><name sortKey="Van Den Eynden, Gert G" sort="Van Den Eynden, Gert G" uniqKey="Van Den Eynden G" first="Gert G." last="Van Den Eynden">Gert G. Van Den Eynden</name><affiliation><nlm:aff id="A18">Translational Cancer Research Unit, Center for Oncological Research, Faculty of Medicine and Health Sciences, University of Antwerp, Antwerp, Belgium</nlm:aff></affiliation><affiliation><nlm:aff id="A34">Department of Pathology, GZA Hospitals Sint-Augustinus, Antwerp, Belgium</nlm:aff></affiliation></author><author><name sortKey="Vermeulen, Peter" sort="Vermeulen, Peter" uniqKey="Vermeulen P" first="Peter" last="Vermeulen">Peter Vermeulen</name><affiliation><nlm:aff id="A18">Translational Cancer Research Unit, Center for Oncological Research, Faculty of Medicine and Health Sciences, University of Antwerp, Antwerp, Belgium</nlm:aff></affiliation><affiliation><nlm:aff id="A34">Department of Pathology, GZA Hospitals Sint-Augustinus, Antwerp, Belgium</nlm:aff></affiliation></author><author><name sortKey="Vincent Salomon, Anne" sort="Vincent Salomon, Anne" uniqKey="Vincent Salomon A" first="Anne" last="Vincent-Salomon">Anne Vincent-Salomon</name><affiliation><nlm:aff id="A35">Institut Curie, Department of Pathology and INSERM U934, 26 rue d’Ulm, 75248 Paris Cedex 05, France</nlm:aff></affiliation></author><author><name sortKey="Yates, Lucy" sort="Yates, Lucy" uniqKey="Yates L" first="Lucy" last="Yates">Lucy Yates</name><affiliation><nlm:aff id="A1">Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, UK</nlm:aff></affiliation></author><author><name sortKey="Caldas, Carlos" sort="Caldas, Carlos" uniqKey="Caldas C" first="Carlos" last="Caldas">Carlos Caldas</name><affiliation><nlm:aff id="A36">Cancer Research UK Cambridge Institute, University of Cambridge, Li Ka Shing Centre, Robinson Way, Cambridge CB2 0RE, United Kingdom</nlm:aff></affiliation></author><author><name sortKey="Van Veer, Laura" sort="Van Veer, Laura" uniqKey="Van Veer L" first="Laura" last="Van Veer">Laura Van Veer</name><affiliation><nlm:aff id="A16">The Netherlands Cancer Institute, 1066CX Amsterdam, The Netherlands</nlm:aff></affiliation></author><author><name sortKey="Tutt, Andrew" sort="Tutt, Andrew" uniqKey="Tutt A" first="Andrew" last="Tutt">Andrew Tutt</name><affiliation><nlm:aff id="A37">Breast Cancer Now Toby Research Unit, King’s College London</nlm:aff></affiliation><affiliation><nlm:aff id="A38">Breast Cancer Now Toby Robin’s Research Centre, Institute of Cancer Research, London</nlm:aff></affiliation></author><author><name sortKey="Knappskog, Stian" sort="Knappskog, Stian" uniqKey="Knappskog S" first="Stian" last="Knappskog">Stian Knappskog</name><affiliation><nlm:aff id="A39">Department of Clinical Science, University of Bergen, 5020 Bergen, Norway</nlm:aff></affiliation><affiliation><nlm:aff id="A40">Department of Oncology, Haukeland University Hospital, 5021 Bergen, Norway</nlm:aff></affiliation></author><author><name sortKey="Tan, Benita Kiat Tee" sort="Tan, Benita Kiat Tee" uniqKey="Tan B" first="Benita Kiat Tee" last="Tan">Benita Kiat Tee Tan</name><affiliation><nlm:aff id="A41">National Cancer Centre Singapore, 11 Hospital Drive, Singapore 169610</nlm:aff></affiliation><affiliation><nlm:aff id="A42">Singapore General Hospital, Outram Road, Singapore 169608</nlm:aff></affiliation></author><author><name sortKey="Jonkers, Jos" sort="Jonkers, Jos" uniqKey="Jonkers J" first="Jos" last="Jonkers">Jos Jonkers</name><affiliation><nlm:aff id="A16">The Netherlands Cancer Institute, 1066CX Amsterdam, The Netherlands</nlm:aff></affiliation></author><author><name sortKey="Borg, Ke" sort="Borg, Ke" uniqKey="Borg " first=" Ke" last="Borg"> Ke Borg</name><affiliation><nlm:aff id="A3">Division of Oncology and Pathology, Department of Clinical Sciences Lund, Lund University, Lund, Sweden</nlm:aff></affiliation></author><author><name sortKey="Ueno, Naoto T" sort="Ueno, Naoto T" uniqKey="Ueno N" first="Naoto T" last="Ueno">Naoto T. Ueno</name><affiliation><nlm:aff id="A24">Morgan Welch Inflammatory Breast Cancer Research Program and Clinic, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX 77030</nlm:aff></affiliation></author><author><name sortKey="Sotiriou, Christos" sort="Sotiriou, Christos" uniqKey="Sotiriou C" first="Christos" last="Sotiriou">Christos Sotiriou</name><affiliation><nlm:aff id="A17">Breast Cancer Translational Research Laboratory, Université Libre de Bruxelles, Institut Jules Bordet, Bd de Waterloo 121, B-1000 Brussels, Belgium</nlm:aff></affiliation></author><author><name sortKey="Viari, Alain" sort="Viari, Alain" uniqKey="Viari A" first="Alain" last="Viari">Alain Viari</name><affiliation><nlm:aff id="A43">Equipe Erable, INRIA Grenoble-Rhône-Alpes, 655, Av. de l’Europe, 38330 Montbonnot-Saint Martin, France</nlm:aff></affiliation><affiliation><nlm:aff id="A44">Synergie Lyon Cancer, Centre Léon Bérard, 28 rue Laënnec, Lyon Cedex 08, France</nlm:aff></affiliation></author><author><name sortKey="Futreal, P Andrew" sort="Futreal, P Andrew" uniqKey="Futreal P" first="P. Andrew" last="Futreal">P. Andrew Futreal</name><affiliation><nlm:aff id="A1">Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, UK</nlm:aff></affiliation><affiliation><nlm:aff id="A45">Department of Genomic Medicine, UT MD Anderson Cancer Center, Houston, TX, 77230</nlm:aff></affiliation></author><author><name sortKey="Campbell, Peter J" sort="Campbell, Peter J" uniqKey="Campbell P" first="Peter J" last="Campbell">Peter J. Campbell</name><affiliation><nlm:aff id="A1">Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, UK</nlm:aff></affiliation></author><author><name sortKey="Span, Paul N" sort="Span, Paul N" uniqKey="Span P" first="Paul N." last="Span">Paul N. Span</name><affiliation><nlm:aff id="A46">Department of Radiation Oncology, and department of Laboratory Medicine, Radboud university medical center, Nijmegen, the Netherlands</nlm:aff></affiliation></author><author><name sortKey="Van Laere, Steven" sort="Van Laere, Steven" uniqKey="Van Laere S" first="Steven" last="Van Laere">Steven Van Laere</name><affiliation><nlm:aff id="A18">Translational Cancer Research Unit, Center for Oncological Research, Faculty of Medicine and Health Sciences, University of Antwerp, Antwerp, Belgium</nlm:aff></affiliation></author><author><name sortKey="Lakhani, Sunil R" sort="Lakhani, Sunil R" uniqKey="Lakhani S" first="Sunil R" last="Lakhani">Sunil R. Lakhani</name><affiliation><nlm:aff id="A30">The University of Queensland: UQ Centre for Clinical Research and School of Medicine, Brisbane, Australia</nlm:aff></affiliation><affiliation><nlm:aff id="A47">Pathology Queensland, The Royal Brisbane and Women’s Hospital, Brisbane, Australia</nlm:aff></affiliation></author><author><name sortKey="Eyfjord, Jorunn E" sort="Eyfjord, Jorunn E" uniqKey="Eyfjord J" first="Jorunn E." last="Eyfjord">Jorunn E. Eyfjord</name><affiliation><nlm:aff id="A31">Cancer Research Laboratory, Faculty of Medicine, University of Iceland, 101 Reykjavik, Iceland</nlm:aff></affiliation></author><author><name sortKey="Thompson, Alastair M" sort="Thompson, Alastair M" uniqKey="Thompson A" first="Alastair M." last="Thompson">Alastair M. Thompson</name><affiliation><nlm:aff id="A24">Morgan Welch Inflammatory Breast Cancer Research Program and Clinic, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX 77030</nlm:aff></affiliation><affiliation><nlm:aff id="A48">Department of Surgical Oncology, University of Texas MD Anderson Cancer Center, 1400 Pressler Street,Houston, Texas 77030</nlm:aff></affiliation></author><author><name sortKey="Birney, Ewan" sort="Birney, Ewan" uniqKey="Birney E" first="Ewan" last="Birney">Ewan Birney</name><affiliation><nlm:aff id="A9">European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Trust Genome Campus,Hinxton, Cambridgeshire, CB10 1SD</nlm:aff></affiliation></author><author><name sortKey="Stunnenberg, Hendrik G" sort="Stunnenberg, Hendrik G" uniqKey="Stunnenberg H" first="Hendrik G" last="Stunnenberg">Hendrik G. Stunnenberg</name><affiliation><nlm:aff id="A8">Radboud University, Department of Molecular Biology, Faculties of Science and Medicine, Nijmegen, Netherlands</nlm:aff></affiliation></author><author><name sortKey="Van De Vijver, Marc J" sort="Van De Vijver, Marc J" uniqKey="Van De Vijver M" first="Marc J" last="Van De Vijver">Marc J. Van De Vijver</name><affiliation><nlm:aff id="A20">Department of Pathology, Academic Medical Center, Meibergdreef 9, 1105 AZ Amsterdam, the Netherlands</nlm:aff></affiliation></author><author><name sortKey="Martens, John W M" sort="Martens, John W M" uniqKey="Martens J" first="John W. M." last="Martens">John W. M. Martens</name><affiliation><nlm:aff id="A7">Erasmus MC Cancer Institute and Cancer Genomics Netherlands, Erasmus University Medical Center, Department of Medical Oncology, Rotterdam, The Netherlands</nlm:aff></affiliation></author><author><name sortKey="B Rresen Dale, Anne Lise" sort="B Rresen Dale, Anne Lise" uniqKey="B Rresen Dale A" first="Anne-Lise" last="B Rresen-Dale">Anne-Lise B Rresen-Dale</name><affiliation><nlm:aff id="A10">Department of Cancer Genetics, Institute for Cancer Research, Oslo University Hospital The Norwegian Radiumhospital</nlm:aff></affiliation><affiliation><nlm:aff id="A11">K.G. Jebsen Centre for Breast Cancer Research, Institute for Clinical Medicine, University of Oslo, Oslo, Norway</nlm:aff></affiliation></author><author><name sortKey="Richardson, Andrea L" sort="Richardson, Andrea L" uniqKey="Richardson A" first="Andrea L." last="Richardson">Andrea L. Richardson</name><affiliation><nlm:aff id="A15">Department of Pathology, Brigham and Women’s Hospital, Boston, MA 02115 USA</nlm:aff></affiliation><affiliation><nlm:aff id="A19">Dana-Farber Cancer Institute, Boston, MA 02215 USA</nlm:aff></affiliation></author><author><name sortKey="Kong, Gu" sort="Kong, Gu" uniqKey="Kong G" first="Gu" last="Kong">Gu Kong</name><affiliation><nlm:aff id="A22">Department of Pathology, College of Medicine, Hanyang University, Seoul, South Korea</nlm:aff></affiliation></author><author><name sortKey="Thomas, Gilles" sort="Thomas, Gilles" uniqKey="Thomas G" first="Gilles" last="Thomas">Gilles Thomas</name><affiliation><nlm:aff id="A44">Synergie Lyon Cancer, Centre Léon Bérard, 28 rue Laënnec, Lyon Cedex 08, France</nlm:aff></affiliation></author><author><name sortKey="Stratton, Michael R" sort="Stratton, Michael R" uniqKey="Stratton M" first="Michael R." last="Stratton">Michael R. Stratton</name><affiliation><nlm:aff id="A1">Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, UK</nlm:aff></affiliation></author></analytic><series><title level="j">Nature</title><idno type="ISSN">0028-0836</idno><idno type="eISSN">1476-4687</idno><imprint><date when="2016">2016</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><p id="P1">We analysed whole genome sequences of 560 breast cancers to advance understanding of the driver mutations conferring clonal advantage and the mutational processes generating somatic mutations. 93 protein-coding cancer genes carried likely driver mutations. Some non-coding regions exhibited high mutation frequencies but most have distinctive structural features probably causing elevated mutation rates and do not harbour driver mutations. Mutational signature analysis was extended to genome rearrangements and revealed 12 base substitution and six rearrangement signatures. Three rearrangement signatures, characterised by tandem duplications or deletions, appear associated with defective homologous recombination based DNA repair: one with deficient BRCA1 function; another with deficient BRCA1 or BRCA2 function; the cause of the third is unknown. This analysis of all classes of somatic mutation across exons, introns and intergenic regions highlights the repertoire of cancer genes and mutational processes operative, and progresses towards a comprehensive account of the somatic genetic basis of breast cancer.</p></div></front><back><div1 type="bibliography"><listBibl><biblStruct><analytic><author><name sortKey="Stratton, Mr" uniqKey="Stratton M">MR Stratton</name></author><author><name sortKey="Campbell, Pj" uniqKey="Campbell P">PJ Campbell</name></author><author><name sortKey="Futreal, Pa" uniqKey="Futreal P">PA Futreal</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Nik Zainal, S" uniqKey="Nik Zainal S">S Nik-Zainal</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Nik Zainal, S" uniqKey="Nik Zainal S">S Nik-Zainal</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Hicks, J" uniqKey="Hicks J">J 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<pmc-dir>properties manuscript</pmc-dir>
