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      Signatures of mutational processes in human cancer

      research-article
      1 , 1 , 2 , 1 , 3 , 4 , 5 , 1 , 6 , 7 , 8 , 9 , 10 , 11 , 1 ,   1 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 1 , 20 , 1 , 21 , 22 , 23 , 24 , 25 , 26 , 22 , 1 , 28 , 29 , 30 , 22 , 27 , 1 , 31 , 32 , 27 , 33 , 34 , 1 , 35 , 36 , 26 , 27 , 7 , 1 , 37 , 38 , 34 , 1 , 1 , 39 , 40 , 41 , 42 , 43 , 22 , 44 , 45 , 1 , 26 , 46 , 34 , 44 , 47 , 48 , 38 , 1 , Australian Pancreatic Cancer Genome Initiative, ICGC Breast Cancer Consortium, ICGC MMML-Seq Consortium, ICGC PedBrain, 28 , 29 , 1 , 1 , 49 , 30 , 39 , 40 , 38 , 42 , 50 , 26 , 27 , 51 , 1 , 12 , 13 , 1
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          Abstract

          All cancers are caused by somatic mutations. However, understanding of the biological processes generating these mutations is limited. The catalogue of somatic mutations from a cancer genome bears the signatures of the mutational processes that have been operative. Here, we analysed 4,938,362 mutations from 7,042 cancers and extracted more than 20 distinct mutational signatures. Some are present in many cancer types, notably a signature attributed to the APOBEC family of cytidine deaminases, whereas others are confined to a single class. Certain signatures are associated with age of the patient at cancer diagnosis, known mutagenic exposures or defects in DNA maintenance, but many are of cryptic origin. In addition to these genome-wide mutational signatures, hypermutation localized to small genomic regions, kataegis, is found in many cancer types. The results reveal the diversity of mutational processes underlying the development of cancer with potential implications for understanding of cancer etiology, prevention and therapy.

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          Most cited references20

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          Exome sequencing of head and neck squamous cell carcinoma reveals inactivating mutations in NOTCH1.

          Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer worldwide. To explore the genetic origins of this cancer, we used whole-exome sequencing and gene copy number analyses to study 32 primary tumors. Tumors from patients with a history of tobacco use had more mutations than did tumors from patients who did not use tobacco, and tumors that were negative for human papillomavirus (HPV) had more mutations than did HPV-positive tumors. Six of the genes that were mutated in multiple tumors were assessed in up to 88 additional HNSCCs. In addition to previously described mutations in TP53, CDKN2A, PIK3CA, and HRAS, we identified mutations in FBXW7 and NOTCH1. Nearly 40% of the 28 mutations identified in NOTCH1 were predicted to truncate the gene product, suggesting that NOTCH1 may function as a tumor suppressor gene rather than an oncogene in this tumor type.
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            Transcription-coupled DNA repair: two decades of progress and surprises.

            Expressed genes are scanned by translocating RNA polymerases, which sensitively detect DNA damage and initiate transcription-coupled repair (TCR), a subpathway of nucleotide excision repair that removes lesions from the template DNA strands of actively transcribed genes. Human hereditary diseases that present a deficiency only in TCR are characterized by sunlight sensitivity without enhanced skin cancer. Although multiple gene products are implicated in TCR, we still lack an understanding of the precise signals that can trigger this pathway. Futile cycles of TCR at naturally occurring non-canonical DNA structures might contribute to genomic instability and genetic disease.
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              BAP1 loss defines a new class of renal cell carcinoma

              The molecular pathogenesis of renal cell carcinoma (RCC) is poorly understood. Whole-genome and exome sequencing followed by innovative tumorgraft analyses (to accurately determine mutant allele ratios) identified several putative two-hit tumor suppressor genes including BAP1. BAP1, a nuclear deubiquitinase, is inactivated in 15% of clear-cell RCCs. BAP1 cofractionates with and binds to HCF-1 in tumorgrafts. Mutations disrupting the HCF-1 binding motif impair BAP1-mediated suppression of cell proliferation, but not H2AK119ub1 deubiquitination. BAP1 loss sensitizes RCC cells in vitro to genotoxic stress. Interestingly, BAP1 and PBRM1 mutations anticorrelate in tumors (P=3×10−5), and combined loss of BAP1 and PBRM1 in a few RCCs was associated with rhabdoid features (q=0.0007). BAP1 and PBRM1 regulate seemingly different gene expression programs, and BAP1 loss was associated with high tumor grade (q=0.0005). Our results establish the foundation for an integrated pathological and molecular genetic classification of RCC, paving the way for subtype-specific treatments exploiting genetic vulnerabilities.
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                Author and article information