<front><journal-meta><journal-id journal-id-type="nlm-journal-id">0410462</journal-id><journal-id journal-id-type="pubmed-jr-id">6011</journal-id><journal-id journal-id-type="nlm-ta">Nature</journal-id><journal-id journal-id-type="iso-abbrev">Nature</journal-id><journal-title-group><journal-title>Nature</journal-title></journal-title-group><issn pub-type="ppub">0028-0836</issn><issn pub-type="epub">1476-4687</issn></journal-meta><article-meta><article-id pub-id-type="pmid">27135926</article-id><article-id pub-id-type="pmc">4910866</article-id><article-id pub-id-type="doi">10.1038/nature17676</article-id><article-id pub-id-type="manuscript">EMS68344</article-id><article-categories><subj-group subj-group-type="heading"><subject>Article</subject></subj-group></article-categories><title-group><article-title>Landscape of somatic mutations in 560 breast cancer whole genome sequences</article-title></title-group><contrib-group><contrib 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Andrew</given-names></name><xref ref-type="aff" rid="A1">1</xref><xref ref-type="aff" rid="A45">45</xref></contrib><contrib contrib-type="author"><name><surname>Campbell</surname><given-names>Peter J</given-names></name><xref ref-type="aff" rid="A1">1</xref></contrib><contrib contrib-type="author"><name><surname>Span</surname><given-names>Paul N.</given-names></name><xref ref-type="aff" rid="A46">46</xref></contrib><contrib contrib-type="author"><name><surname>Van Laere</surname><given-names>Steven</given-names></name><xref ref-type="aff" rid="A18">18</xref></contrib><contrib contrib-type="author"><name><surname>Lakhani</surname><given-names>Sunil R</given-names></name><xref ref-type="aff" rid="A30">30</xref><xref ref-type="aff" rid="A47">47</xref></contrib><contrib contrib-type="author"><name><surname>Eyfjord</surname><given-names>Jorunn E.</given-names></name><xref ref-type="aff" rid="A31">31</xref></contrib><contrib contrib-type="author"><name><surname>Thompson</surname><given-names>Alastair M.</given-names></name><xref ref-type="aff" rid="A24">24</xref><xref ref-type="aff" rid="A48">48</xref></contrib><contrib contrib-type="author"><name><surname>Birney</surname><given-names>Ewan</given-names></name><xref ref-type="aff" rid="A9">9</xref></contrib><contrib contrib-type="author"><name><surname>Stunnenberg</surname><given-names>Hendrik G</given-names></name><xref ref-type="aff" rid="A8">8</xref></contrib><contrib contrib-type="author"><name><surname>van de Vijver</surname><given-names>Marc J</given-names></name><xref ref-type="aff" rid="A20">20</xref></contrib><contrib contrib-type="author"><name><surname>Martens</surname><given-names>John W.M.</given-names></name><xref ref-type="aff" rid="A7">7</xref></contrib><contrib contrib-type="author"><name><surname>Børresen-Dale</surname><given-names>Anne-Lise</given-names></name><xref ref-type="aff" rid="A10">10</xref><xref ref-type="aff" rid="A11">11</xref></contrib><contrib contrib-type="author"><name><surname>Richardson</surname><given-names>Andrea L.</given-names></name><xref ref-type="aff" rid="A15">15</xref><xref ref-type="aff" rid="A19">19</xref></contrib><contrib contrib-type="author"><name><surname>Kong</surname><given-names>Gu</given-names></name><xref ref-type="aff" rid="A22">22</xref></contrib><contrib contrib-type="author"><name><surname>Thomas</surname><given-names>Gilles</given-names></name><xref ref-type="aff" rid="A44">44</xref></contrib><contrib contrib-type="author"><name><surname>Stratton</surname><given-names>Michael R.</given-names></name><xref ref-type="aff" rid="A1">1</xref></contrib></contrib-group><aff id="A1"><label>1</label>Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, UK</aff><aff id="A2"><label>2</label>East Anglian Medical Genetics Service, Cambridge University Hospitals NHS Foundation Trust, Cambridge CB2 9NB, UK</aff><aff id="A3"><label>3</label>Division of Oncology and Pathology, Department of Clinical Sciences Lund, Lund University, Lund, Sweden</aff><aff id="A4"><label>4</label>Theoretical Biology and Biophysics (T-6), Los Alamos National Laboratory, Los Alamos, New Mexico, United States of America</aff><aff id="A5"><label>5</label>Center for Nonlinear Studies, Los Alamos National Laboratory, Los Alamos, New Mexico, United States of America</aff><aff id="A6"><label>6</label>Department of Human Genetics, University of Leuven, B-3000 Leuven, Belgium</aff><aff id="A7"><label>7</label>Erasmus MC Cancer Institute and Cancer Genomics Netherlands, Erasmus University Medical Center, Department of Medical Oncology, Rotterdam, The Netherlands</aff><aff id="A8"><label>8</label>Radboud University, Department of Molecular Biology, Faculties of Science and Medicine, Nijmegen, Netherlands</aff><aff id="A9"><label>9</label>European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Trust Genome Campus,Hinxton, Cambridgeshire, CB10 1SD</aff><aff id="A10"><label>10</label>Department of Cancer Genetics, Institute for Cancer Research, Oslo University Hospital The Norwegian Radiumhospital</aff><aff id="A11"><label>11</label>K.G. Jebsen Centre for Breast Cancer Research, Institute for Clinical Medicine, University of Oslo, Oslo, Norway</aff><aff id="A12"><label>12</label>Department of Computer Science, University of Oslo, Oslo, Norway</aff><aff id="A13"><label>13</label>Gachon Institute of Genome Medicine and Science, Gachon University Gil Medical Center, Incheon, South Korea</aff><aff id="A14"><label>14</label>Translational Research Lab, Centre Léon Bérard, 28, rue Laënnec, 69373 Lyon Cedex 08, France</aff><aff id="A15"><label>15</label>Department of Pathology, Brigham and Women’s Hospital, Boston, MA 02115 USA</aff><aff id="A16"><label>16</label>The Netherlands Cancer Institute, 1066CX Amsterdam, The Netherlands</aff><aff id="A17"><label>17</label>Breast Cancer Translational Research Laboratory, Université Libre de Bruxelles, Institut Jules Bordet, Bd de Waterloo 121, B-1000 Brussels, Belgium</aff><aff id="A18"><label>18</label>Translational Cancer Research Unit, Center for Oncological Research, Faculty of Medicine and Health Sciences, University of Antwerp, Antwerp, Belgium</aff><aff id="A19"><label>19</label>Dana-Farber Cancer Institute, Boston, MA 02215 USA</aff><aff id="A20"><label>20</label>Department of Pathology, Academic Medical Center, Meibergdreef 9, 1105 AZ Amsterdam, the Netherlands</aff><aff id="A21"><label>21</label>Department of Pathology, Asan Medical Center, College of Medicine, Ulsan University, South Korea</aff><aff id="A22"><label>22</label>Department of Pathology, College of Medicine, Hanyang University, Seoul, South Korea</aff><aff id="A23"><label>23</label>Memorial Sloan Kettering Cancer Center, 1275 York Ave, New York, NY 10065, United States</aff><aff id="A24"><label>24</label>Morgan Welch Inflammatory Breast Cancer Research Program and Clinic, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX 77030</aff><aff id="A25"><label>25</label>Institute for Bioengineering and Biopharmaceutical Research (IBBR), Hanyang University, Seoul, South Korea</aff><aff id="A26"><label>26</label>Institut National du Cancer, Research Division, Clinical Research Department, 52 avenue Morizet, 92513 Boulogne-Billancourt, France</aff><aff id="A27"><label>27</label>University Hospital of Minjoz, INSERM UMR 1098, Bd Fleming, Besançon 25000, France</aff><aff id="A28"><label>28</label>Pathology Department, Ninewells Hospital & Medical School, Dundee DD1 9SY, UK</aff><aff id="A29"><label>29</label>Oncologie Sénologie, ICM Institut Régional du Cancer, Montpellier, France</aff><aff id="A30"><label>30</label>The University of Queensland: UQ Centre for Clinical Research and School of Medicine, Brisbane, Australia</aff><aff id="A31"><label>31</label>Cancer Research Laboratory, Faculty of Medicine, University of Iceland, 101 Reykjavik, Iceland</aff><aff id="A32"><label>32</label>IRCCS Istituto Tumori “Giovanni Paolo II”, Bari, Italy</aff><aff id="A33"><label>33</label>Department of Pathology, Centre Léon Bérard, 28 rue Laënnec, 69373 Lyon Cédex 08, France</aff><aff id="A34"><label>34</label>Department of Pathology, GZA Hospitals Sint-Augustinus, Antwerp, Belgium</aff><aff id="A35"><label>35</label>Institut Curie, Department of Pathology and INSERM U934, 26 rue d’Ulm, 75248 Paris Cedex 05, France</aff><aff id="A36"><label>36</label>Cancer Research UK Cambridge Institute, University of Cambridge, Li Ka Shing Centre, Robinson Way, Cambridge CB2 0RE, United Kingdom</aff><aff id="A37"><label>37</label>Breast Cancer Now Toby Research Unit, King’s College London</aff><aff id="A38"><label>38</label>Breast Cancer Now Toby Robin’s Research Centre, Institute of Cancer Research, London</aff><aff id="A39"><label>39</label>Department of Clinical Science, University of Bergen, 5020 Bergen, Norway</aff><aff id="A40"><label>40</label>Department of Oncology, Haukeland University Hospital, 5021 Bergen, Norway</aff><aff id="A41"><label>41</label>National Cancer Centre Singapore, 11 Hospital Drive, Singapore 169610</aff><aff id="A42"><label>42</label>Singapore General Hospital, Outram Road, Singapore 169608</aff><aff id="A43"><label>43</label>Equipe Erable, INRIA Grenoble-Rhône-Alpes, 655, Av. de l’Europe, 38330 Montbonnot-Saint Martin, France</aff><aff id="A44"><label>44</label>Synergie Lyon Cancer, Centre Léon Bérard, 28 rue Laënnec, Lyon Cedex 08, France</aff><aff id="A45"><label>45</label>Department of Genomic Medicine, UT MD Anderson Cancer Center, Houston, TX, 77230</aff><aff id="A46"><label>46</label>Department of Radiation Oncology, and department of Laboratory Medicine, Radboud university medical center, Nijmegen, the Netherlands</aff><aff id="A47"><label>47</label>Pathology Queensland, The Royal Brisbane and Women’s Hospital, Brisbane, Australia</aff><aff id="A48"><label>48</label>Department of Surgical Oncology, University of Texas MD Anderson Cancer Center, 1400 Pressler Street,Houston, Texas 77030</aff><author-notes><corresp id="CR1"><bold>Corresponding authors:</bold> Gu Kong (<email>gkong@hanyang.ac.kr</email>), Serena Nik-Zainal (<email>snz@sanger.ac.uk</email>), Mike Stratton (<email>mrs@sanger.ac.uk</email>), Alain Viari (<email>Alain.Viari@inria.fr</email>)</corresp></author-notes><pub-date pub-type="nihms-submitted"><day>11</day><month>6</month><year>2016</year></pub-date><pub-date pub-type="epub"><day>2</day><month>5</month><year>2016</year></pub-date><pub-date pub-type="collection"><day>2</day><month>5</month><year>2016</year></pub-date><pub-date pub-type="pmc-release"><day>02</day><month>11</month><year>2016</year></pub-date><volume>534</volume><issue>7605</issue><fpage>47</fpage><lpage>54</lpage><pmc-comment>elocation-id from pubmed: 10.1038/nature17676</pmc-comment>
<permissions><license><license-p>Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:<ext-link ext-link-type="uri" xlink:href="http://www.nature.com/authors/editorial_policies/license.html#terms">http://www.nature.com/authors/editorial_policies/license.html#terms</ext-link></license-p></license></permissions><abstract><p id="P1">We analysed whole genome sequences of 560 breast cancers to advance understanding of the driver mutations conferring clonal advantage and the mutational processes generating somatic mutations. 93 protein-coding cancer genes carried likely driver mutations. Some non-coding regions exhibited high mutation frequencies but most have distinctive structural features probably causing elevated mutation rates and do not harbour driver mutations. Mutational signature analysis was extended to genome rearrangements and revealed 12 base substitution and six rearrangement signatures. Three rearrangement signatures, characterised by tandem duplications or deletions, appear associated with defective homologous recombination based DNA repair: one with deficient BRCA1 function; another with deficient BRCA1 or BRCA2 function; the cause of the third is unknown. This analysis of all classes of somatic mutation across exons, introns and intergenic regions highlights the repertoire of cancer genes and mutational processes operative, and progresses towards a comprehensive account of the somatic genetic basis of breast cancer.</p></abstract></article-meta></front><body><sec sec-type="intro" id="S1"><title>Introduction</title><p id="P2">The mutational theory of cancer proposes that changes in DNA sequence, termed “driver” mutations, confer proliferative advantage upon a cell, leading to outgrowth of a neoplastic clone<xref rid="R1" ref-type="bibr">1</xref>. Some driver mutations are inherited in the germline, but most arise in somatic cells during the lifetime of the cancer patient, together with many “passenger” mutations not implicated in cancer development<xref rid="R1" ref-type="bibr">1</xref>. Multiple mutational processes, including endogenous and exogenous mutagen exposures, aberrant DNA editing, replication errors and defective DNA maintenance, are responsible for generating these mutations<xref rid="R1" ref-type="bibr">1</xref>–<xref rid="R3" ref-type="bibr">3</xref>.</p><p id="P3">Over the past five decades, several waves of technology have advanced the characterisation of mutations in cancer genomes. Karyotype analysis revealed rearranged chromosomes and copy number alterations. Subsequently, loss of heterozygosity analysis, hybridisation of cancer-derived DNA to microarrays and other approaches provided higher resolution insights into copy number changes<xref rid="R4" ref-type="bibr">4</xref>–<xref rid="R8" ref-type="bibr">8</xref>. Recently, DNA sequencing has enabled systematic characterisation of the full repertoire of mutation types including base substitutions, small insertions/deletions, rearrangements and copy number changes<xref rid="R9" ref-type="bibr">9</xref>–<xref rid="R13" ref-type="bibr">13</xref>, yielding substantial insights into the mutated cancer genes and mutational processes operative in human cancer.</p><p id="P4">As for many cancer classes, most currently available breast cancer genome sequences target protein-coding exons<xref rid="R8" ref-type="bibr">8</xref>,<xref rid="R11" ref-type="bibr">11</xref>–<xref rid="R15" ref-type="bibr">15</xref>. Consequently, there has been limited consideration of mutations in untranslated, intronic and intergenic regions, leaving central questions pertaining to the molecular pathogenesis of the disease unresolved. First, the role of activating driver rearrangements<xref rid="R16" ref-type="bibr">16</xref>–<xref rid="R18" ref-type="bibr">18</xref> forming chimeric (fusion) genes/proteins or relocating genes adjacent to new regulatory regions as observed in haematological and other malignancies<xref rid="R19" ref-type="bibr">19</xref>. Second, the role of driver substitutions and indels in non-coding regions of the genome<xref rid="R20" ref-type="bibr">20</xref>,<xref rid="R21" ref-type="bibr">21</xref>. Common inherited variants conferring susceptibility to human disease are generally in non-coding regulatory regions and the possibility that similar mechanisms operate somatically in cancer was highlighted by the discovery of somatic driver substitutions in the <italic>TERT</italic> gene promoter<xref rid="R22" ref-type="bibr">22</xref>,<xref rid="R23" ref-type="bibr">23</xref>. Third, which mutational processes generate the somatic mutations found in breast cancer<xref rid="R2" ref-type="bibr">2</xref>,<xref rid="R24" ref-type="bibr">24</xref>. Addressing this question has been constrained because exome sequences do not inform on genome rearrangements and capture relatively few base substitution mutations, thus limiting statistical power to extract the mutational signatures imprinted on the genome by these processes<xref rid="R24" ref-type="bibr">24</xref>,<xref rid="R25" ref-type="bibr">25</xref>.</p><p id="P5">Here we analyse whole genome sequences of 560 cases in order to address these and other questions and to pave the way to a comprehensive understanding of the origins and consequences of somatic mutations in breast cancer.</p></sec><sec sec-type="results" id="S2"><title>Results</title><sec id="S3"><title>Cancer genes and driver mutations</title><p id="P6">The whole genomes of 560 breast cancers and non-neoplastic tissue from each individual (556 female and four male) were sequenced (Fig.S1, <xref ref-type="supplementary-material" rid="SD4">Supplementary Table 1</xref>). 3,479,652 somatic base substitutions, 371,993 small indels and 77,695 rearrangements were detected, with substantial variation in the number of each between individual samples (<xref ref-type="fig" rid="F1">Fig.1A</xref>, <xref ref-type="supplementary-material" rid="SD4">Supplementary Table 3</xref>). Transcriptome sequence, microRNA expression, array based copy number and DNA methylation data were obtained from subsets of cases.</p><p id="P7">To identify new cancer genes, we combined somatic substitutions and indels in protein-coding exons with data from other series<xref rid="R12" ref-type="bibr">12</xref>–<xref rid="R15" ref-type="bibr">15</xref>,<xref rid="R26" ref-type="bibr">26</xref>, constituting a total of 1,332 breast cancers, and searched for mutation clustering in each gene beyond that expected by chance. Five cancer genes were found for which evidence was previously absent or equivocal (<italic>MED23</italic>, <italic>FOXP1</italic>, <italic>MLLT4</italic>, <italic>XBP1</italic>, <italic>ZFP36L1</italic>), or for which the mutations indicate the gene acts in breast cancer in a recessive rather than in a dominant fashion, as previously reported in other cancer types (<xref ref-type="supplementary-material" rid="SD1">Supplementary Methods section 7.4</xref> for detailed descriptions). From published reports on all cancer types (<ext-link ext-link-type="uri" xlink:href="http://cancer.sanger.ac.uk/census">http://cancer.sanger.ac.uk/census</ext-link>), we then compiled a list of 727 human cancer genes (<xref ref-type="supplementary-material" rid="SD4">Supplementary Table 12</xref>). Based on driver mutations found previously, we defined conservative rules for somatic driver base substitutions and indel mutations in each gene and sought mutations conforming to these rules in the 560 breast cancers. 916 likely driver mutations of these classes were identified (<xref ref-type="fig" rid="F1">Fig.1B</xref>, <xref ref-type="supplementary-material" rid="SD4">Supplementary Table 14</xref>, <xref ref-type="fig" rid="F6">Extended Data Figure 1</xref>).</p><p id="P8">To explore the role of genomic rearrangements as driver mutations<xref rid="R16" ref-type="bibr">16</xref>,<xref rid="R18" ref-type="bibr">18</xref>,<xref rid="R19" ref-type="bibr">19</xref>,<xref rid="R27" ref-type="bibr">27</xref>, we sought predicted in-frame fusion genes that might create activated, dominant cancer genes. 1,278 unique and 39 infrequently recurrent in-frame gene fusions were identified (<xref ref-type="supplementary-material" rid="SD4">Supplementary Table 15</xref>). Many of the latter, however, were in regions of high rearrangement density, including amplicons<xref rid="R28" ref-type="bibr">28</xref> and fragile sites, and their recurrence is likely attributable to chance<xref rid="R27" ref-type="bibr">27</xref>. Furthermore, transcriptome sequences from 260 cancers did not show expression of these fusions and generally confirmed the rarity of recurrent in-frame fusion genes. By contrast, recurrent rearrangements interrupting the gene footprints of <italic>CDKN2A, RB1, MAP3K1, PTEN, MAP2K4, ARID1B, FBXW7</italic>, <italic>MLLT4</italic> and <italic>TP53</italic> were found beyond the numbers expected from local background rearrangement rates, indicating that they contribute to the driver mutation burden of recessive cancer genes. Several other recurrently rearranged genomic regions were observed, including dominantly-acting cancer genes <italic>ETV6</italic> and <italic>ESR1</italic> without consistent elevation in expression levels, L1-retrotransposition sites<xref rid="R29" ref-type="bibr">29</xref> and fragile sites. The significance of these recurrently rearranged regions remain unclear (<xref ref-type="fig" rid="F7">Extended Data Figure 2</xref>).</p><p id="P9">Incorporation of recurrent copy number changes, including homozygous deletions and amplifications, generated a final tally of 1,628 likely driver mutations in 93 cancer genes (<xref ref-type="fig" rid="F1">Fig.1B</xref>). At least one driver was identifiable in 95% of cancers. The 10 most frequently mutated genes were <italic>TP53, PIK3CA, MYC, CCND1, PTEN, ERBB2, chr8:ZNF703/FGFR1 locus, GATA3, RB1</italic> and <italic>MAP3K1</italic> (<xref ref-type="fig" rid="F1">Fig.1B</xref>, <xref ref-type="fig" rid="F6">Extended Data Figure 1</xref>) and accounted for 62% of drivers.</p></sec><sec id="S4"><title>Recurrent somatic mutations in non-coding genomic regions</title><p id="P10">To investigate non-coding somatic driver substitutions and indels, we searched for non-coding genomic regions with more mutations than expected by chance (<xref ref-type="fig" rid="F2">Fig.2A</xref>, <xref ref-type="supplementary-material" rid="SD4">Supplementary Table 16</xref>, <xref ref-type="fig" rid="F8">Extended Data Figure 3</xref>). The promoter of <italic>PLEKHS1</italic> (pleckstrin homology domain containing, family S member 1) exhibited recurrent mutations at two genomic positions<xref rid="R30" ref-type="bibr">30</xref> (<xref ref-type="fig" rid="F2">Fig.2A</xref>), the underlined bases in the sequence CAGCAAGC T<underline>G</underline>AA<underline>C</underline>A GCTTGCTG (as previously reported<xref rid="R30" ref-type="bibr">30</xref>). The two mutated bases are flanked on either side by 9bp of palindromic sequence forming inverted repeats<xref rid="R31" ref-type="bibr">31</xref>. Most cancers with these mutations showed many base substitutions of mutational signatures 2 and 13 that have been attributed to activity of APOBEC DNA-editing proteins that target the T<underline>C</underline>N sequence motif. One of the mutated bases is a cytosine in a T<underline>C</underline>A sequence context (shown above as the reverse complement, T<underline>G</underline>A) at which predominantly C>T substitutions were found. The other is a cytosine in A<underline>C</underline>A context which showed both C>T and C>G mutations.</p><p id="P11">The T<underline>G</underline>AA<underline>C</underline>A core sequence was mutated at the same two positions at multiple locations elsewhere in the genome (<xref ref-type="supplementary-material" rid="SD4">Supplementary Table 16C</xref>) where the T<underline>G</underline>AA<underline>C</underline>A core was also flanked by palindromes (inverted repeat), albeit of different sequences and lengths (<xref ref-type="supplementary-material" rid="SD4">Supplementary Table 16C</xref>). These mutations were also usually found in cancers with many signature 2 and 13 mutations (<xref ref-type="fig" rid="F2">Fig.2A</xref>). T<underline>G</underline>AA<underline>C</underline>A core sequences with longer flanking palindromes generally exhibited a higher mutation rate, and T<underline>G</underline>AA<underline>C</underline>A sequences flanked by 9bp palindromes exhibited a ~265-fold higher mutation rate than sequences without them (<xref ref-type="fig" rid="F2">Fig.2B</xref>, <xref ref-type="supplementary-material" rid="SD4">Supplementary Table 16D</xref>). However, additional factors must influence the mutation rate because it varied markedly between T<underline>G</underline>AA<underline>C</underline>A core sequences with different palindromes of the same length (<xref ref-type="fig" rid="F2">Fig.2C</xref>). Some T<underline>G</underline>AA<underline>C</underline>A-inverted repeat sites were in regulatory regions but others were intronic or intergenic without functional annotation (examples in <xref ref-type="supplementary-material" rid="SD4">Supplementary Table 16C</xref>) or exonic. The propensity for mutation recurrence at specific positions in a distinctive sequence motif in cancers with numerous mutations of particular signatures renders it plausible that these are hypermutable hotspots<xref rid="R32" ref-type="bibr">32</xref>–<xref rid="R34" ref-type="bibr">34</xref>, perhaps through formation of DNA hairpin structures<xref rid="R35" ref-type="bibr">35</xref>, which are single stranded at their tips enabling attack by APOBEC enzymes, rather than driver mutations.</p><p id="P12">Two recurrently mutated sites were also observed in the promoter of <italic>TBC1D12</italic> (TBC1 domain family, member 12) (q-value 4.5e<sup>-2</sup>) (<xref ref-type="fig" rid="F2">Fig.2A</xref>). The mutations were characteristic of signatures 2 and 13 and enriched in cancers with many signature 2 and 13 mutations (<xref ref-type="fig" rid="F2">Fig.2A</xref>). The mutations were within the <italic>TBC1D12</italic> Kozak consensus sequence (CCC<underline>C</underline>A<underline>G</underline><bold>ATG</bold>GTGGG)) shifting it away from the consensus<xref rid="R36" ref-type="bibr">36</xref>. The association with particular mutational signatures suggests that these may also be in a region of hypermutability rather than drivers.</p><p id="P13">The <italic>WDR74</italic> (WD repeat domain 74) promoter showed base substitutions and indels (q-value 4.6e<sup>-3</sup>) forming a cluster of overlapping mutations (<xref ref-type="fig" rid="F2">Fig.2A</xref>)<xref rid="R20" ref-type="bibr">20</xref>. Coding sequence driver mutations in <italic>WDR74</italic> have not been reported. No differences were observed in <italic>WDR74</italic> transcript levels between cancers with <italic>WDR74</italic> promoter mutations compared to those without. Nevertheless, the pattern of this non-coding mutation cluster, with overlapping and different mutation types, is more compatible with the possibility of the mutations being drivers.