                Journal
                0410462
                6011
                Nature
                Nature
                Nature
                0028-0836
                1476-4687
                9 September 2013
                14 August 2013
                22 August 2013
                22 February 2014
                : 500
                : 7463
                : 415-421
                Affiliations
                [1 ]Cancer Genome Project, Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridgeshire, CB10 1SA
                [2 ]Department of Medical Genetics, Box 134, Addenbrooke’s Hospital NHS Trust, Hills Road, Cambridge CB2 0QQ
                [3 ]Molecular Oncology, Michael Smith Genome Sciences Centre, BC Cancer Agency, 675 West 10th Avenue, Vancouver V5Z 1L3, Canada
                [4 ]Centre for Translational and Applied Genomics, Michael Smith Genome Sciences Centre, BC Cancer Agency, 675 West 10th Avenue, Vancouver V5Z 1L3, Canada
                [5 ]Department of Pathology, University of British Columbia, G227-2211 Wesbrook Mall, British Columbia, Vancouver V6T 2B5, Canada
                [6 ]Department of Paediatrics, University of Cambridge, Hills Road, Cambridge, CB2 2XY
                [7 ]Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, Garscube Estate, Switchback Road, Bearsden, Glasgow, Scotland G61 1BD, United Kingdom.
                [8 ]West of Scotland Pancreatic Unit, Glasgow Royal Infirmary, Glasgow, Scotland G4 0SF, United Kingdom
                [9 ]The Kinghorn Cancer Centre, 370 Victoria Street, Darlinghurst, and the Cancer Research Program, Garvan Institute of Medical Research, 384 Victoria Street, Darlinghurst, Sydney, New South Wales 2010, Australia
                [10 ]Department of Surgery, Bankstown Hospital, Eldridge Road, Bankstown, Sydney, New South Wales 2200, Australia
                [11 ]South Western Sydney Clinical School, Faculty of Medicine, University of New South Wales, Liverpool, New South Wales 2170, Australia
                [12 ]Department of Haematology, Addenbrooke’s Hospital, Cambridge CB2 0QQ, UK
                [13 ]Department of Haematology, University of Cambridge, Cambridge CB2 2XY, UK
                [14 ]Department of Oncology, Lund University, SE-221 85 Lund, Sweden
                [15 ]Department of Genetics, Institute for Cancer Research, Oslo University Hospital, The Norwegian Radium Hospital, Montebello, 0310 Oslo, Norway
                [16 ]The K.G. Jebsen Center for Breast Cancer Research, Institute for Clinical Medicine, Faculty of Medicine, University of Oslo, Norway
                [17 ]Plateforme de Bioinformatique Synergie Lyon Cancer, Centre Léon Bérard, 28 rue Laennec, 69373 LYON CEDEX 08
                [18 ]NHL-BFM Study Center and Department of Pediatric Hematology and Oncology, University Children’s Hospital, Münster, Germany
                [19 ]NHL-BFM Study Center and Department of Pediatric Hematology and Oncology, University Children’s Hospital, Giessen, Germany
                [20 ]Cancer Research UK Cambridge Institute, University of Cambridge, Li Ka Shing Centre, Cambridge CB2 0RE
                [21 ]Breast Cancer Translational Res Lab - BCTL, Université Libre de Bruxelles - Institut Jules Bordet, Boulevard de Waterloo, 125, B-1000 Brussels
                [22 ]Department of Theoretical Bioinformatics (B080), German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, Heidelberg, Germany
                [23 ]Cancer Research Laboratory, Faculty of Medicine, Biomedical Centre, University of Iceland, 101 Reykjavik, Iceland
                [24 ]Department of Medical Oncology, Erasmus MC Cancer Institute, Rotterdam, The Netherlands
                [25 ]Department of Haemato-oncology, Institute of Cancer Research, London
                [26 ]Division of Cancer Genomics, National Cancer Center Research Institute, Chuo-ku, Tokyo, 104-0045, Japan
                [27 ]Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ), Heidelberg, Germany
                [28 ]INSERM, UMR-674, Génomique Fonctionnelle des Tumeurs Solides, Institut Universitaire d’Hematologie (IUH), Paris, France
                [29 ]Université Paris Descartes, Labex Immuno-oncology, Sorbonne Paris Cité, Faculté de Médecine, Paris, France
                [30 ]The Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA
                [31 ]Section of Oncology, Department of Clinical Science, University of Bergen, 5020 Bergen, Norway
                [32 ]Department of Oncology, Haukeland University Hospital, 5021 Bergen, Norway
                [33 ]The University of Queensland Centre for Clinical Research, School of Medicine and Pathology Queensland, The Royal Brisbane & Women’s Hospital, Herston 4029,Brisbane, QLD, Australia
                [34 ]Dpt. Bioquímica y Biología Molecular, IUOPA-Universidad de Oviedo, 33006 Oviedo, Spain
                [35 ]Jerome Lipper Multiple Myeloma Disease Center, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA
                [36 ]Boston Veterans Administration Healthcare System, West Roxbury, MA
                [37 ]Clinical Experimental Oncology Laboratory, National Cancer Institute, Via Amendola, 209, 70126, Bari, Italy
                [38 ]Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, The University of Queensland, St Lucia, Brisbane, Queensland 4072, Australia
                [39 ]Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston, MA 02215, USA
                [40 ]Harvard Medical School, Boston, Massachusetts, USA
                [41 ]Department of Pathology, Brigham and Women’s Hospital 75 Francis St. Boston, MA 02115, USA
                [42 ]Institute of Human Genetics, Christian-Albrechts-University, Kiel, Germany
                [43 ]Institute of Clinical Molecular Biology, Christian-Albrechts-University,Kiel, Germany
                [44 ]Division of Immunology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX, Amsterdam, The Netherlands
                [45 ]Department of Radiation Oncology and department of Laboratory Medicine, Radboud University Nijmegen Medical Centre, PO Box 9101, 6500HB Nijmegen,the Netherlands
                [46 ]Breakthrough Breast Cancer Research Unit, King’s College London School of Medicine, London, UK
                [47 ]The Netherlands Cancer Institute, 121 Plesmanlaan, 1066 CX Amsterdam, The Netherlands
                [48 ]Institut Curie , Departement de Pathologie, INSERM U830, 26 rue d’Ulm 75248 PARIS CEDEX 05, France
                [49 ]Division of Molecular Genetics, German Cancer Research Center (DKFZ), Heidelberg, Germany
                [50 ]Unidad de Hematopatología, Servicio de Anatomía Patológica, Hospital Clínic, Universitat de Barcelona, IDIBAPS, 08036 Barcelona, Spain
                [51 ]Department of Pediatric Hematology and Oncology, Heidelberg
                Author notes
                Address for correspondence Michael R. Stratton Wellcome Trust Sanger Institute, Hinxton Cambridgeshire CB10 1SA United Kingdom mrs@ 123456sanger.ac.uk