</p><p id="P14">Two long non-coding RNAs, <italic>MALAT1</italic> (q-value 8.7e<sup>-11</sup>, as previously reported<xref rid="R12" ref-type="bibr">12</xref>) and <italic>NEAT1</italic> (q-value 2.1e<sup>-2</sup>) were enriched with mutations. Transcript levels were not significantly different between mutated and non-mutated samples. Whether these mutations are drivers, or result from local hypermutability, is unclear.</p></sec><sec id="S5"><title>Mutational signatures</title><p id="P15">Mutational processes generating somatic mutations imprint particular patterns of mutations on cancer genomes, termed signatures<xref rid="R2" ref-type="bibr">2</xref>,<xref rid="R24" ref-type="bibr">24</xref>,<xref rid="R37" ref-type="bibr">37</xref>. Applying a mathematical approach<xref rid="R25" ref-type="bibr">25</xref> to extract mutational signatures previously revealed five base substitution signatures in breast cancer; signatures 1, 2, 3, 8 and 13<xref rid="R2" ref-type="bibr">2</xref>,<xref rid="R24" ref-type="bibr">24</xref>. Using this method in the 560 cases revealed 12 signatures, including those previously observed and a further seven, of which five have formerly been detected in other cancer types (signatures 5, 6, 17, 18 and 20) and two are new (signatures 26 and 30) (<xref ref-type="fig" rid="F3">Fig.3A-B</xref>, <xref ref-type="fig" rid="F4">Fig.4A</xref>, <xref ref-type="supplementary-material" rid="SD4">Supplementary Table 21A-C</xref>, <xref ref-type="supplementary-material" rid="SD1">Supplementary Methods 15</xref> for further details). Two indel signatures were also found<xref rid="R2" ref-type="bibr">2</xref>,<xref rid="R24" ref-type="bibr">24</xref>.</p><p id="P16">Signatures of rearrangement mutational processes have not previously been formally investigated. To enable this we adopted a rearrangement classification incorporating 32 subclasses. In many cancer genomes, large numbers of rearrangements are regionally clustered, for example in zones of gene amplification. Therefore, we first classified rearrangements into those inside and outside clusters, further subclassified them into deletions, inversions and tandem duplications, and then according to the size of the rearranged segment. The final category in both groups was interchromosomal translocations.</p><p id="P17">Application of the mathematical framework used for base substitution signatures<xref rid="R2" ref-type="bibr">2</xref>,<xref rid="R24" ref-type="bibr">24</xref>,<xref rid="R25" ref-type="bibr">25</xref> extracted six rearrangement signatures (<xref ref-type="fig" rid="F4">Fig.4B</xref>, <xref ref-type="supplementary-material" rid="SD4">Supplementary Table 21</xref>). Unsupervised hierarchical clustering on the basis of the proportion of rearrangements attributed to each signature in each breast cancer yielded seven major subgroups exhibiting distinct associations with other genomic, histological or gene expression features (<xref ref-type="fig" rid="F5">Fig.5</xref>, <xref ref-type="fig" rid="F9">Extended Data Figure 4</xref>-<xref ref-type="fig" rid="F11">6</xref>).</p><p id="P18">Rearrangement Signature 1 (9% of all rearrangements) and Rearrangement Signature 3 (18% rearrangements) were characterised predominantly by tandem duplications (<xref ref-type="fig" rid="F4">Fig.4B</xref>). Tandem duplications associated with Rearrangement Signature 1 were mostly >100kb (<xref ref-type="fig" rid="F4">Fig.4B</xref>), and those with Rearrangement Signature 3 <10kb (<xref ref-type="fig" rid="F4">Fig.4B</xref>, <xref ref-type="fig" rid="F12">Extended Data Figure 7</xref>). More than 95% of Rearrangement Signature 3 tandem duplications were concentrated in 15% of cancers (Cluster D, <xref ref-type="fig" rid="F5">Fig.5</xref>), many with several hundred rearrangements of this type. Almost all cancers (91%) with <italic>BRCA1</italic> mutations or promoter hypermethylation were in this group, which was enriched for basal-like, triple negative cancers and copy number classification of a high Homologous Recombination Deficiency (HRD) index<xref rid="R38" ref-type="bibr">38</xref>–<xref rid="R40" ref-type="bibr">40</xref>. Thus, inactivation of <italic>BRCA1</italic>, but not <italic>BRCA2</italic>, may be responsible for the Rearrangement Signature 3 small tandem duplication mutator phenotype.</p><p id="P19">More than 35% of Rearrangement Signature 1 tandem duplications were found in just 8.5% of the breast cancers and some cases had hundreds of these (Cluster F, <xref ref-type="fig" rid="F5">Fig.5</xref>). The cause of this large tandem duplication mutator phenotype (<xref ref-type="fig" rid="F4">Fig.4B</xref>) is unknown. Cancers exhibiting it are frequently TP53-mutated, relatively late diagnosis, triple-negative breast cancers, showing enrichment for base substitution signature 3 and a high Homologous Recombination Deficiency (HRD) index (<xref ref-type="fig" rid="F5">Fig.5</xref>) but do not have <italic>BRCA1</italic>/2 mutations or <italic>BRCA1</italic> promoter hypermethylation.</p><p id="P20">Rearrangement Signature 1 and 3 tandem duplications (<xref ref-type="fig" rid="F12">Extended Data Figure 7</xref>) were generally evenly distributed over the genome. However, there were nine locations at which recurrence of tandem duplications was found across the breast cancers and which often showed multiple, nested tandem duplications in individual cases (<xref ref-type="fig" rid="F13">Extended Data Figure 8</xref>). These may be mutational hotspots specific for these tandem duplication mutational processes although we cannot exclude the possibility that they represent driver events.</p><p id="P21">Rearrangement Signature 5 (accounting for 14% rearrangements) was characterised by deletions <100kb. It was strongly associated with the presence of <italic>BRCA1</italic> mutations or promoter hypermethylation (Cluster D, <xref ref-type="fig" rid="F5">Fig.5</xref>), <italic>BRCA2</italic> mutations (Cluster G, <xref ref-type="fig" rid="F5">Fig.5</xref>) and with Rearrangement Signature 1 large tandem duplications (Cluster F, <xref ref-type="fig" rid="F5">Fig.5</xref>).</p><p id="P22">Rearrangement Signature 2 (accounting for 22% rearrangements) was characterised by non-clustered deletions (>100kb), inversions and interchromosomal translocations, was present in most cancers but was particularly enriched in ER positive cancers with quiet copy number profiles (Cluster E, GISTIC Cluster 3, <xref ref-type="fig" rid="F5">Fig.5</xref>). Rearrangement Signature 4 (accounting for 18% of rearrangements) was characterised by clustered interchromosomal translocations while Rearrangement Signature 6 (19% of rearrangements) by clustered inversions and deletions (Clusters A, B, C, <xref ref-type="fig" rid="F5">Fig.5</xref>).</p><p id="P23">Short segments (1-5bp) of overlapping microhomology characteristic of alternative methods of end joining repair were found at most rearrangements<xref rid="R2" ref-type="bibr">2</xref>,<xref rid="R14" ref-type="bibr">14</xref>. Rearrangement Signatures 2, 4 and 6 were characterised by a peak at 1bp of microhomology while Rearrangement Signatures 1, 3 and 5, associated with homologous recombination DNA repair deficiency, exhibited a peak at 2bp (<xref ref-type="fig" rid="F14">Extended Data Figure 9</xref>). Thus, different end-joining mechanisms may operate with different rearrangement processes. A proportion of breast cancers showed Rearrangement Signature 5 deletions with longer (>10bp) microhomologies involving sequences from short-interspersed nuclear elements (SINEs), most commonly AluS (63%) and AluY (15%) family repeats (<xref ref-type="fig" rid="F14">Extended Data Figure 9</xref>). Long segments (more than 10bp) of non-templated sequence were particularly enriched amongst clustered rearrangements.</p></sec><sec id="S6"><title>Localised hypermutation: <italic>kataegis</italic></title><p id="P24">Focal base substitution hypermutation, termed <italic>kataegis</italic>, is generally characterised by substitutions with characteristic features of signatures 2 and 13<xref rid="R2" ref-type="bibr">2</xref>,<xref rid="R24" ref-type="bibr">24</xref>. <italic>Kataegis</italic> was observed in 49% breast cancers, with 4% exhibiting 10 or more foci (<xref ref-type="supplementary-material" rid="SD4">Supplementary Table 21C</xref>). <italic>Kataegis</italic> colocalises with clustered rearrangements characteristic of rearrangement signatures 4 and 6 (<xref ref-type="fig" rid="F4">Fig.4B</xref>). Cancers with tandem duplications or deletions of rearrangement signatures 1, 3 and 5 did not usually demonstrate <italic>kataegis</italic>. However, there must be additional determinants of <italic>kataegis</italic> since only 2% of rearrangements are associated with it. A rare (14/1,557 foci, 0.9%), alternative form of <italic>kataegis</italic> colocalising with rearrangements but with a base substitution pattern characterised by T>G and T>C mutations predominantly at NTT and NTA sequences was also observed (<xref ref-type="fig" rid="F15">Extended Data Figure 10</xref>). This pattern of base substitutions most closely matches Signature 9 (<xref ref-type="fig" rid="F15">Extended Data Figure 10</xref>) (<ext-link ext-link-type="uri" xlink:href="http://cancer.sanger.ac.uk/cosmic/signatures">http://cancer.sanger.ac.uk/cosmic/signatures</ext-link>), previously observed in B lymphocyte neoplasms and attributed to polymerase eta activity <xref rid="R41" ref-type="bibr">41</xref>.</p></sec><sec id="S7"><title>Mutational signatures exhibit distinct DNA replication strand biases</title><p id="P25">The distributions of mutations attributable to each of the 20 mutation signatures (12 base substitution, two indel and six rearrangement) were explored<xref rid="R42" ref-type="bibr">42</xref> with respect to DNA replication strand. We found an asymmetric distribution of mutations between leading and lagging replication strands for many, but not all signatures<xref rid="R42" ref-type="bibr">42</xref> (<xref ref-type="fig" rid="F4">Fig.4A</xref>). Notably, Signatures 2 and 13, due to APOBEC deamination, showed marked lagging replication strand bias (<xref ref-type="fig" rid="F4">Fig.4A</xref>) suggesting that lagging strand replication provides single-stranded DNA for APOBEC deamination. Of the three signatures associated with mismatch repair deficiency (Signatures 6, 20, 26), only Signature 26 exhibited replicative strand bias, highlighting how different signatures arising from defects of the same pathway can exhibit distinct relationships with replication.</p></sec><sec id="S8"><title>Mutational signatures associated with <italic>BRCA1</italic> and <italic>BRCA2</italic> mutations</title><p id="P26">Of the 560 breast cancers, 90 had germline (60) or somatic (14) inactivating mutations in <italic>BRCA1</italic> (35) or <italic>BRCA2</italic> (39) or showed methylation of the <italic>BRCA1</italic> promoter (16). Loss of the wild-type chromosome 17 or 13 was observed in 80/90 cases. The latter exhibited many base substitution mutations of signature 3, accompanied by deletions of >3bp with microhomology at rearrangement breakpoints, and signature 8 together with CC>AA double nucleotide substitutions. Cases in which the wild type chromosome 17 or 13 was retained did not show these signatures. Thus signature 3 and, to a lesser extent, signature 8 are associated with absence of BRCA1 and BRCA2 functions.</p><p id="P27">Cancers with inactivating <italic>BRCA1</italic> or <italic>BRCA2</italic> mutations usually carry many genomic rearrangements. Cancers with <italic>BRCA1</italic>, but not <italic>BRCA2</italic>, mutations exhibit large numbers of Rearrangement Signature 3 small tandem duplications. Cancers with <italic>BRCA1</italic> or <italic>BRCA2</italic> mutations show substantial numbers of Rearrangement Signature 5 deletions. No other Rearrangement Signatures were associated with <italic>BRCA1</italic> or <italic>BRCA2</italic> null cases (Clusters D and G, <xref ref-type="fig" rid="F5">Fig.5</xref>). Some breast cancers without identifiable <italic>BRCA1/2</italic> mutations or <italic>BRCA1</italic> promoter methylation showed these features and segregated with <italic>BRCA1/2</italic> null cancers in hierarchical clustering analysis (<xref ref-type="fig" rid="F5">Fig.5</xref>). In such cases, the <italic>BRCA1</italic>/2 mutations may have been missed or other mutated or promoter methylated genes may be exerting similar effects (Please see <ext-link ext-link-type="uri" xlink:href="http://cancer.sanger.ac.uk/cosmic/sample/genomes">http://cancer.sanger.ac.uk/cosmic/sample/genomes</ext-link> for examples of whole genome profiles of typical BRCA1 null (e.g. PD6413a, PD7215a) and BRCA2 null tumours (e.g. PD4952a, PD4955a)).</p><p id="P28">A further subset of cancers (Cluster F, <xref ref-type="fig" rid="F5">Fig.5</xref>) show similarities in mutational pattern to BRCA1/2 null cancers, with many Rearrangement Signature 5 deletions and enrichment for base substitution signatures 3 and 8. However, these do not segregate together with <italic>BRCA1/2</italic> null cases in hierarchical clustering analysis, have Rearrangement Signature 1 large tandem duplications and do not show <italic>BRCA1</italic>/<italic>2</italic> mutations. Somatic and germline mutations in genes associated with the DNA double-strand break repair pathway including <italic>ATM</italic>, <italic>ATR</italic>, <italic>PALB2</italic>, <italic>RAD51C</italic>, <italic>RAD50, TP53, CHEK2</italic> and <italic>BRIP1</italic>, were sought in these cancers. We did not observe any clear-cut relationships between mutations in these genes and these mutational patterns.</p><p id="P29">Cancers with <italic>BRCA1</italic>/<italic>2</italic> mutations are particularly responsive to cisplatin and PARP inhibitors<xref rid="R43" ref-type="bibr">43</xref>–<xref rid="R45" ref-type="bibr">45</xref>. Combinations of base substitution, indel and rearrangement mutational signatures may be better biomarkers of defective homologous recombination based DNA double strand break repair and responsiveness to these drugs<xref rid="R46" ref-type="bibr">46</xref> than <italic>BRCA1/2</italic> mutations or promoter methylation alone and thus may constitute the basis of future diagnostics.</p></sec></sec><sec sec-type="conclusions" id="S9"><title>Conclusions</title><p id="P30">A comprehensive perspective on the somatic genetics of breast cancer is drawing closer (please see website for individual patient genome profiles: <ext-link ext-link-type="uri" xlink:href="http://cancer.sanger.ac.uk/cosmic/sample/genomes">http://cancer.sanger.ac.uk/cosmic/sample/genomes</ext-link>, <xref ref-type="supplementary-material" rid="SD1">Methods Section 10</xref> for orientation). At least 12 base substitution mutational signatures and six rearrangement signatures contribute to the somatic mutations found. 93 mutated cancer genes (31 dominant, 60 recessive, 2 uncertain) are implicated in genesis of the disease. However, dominantly-acting activated fusion genes and non-coding driver mutations appear rare. Additional infrequently mutated cancer genes probably exist. However, the genes harbouring the substantial majority of driver mutations are now known.</p><p id="P31">Nevertheless, important questions remain to be addressed. Recurrent mutational events including whole chromosome copy number changes and unexplained regions with recurrent rearrangements could harbour additional cancer genes. Identifying non-coding drivers is challenging and requires further investigation. Although almost all breast cancers have at least one identifiable driver mutation, the number with only a single identified driver is perhaps surprising. The roles of viruses or other microbes have not been exhaustively examined. Thus, further exploration and analysis of whole genome sequences from breast cancer patients will be required to complete our understanding of the somatic mutational basis of the disease.</p></sec><sec sec-type="methods" id="S10" specific-use="web-only"><title>Methods</title><sec id="S11"><label>1</label><title>Sample selection</title><p id="P32">DNA was extracted from 560 breast cancers and normal tissue (peripheral blood lymphocytes, adjacent normal breast tissue or skin) and total RNA extracted from 268 of the same individuals. Samples were subjected to pathology review and only samples assessed as being composed of > 70% tumor cells, were accepted for inclusion in the study (<xref ref-type="supplementary-material" rid="SD4">Supplementary Table 1</xref>).</p></sec><sec id="S12"><label>2</label><title>Massively-parallel sequencing and alignment</title><p id="P33">Short insert 500bp genomic libraries and 350bp poly-A selected transcriptomic libraries were constructed, flowcells prepared and sequencing clusters generated according to Illumina library protocols<xref rid="R47" ref-type="bibr">47</xref>. 108 base/100 base (genomic), or 75 base (transcriptomic) paired-end sequencing were performed on Illumina GAIIx, Hiseq 2000 or Hiseq 2500 genome analyzers in accordance with the Illumina Genome Analyzer operating manual. The average sequence coverage was 40.4 fold for tumour samples and 30.2 fold for normal samples (<xref ref-type="supplementary-material" rid="SD4">Supplementary Table 2</xref>).</p><p id="P34">Short insert paired-end reads were aligned to the reference human genome (GRCh37) using Burrows-Wheeler Aligner, BWA (v0.5.9)<xref rid="R48" ref-type="bibr">48</xref>. RNA-seq data was aligned to the human reference genome (GRCh37) using TopHat (v1.3.3) (<ext-link ext-link-type="uri" xlink:href="http://ccb.jhu.edu/software/tophat/index.shtml">http://ccb.jhu.edu/software/tophat/index.shtml</ext-link>).</p></sec><sec id="S13"><label>3</label><title>Processing of genomic data</title><p id="P35">CaVEMan (Cancer Variants Through Expectation Maximization: <ext-link ext-link-type="uri" xlink:href="http://cancerit.github.io/CaVEMan/">http://cancerit.github.io/CaVEMan/</ext-link>) was used for calling somatic substitutions.</p><p id="P36">Indels in the tumor and normal genomes were called using a modified Pindel version 2.0. (<ext-link ext-link-type="uri" xlink:href="http://cancerit.github.io/cgpPindel/">http://cancerit.github.io/cgpPindel/</ext-link>) on the NCBI37 genome build <xref rid="R49" ref-type="bibr">49</xref>.</p><p id="P37">Structural variants were discovered using a bespoke algorithm, BRASS (BReakpoint AnalySiS) (<ext-link ext-link-type="uri" xlink:href="https://github.com/cancerit/BRASS">https://github.com/cancerit/BRASS</ext-link>) through discordantly mapping paired-end reads. Next, discordantly mapping read pairs that were likely to span breakpoints, as well as a selection of nearby properly-paired reads, were grouped for each region of interest. Using the Velvet de novo assembler<xref rid="R50" ref-type="bibr">50</xref>, reads were locally assembled within each of these regions to produce a contiguous consensus sequence of each region. Rearrangements, represented by reads from the rearranged derivative as well as the corresponding non-rearranged allele were instantly recognisable from a particular pattern of five vertices in the de Bruijn graph (a mathematical method used in de novo assembly of (short) read sequences) of component of Velvet. Exact coordinates and features of junction sequence (e.g. microhomology or non-templated sequence) were derived from this, following aligning to the reference genome, as though they were split reads.</p><p id="P38"><xref ref-type="supplementary-material" rid="SD4">Supplementary Table 3</xref> for summary of somatic variants. Annotation was according to ENSEMBL version 58.</p><p id="P39">Single nucleotide polymorphism (SNP) array hybridization using the Affymetrix SNP6.0 platform was performed according to Affymetrix protocols. Allele-specific copy number analysis of tumors was performed using ASCAT (v2.1.1), to generate integral allele-specific copy number profiles for the tumor cells<xref rid="R51" ref-type="bibr">51</xref> (<xref ref-type="supplementary-material" rid="SD4">Supplementary Table 4 and 5</xref>). ASCAT was also applied to NGS data directly with highly comparable results.</p><p id="P40">12.5% of the breast cancers were sampled for validation of substitutions, indels and/or rearrangements in order to make an assessment of the positive predictive value of mutation-calling (<xref ref-type="supplementary-material" rid="SD4">Supplementary Table 6</xref>).</p><p id="P41">Further details of these processing steps as well as processing of transcriptomic and miRNA data (<xref ref-type="supplementary-material" rid="SD4">Supplementary Table 7 and 8</xref>) can be found in <xref ref-type="supplementary-material" rid="SD1">Supplementary Methods</xref>.</p></sec><sec id="S14"><label>4</label><title>Identification of novel breast cancer genes</title><p id="P42">To identify recurrently mutated driver genes, a dN/dS method that considers the mutation spectrum, the sequence of each gene, the impact of coding substitutions (synonymous, missense, nonsense, splice site) and the variation of the mutation rate across genes<xref rid="R52" ref-type="bibr">52</xref>,<xref rid="R53" ref-type="bibr">53</xref> was used for substitutions (<xref ref-type="supplementary-material" rid="SD4">Supplementary Table 9</xref>). Owing to the lack of a neutral reference for the indel rate in coding sequences, a different approach was required (<xref ref-type="supplementary-material" rid="SD4">Supplementary Table 10</xref>, <xref ref-type="supplementary-material" rid="SD1">Supplementary Methods</xref> for details). To detect genes under significant selective pressure by either point mutations or indels, for each gene the <italic>P</italic>-values from the dN/dS analysis of substitutions and from the recurrence analysis of indels were combined using Fisher’s method. Multiple testing correction (Benjamini-Hochberg FDR) was performed separately for the 600+ putative driver genes and for all other genes, stratifying the FDR correction to increase sensitivity (as described in Sun <italic>et al</italic>. 2006<xref rid="R54" ref-type="bibr">54</xref>). To achieve a low false discovery rate a conservative q-value cutoff of <0.01 was used for significance (<xref ref-type="supplementary-material" rid="SD4">Supplementary Table 11</xref>).</p><p id="P43">This analysis was applied to the new whole genome sequences of 560 breast cancers as well as a further 772 breast cancers that have been sequenced previously by other institutions.</p><p id="P44">Please see <xref ref-type="supplementary-material" rid="SD1">Supplementary Methods</xref> for detailed explanations of these methods.</p></sec><sec id="S15"><label>5</label><title>Recurrence in the non-coding regions</title><sec id="S16"><label>5.1</label><title>Partitioning the genome into functional regulatory elements/gene features</title><p id="P45">To identify non-coding regions with significant recurrence, we used a method similar to the one described for searching for novel indel drivers (<xref ref-type="supplementary-material" rid="SD1">Supplementary Methods</xref> for detailed description).</p><p id="P46">The genome was partitioned according to different sets of regulatory elements/gene features, with a separate analysis performed for each set of elements, including exons (n=20,245 genes), core promoters (n=20,245 genes, where a core promoter is the interval [−250,+250] bp from any transcription start site (TSS) of a coding transcript of the gene, excluding any overlap with coding regions), 5’ UTR (n=9,576 genes), 3’ UTR (n=19,502 genes), intronic regions flanking exons (n=20,212 genes, represents any intronic sequence within 75bp from an exon, excluding any base overlapping with any of the above elements. This attempts to capture recurrence in essential splice site or proximal splicing-regulatory elements), any other sequence within genes (n=18,591 genes, for every protein-coding gene, this contains any region within the start and end of transcripts not included in any of the above categories), ncRNAs (n=10,684, full length lincRNAs, miRNAs or rRNAs), enhancers (n=194,054) <xref rid="R55" ref-type="bibr">55</xref>, ultra-conserved regions (n=187,057, a collection of regions under negative selection based on 1,000 genomes data <xref rid="R20" ref-type="bibr">20</xref>.