                AUTHOR CONTRIBUTIONS L.B.A., S.N.Z., M.R.S. conceptualized the study and analyzed the mutational signatures and kataegis data. L.B.A. performed data curation, data filtering, and mutational signature extraction. S.N.Z. and D.C.W. performed kataegis identification. S.N.Z. performed visual validation. A.P.B., K.R., J.W.T., D.J. provided bioinformatics support for mutational signature and kataegis analysis. S.A.J.R.A., S.B., A.V.B., G.R.B., N.B., A.B., A.L.B.D., S.B., B.B., C.C., H.R.D., C.D., R.E., J.E.E., J.A.F., M.G., F.H., B.H., T.I., S.I., M.I., N.J., D.T.W.J., S.K., M.K., S.R.L., C.L.O., S.M., N.C.M., H.N., P.A.N., M.P., E.P., A.P., J.V.P., X.S.P, M.R., A.L.R., J.R., P.R., M.S., T.N.S., P.N.S., Y.T., A.N.J.T., R.V.M., M.M.B., L.V., A.V.S., N.W., L.R.Y., J.Z.R., P.A.F., U.M., P.L., M.M., S.M.G., R.S., E.C., T.S., S.M.P., P.J.C. contributed samples, clinical data and scientific advice. M.R.S. and L.B.A. wrote the manuscript. M.R.S. directed the overall research.

                Article
                EMS54099
                10.1038/nature12477
                3776390
                23945592
                24416bec-4f82-4f71-b3ce-6cf412c824d4

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                Funding
                Funded by: Wellcome Trust :
                Award ID: 093867 || WT
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