</p><p id="P47">Every element set listed above was analysed separately to allow for different mutation rates across element types and to stratify the FDR correction <xref rid="R54" ref-type="bibr">54</xref>. Within each set of elements, we used a negative binomial regression approach to learn the underlying variation of the mutation rate across elements. The offset reflects the expected number of mutations in each element assuming uniform mutation rates across them (<italic>i.e</italic>. <italic>E<sub>subs,element</sub></italic> = Σ<sub> j∈{1,2,…,192}Extende</sub> (<italic>t</italic>*<italic>r<sub>j</sub></italic>*<italic>S<sub>j</sub></italic>), and, <italic>E<sub>indels,element</sub></italic> = <italic>μ<sub>indel</sub></italic> * <italic>S<sub>indel,element</sub></italic> ). As covariate here we used the local density of mutations in neighbouring non-coding regions, corrected for sequence composition and trinucleotide mutation rates, that is, the <italic>t</italic> parameter of the dN/dS equations described in section 7.1 of <xref ref-type="supplementary-material" rid="SD1">Supplementary Methods</xref>. Normalised local rates were pre-calculated for 100kb non-overlapping bins of the genome and used in all analyses. Other covariates (expression, replication time or HiC) were not used here as they were not found to substantially improve the model once the local mutation rate was used as a covariate. A separate regression analysis was performed for substitutions and indels, to account for the different level of uncertainty in the distribution of substitution and indel rates across elements.</p><p id="P48">model<sub>subs</sub> = glm.nb(formula = <italic>n<sub>subs</sub></italic> ~ offset(log(<italic>E<sub>subs</sub></italic>)) + <italic>μ<sub>local,subs</sub></italic> )</p><p id="P49">model<sub>indels</sub> = glm.nb(formula = <italic>n<sub>indels</sub></italic> ~ offset(log(<italic>E<sub>indels</sub></italic>)) + <italic>μ<sub>local,indels</sub></italic> )</p><p id="P50">The observed counts for each element (<italic>n<sub>subs,element</sub></italic> and <italic>n<sub>indels,element</sub></italic>) are compared to the background distributions using a negative binomial test, with the estimated overdispersion parameters (<italic>θ<sub>subs</sub></italic> and <italic>θ<sub>indels</sub></italic>) estimated by the negative binomial regression, yielding <italic>P</italic>-values for substitution and indel recurrence for each element. These <italic>P</italic>-values were combined using Fisher’s method and corrected for multiple testing using FDR (<xref ref-type="supplementary-material" rid="SD4">Supplementary Table 16A</xref>).</p></sec><sec id="S17"><label>5.2</label><title>Partitioning the genome into discrete bins</title><p id="P51">We performed a genome-wide screening of recurrence in 1kb non-overlapping bins. We employed the method described in earlier section, using as covariate the local mutation rate calculated from 5Mb up and downstream from the bin of interest and excluding any low-coverage region from the estimate (<xref ref-type="supplementary-material" rid="SD4">Supplementary Table 16B</xref>, <xref ref-type="fig" rid="F8">Extended Data Figure 3A</xref> for example). Significant hits were subjected to manual curation to remove false positives caused by sequencing or mapping artefacts.</p></sec></sec><sec id="S18"><label>6</label><title>Mutational signatures analysis</title><p id="P52">Mutational signatures analysis was performed following a three-step process: (i) hierarchical <italic>de novo</italic> extraction based on somatic substitutions and their immediate sequence context, (ii) updating the set of consensus signatures using the mutational signatures extracted from breast cancer genomes, and (iii) evaluating the contributions of each of the updated consensus signatures in each of the breast cancer samples. These three steps are discussed in more details in the next sections.</p><sec id="S19"><label>6.1</label><title>Hierarchical <italic>de novo</italic> extraction of mutational signatures</title><p id="P53">The mutational catalogues of the 560 breast cancer whole genome sequences were analysed for mutational signatures using a hierarchical version of the Wellcome Trust Sanger Institute mutational signatures framework <xref rid="R25" ref-type="bibr">25</xref>. Briefly, we converted all mutation data into a matrix, <italic>M</italic>, that is made up of 96 features comprising mutations counts for each mutation type (C>A, C>G, C>T, T>A, T>C, and T>G; all substitutions are referred to by the pyrimidine of the mutated Watson–Crick base pair) using each possible 5’ (C, A, G, and T) and 3’ (C, A, G, and T) context for all samples. After conversion, the previously developed algorithm was applied in a hierarchical manner to the matrix <italic>M</italic> that contains <italic>K</italic> mutation types and <italic>G</italic> samples. The algorithm deciphers the minimal set of mutational signatures that optimally explains the proportion of each mutation type and then estimates the contribution of each signature across the samples. More specifically, the algorithm makes use of a well-known blind source separation technique, termed nonnegative matrix factorization (NMF). NMF identifies the matrix of mutational signature, <italic>P</italic>, and the matrix of the exposures of these signatures, <italic>E</italic>, by minimizing a Frobenius norm while maintaining non-negativity:<disp-formula id="FD1"><mml:math display="block" id="M1" overflow="scroll"><mml:mrow><mml:munder><mml:mrow><mml:mtext>min</mml:mtext></mml:mrow><mml:mrow><mml:mi>P</mml:mi><mml:mo>∈</mml:mo><mml:msubsup><mml:mi mathvariant="double-struck">M</mml:mi><mml:mrow><mml:msub><mml:mi>ℝ</mml:mi><mml:mo>+</mml:mo></mml:msub></mml:mrow><mml:mrow><mml:mo stretchy="false">(</mml:mo><mml:mover accent="true"><mml:mi>K</mml:mi><mml:mo>˙</mml:mo></mml:mover><mml:mo>,</mml:mo><mml:mi>N</mml:mi><mml:mo stretchy="false">)</mml:mo></mml:mrow></mml:msubsup><mml:mi>E</mml:mi><mml:mo>∈</mml:mo><mml:msubsup><mml:mi mathvariant="double-struck">M</mml:mi><mml:mrow><mml:msub><mml:mi>ℝ</mml:mi><mml:mo>+</mml:mo></mml:msub></mml:mrow><mml:mrow><mml:mo stretchy="false">(</mml:mo><mml:mi>N</mml:mi><mml:mo>,</mml:mo><mml:mi>G</mml:mi><mml:mo stretchy="false">)</mml:mo></mml:mrow></mml:msubsup></mml:mrow></mml:munder><mml:mo stretchy="false">|</mml:mo><mml:mo stretchy="false">|</mml:mo><mml:mtext>M</mml:mtext><mml:mo>−</mml:mo><mml:mi>P</mml:mi><mml:mo>×</mml:mo><mml:mi>E</mml:mi><mml:mo stretchy="false">|</mml:mo><mml:msubsup><mml:mo stretchy="false">|</mml:mo><mml:mi>F</mml:mi><mml:mn>2</mml:mn></mml:msubsup></mml:mrow></mml:math></disp-formula> The method for deciphering mutational signatures, including evaluation with simulated data and list of limitations, can be found in ref <xref rid="R25" ref-type="bibr">25</xref>. The framework was applied in a hierarchical manner to increase its ability to find mutational signatures present in few samples as well as mutational signatures exhibiting a low mutational burden. More specifically, after application to the original matrix <italic>M</italic> containing 560 samples, we evaluated the accuracy of explaining the mutational patterns of each of the 560 breast cancers with the extracted mutational signatures. All samples that were well explained by the extracted mutational signatures were removed and the framework was applied to the remaining sub-matrix of <italic>M</italic>. This procedure was repeated until the extraction process did not reveal any new mutational signatures. Overall, the approach extracted 12 unique mutational signatures operative across the 560 breast cancers (<xref ref-type="fig" rid="F3">Figure 3</xref>, <xref ref-type="supplementary-material" rid="SD4">Supplementary Table 21</xref>).</p></sec><sec id="S20"><label>6.2</label><title>Updating the set of consensus mutational signatures</title><p id="P54">The 12 hierarchically extracted breast cancer signatures were compared to the census of consensus mutational signatures <xref rid="R25" ref-type="bibr">25</xref>. 11 of the 12 signatures closely resembled previously identified mutational patterns. The patterns of these 11 signatures, weighted by the numbers of mutations contributed by each signature in the breast cancer data, were used to update the set of consensus mutational signatures as previously done in <xref rid="R25" ref-type="bibr">ref 25</xref>. 1 of the 12 extracted signatures is novel and at present, unique for breast cancer. This novel signature is consensus signature 30 (<ext-link ext-link-type="uri" xlink:href="http://cancer.sanger.ac.uk/cosmic/signatures">http://cancer.sanger.ac.uk/cosmic/signatures</ext-link>).</p></sec><sec id="S21"><label>6.3</label><title>Evaluating the contributions of consensus mutational signatures in 560 breast cancers</title><p id="P55">The complete compendium of consensus mutational signatures that was found in breast cancer includes: signatures 1, 2, 3, 5, 6, 8, 13, 17, 18, 20, 26, and 30. We evaluated the presence of all these signatures in the 560 breast cancer genomes by re-introducing them into each sample. More specifically, the updated set of consensus mutational signatures was used to minimize the constrained linear function for each sample: <disp-formula id="FD2"><mml:math display="block" id="M2" overflow="scroll"><mml:munder><mml:mrow><mml:mi>min</mml:mi><mml:mo></mml:mo></mml:mrow><mml:mrow><mml:mi>E</mml:mi><mml:mi>x</mml:mi><mml:mi>p</mml:mi><mml:mi>o</mml:mi><mml:mi>s</mml:mi><mml:mi>u</mml:mi><mml:mi>r</mml:mi><mml:mi>e</mml:mi><mml:msub><mml:mi>s</mml:mi><mml:mi>i</mml:mi></mml:msub><mml:mo>≥</mml:mo><mml:mn>0</mml:mn></mml:mrow></mml:munder><mml:mo stretchy="false">|</mml:mo><mml:mo stretchy="false">|</mml:mo><mml:mi>S</mml:mi><mml:mi>a</mml:mi><mml:mi>m</mml:mi><mml:mi>p</mml:mi><mml:mi>l</mml:mi><mml:mi>e</mml:mi><mml:mi>M</mml:mi><mml:mi>u</mml:mi><mml:mi>t</mml:mi><mml:mi>a</mml:mi><mml:mi>t</mml:mi><mml:mi>i</mml:mi><mml:mi>o</mml:mi><mml:mi>n</mml:mi><mml:mi>s</mml:mi><mml:mo>−</mml:mo><mml:mstyle displaystyle="true"><mml:munderover><mml:mo>∑</mml:mo><mml:mrow><mml:mi>i</mml:mi><mml:mo>=</mml:mo><mml:mn>1</mml:mn></mml:mrow><mml:mi>N</mml:mi></mml:munderover><mml:mrow><mml:mo stretchy="false">(</mml:mo><mml:mover accent="true"><mml:mrow><mml:mi>S</mml:mi><mml:mi>i</mml:mi><mml:mi>g</mml:mi><mml:mi>n</mml:mi><mml:mi>a</mml:mi><mml:mi>t</mml:mi><mml:mi>u</mml:mi><mml:mi>r</mml:mi><mml:msub><mml:mi>e</mml:mi><mml:mi>i</mml:mi></mml:msub></mml:mrow><mml:mo stretchy="true">→</mml:mo></mml:mover><mml:mo>∗</mml:mo><mml:mi>E</mml:mi><mml:mi>x</mml:mi><mml:mi>p</mml:mi><mml:mi>o</mml:mi><mml:mi>s</mml:mi><mml:mi>u</mml:mi><mml:mi>r</mml:mi><mml:msub><mml:mi>e</mml:mi><mml:mi>i</mml:mi></mml:msub><mml:mo stretchy="false">)</mml:mo><mml:mo stretchy="false">|</mml:mo><mml:msubsup><mml:mo stretchy="false">|</mml:mo><mml:mi>F</mml:mi><mml:mn>2</mml:mn></mml:msubsup></mml:mrow></mml:mstyle></mml:math></disp-formula> Here, <inline-formula><mml:math display="inline" id="M3" overflow="scroll"><mml:mrow><mml:mover accent="true"><mml:mrow><mml:mi>S</mml:mi><mml:mi>i</mml:mi><mml:mi>g</mml:mi><mml:mi>n</mml:mi><mml:mi>a</mml:mi><mml:mi>t</mml:mi><mml:mi>u</mml:mi><mml:mi>r</mml:mi><mml:msub><mml:mi>e</mml:mi><mml:mi>i</mml:mi></mml:msub></mml:mrow><mml:mo stretchy="true">→</mml:mo></mml:mover></mml:mrow></mml:math></inline-formula> represents a vector with 96 components (corresponding to a consensus mutational signature with its six somatic substitutions and their immediate sequencing context) and <italic>Exposure<sub>i</sub></italic> is a nonnegative scalar reflecting the number of mutations contributed by this signature. <italic>N</italic> is equal to 12 and it reflects the number of all possible signatures that can be found in a single breast cancer sample. Mutational signatures that did not contribute large numbers (or proportions) of mutations or that did not significantly improve the correlation between the original mutational pattern of the sample and the one generated by the mutational signatures were excluded from the sample. This procedure reduced over-fitting the data and allowed only the essential mutational signatures to be present in each sample (<xref ref-type="supplementary-material" rid="SD4">Supplementary Table 21B</xref>).</p></sec></sec><sec id="S22"><label>7</label><title>Kataegis</title><p id="P56">Kataegis or foci of localized hypermutation has been previously defined <xref rid="R25" ref-type="bibr">25</xref> as 6 or more consecutive mutations with an average intermutation distance of less than or equal to 1,000 bp. Kataegis were sought in 560 whole-genome sequenced breast cancers from high-quality base substitution data using the method described previously <xref rid="R25" ref-type="bibr">25</xref>. This method likely misses some foci of kataegis sacrificing sensitivity of detection for a higher positive predictive value of kataegic foci (<xref ref-type="supplementary-material" rid="SD4">Supplementary Table 21C</xref>).</p></sec><sec id="S23"><label>8</label><title>Rearrangement signatures</title><sec id="S24"><label>8.1</label><title>Clustered vs non-clustered rearrangements</title><p id="P57">We sought to separate rearrangements that occurred as focal catastrophic events or focal driver amplicons from genome-wide rearrangement mutagenesis using a piecewise constant fitting (PCF) method. For each sample, both breakpoints of each rearrangement were considered individually and all breakpoints were ordered by chromosomal position. The inter-rearrangement distance, defined as the number of base pairs from one rearrangement breakpoint to the one immediately preceding it in the reference genome, was calculated. Putative regions of clustered rearrangements were identified as having an average inter-rearrangement distance that was at least 10 times greater than the whole genome average for the individual sample. PCF parameters used were γ = 25 and <italic>k</italic>min = 10. The respective partner breakpoint of all breakpoints involved in a clustered region are likely to have arisen at the same mechanistic instant and so were considered as being involved in the cluster even if located at a distant chromosomal site. Extended Data Table 4A summarises the rearrangements within clusters (“clustered”) and not within clusters (“non-clustered”).</p></sec><sec id="S25"><label>8.2</label><title>Classification – types and size</title><p id="P58">In both classes of rearrangements, clustered and non-clustered, rearrangements were subclassified into deletions, inversions and tandem duplications, and then further subclassified according to size of the rearranged segment (1-10kb, 10kb-100kb, 100kb-1Mb, 1Mb-10Mb, more than 10Mb). The final category in both groups was interchromosomal translocations.</p></sec><sec id="S26"><label>8.3</label><title>Rearrangement signatures by NNMF</title><p id="P59">The classification produces a matrix of 32 distinct categories of structural variants across 544 breast cancer genomes. This matrix was decomposed using the previously developed approach for deciphering mutational signatures by searching for the optimal number of mutational signatures that best explains the data without over-fitting the data <xref rid="R25" ref-type="bibr">25</xref> (<xref ref-type="supplementary-material" rid="SD4">Supplementary Table 21D-E</xref>).</p></sec><sec id="S27"><label>8.4</label><title>Consensus clustering of rearrangement signatures</title><p id="P60">To identify subgroups of samples sharing similar combinations of six identified rearrangement signatures derived from whole genome sequencing analysis we performed consensus clustering using the ConsensusClusterPlus R package <xref rid="R56" ref-type="bibr">56</xref>. Input data for each sample (n=544, a subset of the full sample cohort) was the proportion of rearrangements assigned to each of the six signatures. Thus, each sample has 6 data values, with a total sum of 1. Proportions for each signature were mean-centred across samples prior to clustering. The following settings were used in the consensus clustering: <list list-type="simple" id="L1"><list-item><label>-</label><p id="P61">Number of repetitions: 1000</p></list-item><list-item><label>-</label><p id="P62">pItem = 0.9 (resampling frequency samples)</p></list-item><list-item><label>-</label><p id="P63">pFeature = 0.9 (resampling frequency)</p></list-item><list-item><label>-</label><p id="P64">Pearson distance metric</p></list-item><list-item><label>-</label><p id="P65">Ward linkage method</p></list-item></list></p></sec></sec><sec id="S28"><label>9</label><title>Distribution of mutational signatures relative to genomic architecture</title><p id="P66">Following extraction of mutational signatures and quantification of the exposures (or contributions) of each signature to each sample, a probability for each mutation belonging to each mutation signature (for a given class of mutation e.g. substitutions) was assigned<xref rid="R42" ref-type="bibr">42</xref>.</p><p id="P67">The distribution of mutations as signatures were assessed across multiple genomic features including replication time, strands, transcriptional strands and nucleosome occupancy. Please see Morganella et al for technical details, per signature results.</p></sec><sec id="S29"><label>10</label><title>Individual patient whole genome profiles</title><p id="P68">Breast cancer whole genome profiles were adapted from the R Circos package<xref rid="R57" ref-type="bibr">57</xref>. Features depicted in circos plots from outermost rings heading inwards: Karyotypic ideogram outermost. Base substitutions next, plotted as rainfall plots (log10 intermutation distance on radial axis, dot colours: blue=C>A, black=C>G, red=C>T, grey=T>A, green=T>C, pink=T>G). Ring with short green lines = insertions, ring with short red lines = deletions. Major copy number allele (green = gain) ring, minor copy number allele ring (pink=loss), Central lines represent rearrangements (green= tandem duplications, pink=deletions, blue=inversions and gray=interchromosomal events. Top right hand panel displays the number of mutations contributing to each mutation signature extracted using NNMF in individual cancers. Middle right hand panel represents indels. Bottom right corner shows histogram of rearrangements present in this cancer. Bottom left corner shows all curated driver mutations, top and middle left panels show clinical and pathology data respectively.</p></sec></sec><sec sec-type="extended-data" id="S30"><title>Extended Data</title><fig id="F6" orientation="portrait" position="anchor"><label>Extended Data Figure 1</label><caption><title>Landscape of driver mutations</title><p id="P69">(A) Summary of subtypes of cohort of 560 breast cancers</p><p id="P70">(B) Driver mutations by mutation type</p><p id="P71">(C) Distribution of rearrangements throughout the genome. Black line represents background rearrangement density (calculation based on rearrangement breakpoints in intergenic regions only). Red lines represent frequency of rearrangement within breast cancer genes.</p></caption><graphic xlink:href="emss-68344-f006"></graphic></fig><fig id="F7" orientation="portrait" position="anchor"><label>Extended Data Figure 2</label><caption><title>Rearrangements in oncogenes</title><p id="P72">(A) Variation in rearrangement and copy number events affecting <italic>ESR1</italic>. Clear amplification in topmost panel, transection of <italic>ESR1</italic> in middle panel and focused tandem duplication events in lower panel.</p><p id="P73">(B) Predicted outcomes of some rearrangements affecting <italic>ETV6</italic>. Red crosses indicate exons deleted as a result of rearrangements within the <italic>ETV6</italic> genes, black dotted lines indicate rearrangement break points resulting in fusions between <italic>ETV6</italic> and <italic>ERC, WNK1, ATP2B1</italic> or <italic>LRP6</italic></p></caption><graphic xlink:href="emss-68344-f007"></graphic></fig><fig id="F8" orientation="portrait" position="anchor"><label>Extended Data Figure 3</label><caption><title>Recurrent non-coding events in breast cancers</title><p id="P74">(A) Manhattan plot demonstrating sites with most significant p-values as identified by binning analysis. Purple highlighted sites were also detected by the method seeking recurrence when partitioned by genomic features.</p><p id="P75">(B) Locus at chr11:65Mb which was identified by independent analyses as being more mutated than expected by chance. In the lowermost panel, a rearrangement hotspot analysis identified this region as a tandem duplication hotspot, with nested tandem duplications noted at this site. Partitioning the genome into different regulatory elements, an analysis of substitutions and indels identified lncRNAs MALAT1 and NEAT1 (topmost panels) with significant p-values.</p></caption><graphic xlink:href="emss-68344-f008"></graphic></fig><fig id="F9" orientation="portrait" position="anchor"><label>Extended Data Figure 4</label><caption><title>Copy number analyses</title><p id="P76">(A) Frequency of copy number aberrations across the cohort. Chromosome position along x-axis, frequency of copy number gains (red) and losses (green) y-axis.</p><p id="P77">(B) Identification of focal recurrent copy number gains by the GISTIC method (<xref ref-type="supplementary-material" rid="SD1">Supplementary Methods</xref>)</p><p id="P78">(C) Identification of focal recurrent copy number losses by the GISTIC method</p><p id="P79">(D) Heatmap of GISTIC regions following unsupervised hierarchical clustering. 5 cluster groups are noted and relationships with expression subtype (basal=red, luminal B=light blue, luminal A=dark blue), immunohistopathology status (ER, PR, HER2 status – black=positive), abrogation of <italic>BRCA1</italic> (red) and <italic>BRCA2</italic> (blue) (whether germline, somatic or through promoter hypermethylation), driver mutations (black=positive), HRD index (top 25% or lowest 25% - black=positive).</p></caption><graphic xlink:href="emss-68344-f009"></graphic></fig><fig id="F10" orientation="portrait" position="anchor"><label>Extended Data Figure 5</label><caption><title>miRNA analyses</title><p id="P80">Hierarchical clustering of the most variant miRNAs using complete linkage and Euclidean distance. miRNA clusters were assigned using the Partitioning Algorithm using Recursive Thresholding (PART) method. Five main patient clusters were revealed. The horizontal annotation bars show (from top to bottom): PART cluster group, PAM50 mRNA expression subtype, GISTIC cluster, rearrangement cluster, lymphocyte infiltration score and histological grade. The heatmap shows clustered and centered miRNA expression data (log2 transformed). Details on colour coding of the annotation bars are presented below the heatmap.</p></caption><graphic xlink:href="emss-68344-f010"></graphic></fig><fig id="F11" orientation="portrait" position="anchor"><label>Extended Data Figure 6</label><caption><title>Rearrangement cluster groups and associated features</title><p id="P81">(A) Overall survival by rearrangement cluster group</p><p id="P82">(B) Age of diagnosis</p><p id="P83">(C) Tumor grade</p><p id="P84">(D) Menopausal status</p><p id="P85">(E) ER status</p><p id="P86">(F) Immune response metagene panel</p><p id="P87">(G) Lymphocytic infiltration score</p></caption><graphic xlink:href="emss-68344-f011"></graphic></fig><fig id="F12" orientation="portrait" position="anchor"><label>Extended Data Figure 7</label><caption><title>Contrasting tandem duplication phenotypes</title><p id="P88">Contrasting tandem duplication phenotypes of two breast cancers using chromosome X. Copy number (y-axis) depicted as black dots. Lines represent rearrangements breakpoints (green=tandem duplications, pink=deletions, blue=inversions, black=translocations with partner breakpoint provided). Top panel, PD4841a, is overwhelmed by large tandem duplications (>100kb, RS1) while PD4833a has many short tandem duplications (< 10kb, RS3) appearing as “single” lines in its plot.</p></caption><graphic xlink:href="emss-68344-f012"></graphic></fig><fig id="F13" orientation="portrait" position="anchor"><label>Extended Data Figure 8</label><caption><title>Hotspots of tandem duplications</title><p id="P89">A tandem duplication hotspot occurring in 6 different patients</p></caption><graphic xlink:href="emss-68344-f013"></graphic></fig><fig id="F14" orientation="portrait" position="anchor"><label>Extended Data Figure 9</label><caption><title>Rearrangement breakpoint junctions</title><p id="P90">(A) Breakpoint features of rearrangements in 560 breast cancers by Rearrangement Signature.</p><p id="P91">(B) Breakpoint features in BRCA and non-BRCA cancers</p></caption><graphic xlink:href="emss-68344-f014"></graphic></fig><fig id="F15" orientation="portrait" position="anchor"><label>Extended Data Figure 10</label><caption><title>Signatures of focal hypermutation</title><p id="P92">(A) Kataegis and alternative kataegis occurring at the same locus (ERBB2 amplicon in PD13164a). Copy number (y-axis) depicted as black dots. Lines represent rearrangements breakpoints (green=tandem duplications, pink=deletions, blue=inversions). Topmost panel showing a ~10Mb region including the ERBB2 locus. Second panel from top zooms in 10-fold to a ~1Mb window highlighting co-occurrence of rearrangement breakpoints, with copy number changes and three different kataegis loci. Third panel from top demonstrates kataegis loci in more detail. Log10 intermutation distance on y axis. Black arrow highlighting kataegis. Blue arrows highlighting alternative kataegis.</p><p id="P93">(B) Sequence context of kataegis and alternative kataegis identified in this dataset.</p></caption><graphic xlink:href="emss-68344-f015"></graphic></fig></sec><sec sec-type="supplementary-material" id="SM"><title>Supplementary Material</title><supplementary-material content-type="local-data" id="SD1"><label>Supplementary Methods</label><media xlink:href="NIHMS68344-supplement-Supplementary_Methods.docx" mimetype="application" mime-subtype="octet-stream" orientation="portrait" xlink:type="simple" id="d37e2713" position="anchor"></media></supplementary-material><supplementary-material content-type="local-data" id="SD2"><label>Supplementary Notes 1</label><media xlink:href="NIHMS68344-supplement-Supplementary_Notes_1.docx" mimetype="application" mime-subtype="octet-stream" orientation="portrait" xlink:type="simple" id="d37e2717" position="anchor"></media></supplementary-material><supplementary-material content-type="local-data" id="SD3"><label>Supplementary Notes 2</label><media xlink:href="NIHMS68344-supplement-Supplementary_Notes_2.docx" mimetype="application" mime-subtype="octet-stream" orientation="portrait" xlink:type="simple" id="d37e2721" position="anchor"></media></supplementary-material><supplementary-material content-type="local-data" id="SD4"><label>Supplementary Tables 1-21</label><media xlink:href="NIHMS68344-supplement-Supplementary_Tables_1-21.zip" mimetype="application" mime-subtype="zip" orientation="portrait" xlink:type="simple" id="d37e2725" position="anchor"></media></supplementary-material></sec></body><back><ack id="S31"><title>Acknowledgements</title><p>This work has been funded through the ICGC Breast Cancer Working group by the Breast Cancer Somatic Genetics Study (BASIS), a European research project funded by the European Community’s Seventh Framework Programme (FP7/2010-2014) under the grant agreement number 242006; the Triple Negative project funded by the Wellcome Trust (grant reference 077012/Z/05/Z) and the HER2+ project funded by Institut National du Cancer (INCa) in France (Grants N° 226-2009, 02-2011, 41-2012, 144-2008, 06-2012). The ICGC Asian Breast Cancer Project was funded through a grant of the Korean Health Technology R&D Project, Ministry of Health & Welfare, Republic of Korea (A111218-SC01).</p><p>Personally funded by grants above: FGR-G, SM, KR, SM were funded by BASIS.</p><p>Recruitment was performed under the auspices of the ICGC breast cancer projects run by the UK, France and Korea.</p><p>For contributions towards instruments, specimens and collections: Tayside Tissue Bank (funded by CRUK, University of Dundee, Chief Scientist Office & Breast Cancer Campaign), Asan Bio-Resource Center of the Korea Biobank Network, Seoul, South Korea, OSBREAC consortium, The Icelandic Centre for Research (RANNIS), The Swedish Cancer Society and the Swedish Research Council, and Fondation Jean Dausset-Centre d’Etudes du polymorphisme humain. Icelandic Cancer Registry, The Brisbane Breast Bank (The University of Queensland, The Royal Brisbane & Women’s Hospital and QIMR Berghofer), Breast Cancer Tissue and Data Bank at KCL and NIHR Biomedical Research Centre at Guy’s and St Thomas’s Hospitals. Breakthrough Breast Cancer and Cancer Research UK Experimental Cancer Medicine Centre at KCL.</p><p>For pathology review: The Mouse Genome Project and Department of Pathology, Cambridge University Hospitals NHS Foundation Trust for microscopes. Andrea Richardson, Anna Ehinger, Anne Vincent-Salomon, Carolien Van Deurzen, Colin Purdie, Denis Larsimont, Dilip Giri, Dorthe Grabau, Elena Provenzano, Gaetan MacGrogan, Gert Van den Eynden, Isabelle Treilleux, Jane E Brock, Jocelyne Jacquemier, Jorge Reis-Filho, Laurent Arnould, Louise Jones, Marc van de Vijver, Øystein Garred, Roberto Salgado, Sarah Pinder, Sunil R Lakhani, Torill Sauer, Violetta Barbashina.</p><p>Illumina UK Ltd for input on optimisation of sequencing throughout this project.</p><p>Wellcome Trust Sanger Institute Sequencing Core Facility, Core IT Facility and Cancer Genome Project Core IT team and Cancer Genome Project Core Laboratory team for general support.</p><p>Personal funding: SN-Z is a Wellcome Beit Fellow and personally funded by a Wellcome Trust Intermediate Fellowship (WT100183MA). LBA is supported through a J. Robert Oppenheimer Fellowship at Los Alamos National Laboratory. ALR is partially supported by the Dana-Farber/Harvard Cancer Center SPORE in Breast Cancer (NIH/NCI 5 P50 CA168504-02). DG was supported by the EU-FP7-SUPPRESSTEM project. AS was supported by Cancer Genomics Netherlands (CGC.nl) through a grant from the Netherlands Organisation of Scientific research (NWO). MS was supported by the EU-FP7-DDR response project. CS and CD are supported by a grant from the Breast Cancer Research Foundation. EB was funded by EMBL. CS is funded by FNRS (Fonds National de la Recherche Scientifique). SJJ is supported by Leading Foreign Research Institute Recruitment Program through the National Research Foundation of Republic Korea (NRF 2011-0030105). GK is supported by National Research Foundation of Korea (NRF) grants funded by the Korean government (NRF 2015R1A2A1A10052578). John Foekens received funding from an ERC Advanced grant (No 322737).</p><p>For general contribution and administrative support: Fondation Synergie Lyon Cancer in France. Jon G Jonasson, Department of Pathology, University Hospital & Faculty of Medicine, University of Iceland. Kaltin Ferguson, Tissue Bank Manager, Brisbane Breast Bank and The Breast Unit, The Royal Brisbane and Women’s Hospital, Brisbane, Australia. The Oslo Breast Cancer Consortium of Norway (OSBREAC). Angelo Paradiso, IRCCS Istituto Tumori “Giovanni Paolo II”, Bari Italy. Antita Vines for administratively supporting to identifying the samples, organizing the bank, and sending out the samples. Margrete Schlooz-Vries, Jolien Tol, Hanneke van Laarhoven, Fred Sweep, Peter Bult in Nijmegen for contributions in Nijmegen. This research used resources provided by the Los Alamos National Laboratory Institutional Computing Program, which is supported by the U.S. Department of Energy National Nuclear Security Administration under Contract No. DE-AC52-06NA25396. Research performed at Los Alamos National Laboratory was carried out under the auspices of the National Nuclear Security Administration of the United States Department of Energy. Nancy Miller (in memoriam) for her contribution in setting up the clinical database.</p><p>Finally, we would like to acknowledge all members of the ICGC Breast Cancer Working Group and ICGC Asian Breast Cancer Project.</p></ack><fn-group><fn id="FN1"><p id="P94"><bold>Accession Numbers</bold></p><p id="P95">Raw data have been submitted to the European-Genome Phenome Archive under the overarching accession number EGAS00001001178 (please see <xref ref-type="supplementary-material" rid="SD2">Supplementary Notes</xref> for breakdown by data type).</p></fn><fn fn-type="con" id="FN2"><p id="P96"><bold>Author Contributions</bold></p><p id="P97">S.N-Z, M.R.S designed the study, analysed data and wrote the manuscript.</p><p id="P98">H.R.M., J.S, M.Ramakrishna, D.G, X.Z. performed curation of data and contributed towards genomic and copy number analyses.</p><p id="P99">M.S., A.B.B., M.R.A., O.C.L., A.L., M.Ringner, contributed towards curation and analysis of non-genomic data (transcriptomic, miRNA, methylation).</p><p id="P100">I.M., L.B.A., D.C.W., P.V.L., S.Morganella, Y.S.J., contributed towards specialist analyses.</p><p id="P101">G.T., G.K., A.L.R., A-L.B-D., J.W.M.M., M.J.v.d.V., H.G.S., E.B., A.Borg., A.V., P.A.F., P.J.C., designed the study, drove the consortium and provided samples.</p><p id="P102">S.Martin was project coordinator.</p><p id="P103">S.McL., S.O.M., K.R., contributed operationally.</p><p id="P104">S-M.A., S.B., J.E.B., A.Brooks., C.D., L.D., A.F., J.A.F., G.K.J.H., S.J.J., H.-Y.K., T.A.K., S.K., H.J.L., J.-Y.L., I.P., X.P., C.P., F.G.R.-G., G.R., A.M.S., P.T.S., O.A.S., S.T., I.T., G.G.V.d.E., P.V., A.V.-S., L.Y., C.C., L.v.V., A.T., S.K., B.K.T.T., J.J., N.t.U., C.S., P.N.S., S.V.L., S.R.L., J.E.E., A.M.T contributed pathology assessment and/or samples.</p><p id="P105">A.Butler., S.D., M.G., D.R.J., Y.L., A.M., V.M., K.R., R.S., L.S., J.T. contributed IT processing and management expertise.</p><p id="P106">All authors discussed the results and 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Indel axis limited to 5,000(*).</p><p>(B) Complete list of curated driver genes sorted by frequency (descending). Fraction of ER positive (left, total 366) and ER negative (right, total 194) samples carrying a mutation in the relevant driver gene presented in grey. Log10 p-value of enrichment of each driver gene towards the ER positive or ER negative cohort is provided in black. Highlighted in green are genes for which there is new or further evidence supporting these as novel breast cancer genes.</p></caption><graphic xlink:href="emss-68344-f001"></graphic></fig><fig id="F2" orientation="portrait" position="float"><label>Figure 2</label><caption><title>Non-coding analyses of breast cancer genomes</title><p>(A) Distributions of substitution (purple dots) and indel (blue dots) mutations within the footprint of five regulatory regions identified as being more significantly mutated than expected is provided on the left. The proportion of base substitution mutation signatures associated with corresponding samples carrying mutations in each of these non-coding regions, is displayed on the right.</p><p>(B) Mutability of T<underline>G</underline>AA<underline>C</underline>A/T<underline>G</underline>TT<underline>C</underline>A motifs within inverted repeats of varying flanking palindromic sequence length compared to motifs not within an inverted repeat.</p><p>(C) Variation in mutability between loci of TGAACA/TGTTCA inverted repeats with 9bp palindromes.</p></caption><graphic xlink:href="emss-68344-f002"></graphic></fig><fig id="F3" orientation="portrait" position="float"><label>Figure 3</label><caption><title>Extraction and contributions of base substitution signatures in 560 breast cancers</title><p>(A) Twelve mutation signatures extracted using Non-Negative Matrix Factorization. Each signature is ordered by mutation class (C>A/G>T, C>G/G>C, C>T/G>A, T>A/A>T, T>C/A>G, T>G/A>C), taking immediate flanking sequence into account. For each class, mutations are ordered by 5’ base (A,C,G,T) first before 3’ base (A,C,G,T).</p><p>(B) The spectrum of base substitution signatures within 560 breast cancers. Mutation signatures are ordered (and coloured) according to broad biological groups: Signatures 1 and 5 are correlated with age of diagnosis, Signatures 2 and 13 are putatively APOBEC-related, Signatures 6, 20 and 26 are associated with MMR deficiency, Signatures 3 and 8 are associated with HR deficiency, Signatures 18, 17 and 30 have unknown etiology. For ease of reading, this arrangement is adopted for the rest of the manuscript. Samples are ordered according to hierarchical clustering performed on mutation signatures. Top panel shows absolute numbers of mutations of each signature in each sample. Lower panel shows proportion of each signature in each sample.</p><p>(C) Distribution of mutation counts for each signature in relevant breast cancer samples. Percentage of samples carrying each signature provided above each signature.</p></caption><graphic xlink:href="emss-68344-f003"></graphic></fig><fig id="F4" orientation="portrait" position="float"><label>Figure 4</label><caption><title>Additional characteristics of base substitution signatures and novel rearrangement signatures in 560 breast cancers</title><p>(A) Contrasting transcriptional strand asymmetry and replication strand asymmetry between twelve base substitution signatures.</p><p>(B) Six rearrangement signatures extracted using Non-Negative Matrix Factorization. Probability of rearrangement element on y-axis. Rearrangement size on x-axis. Del= deletion, tds = tandem duplication, inv = inversion, trans = translocation.</p></caption><graphic xlink:href="emss-68344-f004"></graphic></fig><fig id="F5" orientation="portrait" position="float"><label>Figure 5</label><caption><title>Integrative analysis of rearrangement signatures</title><p>Heatmap of rearrangement signatures (RS) following unsupervised hierarchical clustering based on proportions of RS in each cancer. 7 cluster groups (A-G) noted and relationships with expression (AIMS) subtype (basal=red, luminal B=light blue, luminal A=dark blue), immunohistopathology status (ER, PR, HER2 status – black=positive), abrogation of <italic>BRCA1</italic> (purple) and <italic>BRCA2</italic> (orange) (whether germline, somatic or through promoter hypermethylation), presence of 3 or more foci of kataegis (black=positive), HRD index (top 25% or lowest 25% - black=positive), GISTIC cluster group (black=positive) and driver mutations in cancer genes. miRNA cluster groups : 0=red, 1=purple, 2=blue, 3=light blue, 4=green, 5=orange. Contribution of base substitution signatures in these 7 cluster groups is provided in the lowermost panel.</p></caption><graphic xlink:href="emss-68344-f005"></graphic></fig></floats-group></pmc></record>Pour manipuler ce document sous Unix (Dilib)
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