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      Signatures of mutational processes in human cancer

      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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          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 references 67

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          Is Open Access

          An integrated map of genetic variation from 1,092 human genomes

          Summary Through characterising the geographic and functional spectrum of human genetic variation, the 1000 Genomes Project aims to build a resource to help understand the genetic contribution to disease. We describe the genomes of 1,092 individuals from 14 populations, constructed using a combination of low-coverage whole-genome and exome sequencing. By developing methodologies to integrate information across multiple algorithms and diverse data sources we provide a validated haplotype map of 38 million SNPs, 1.4 million indels and over 14 thousand larger deletions. We show that individuals from different populations carry different profiles of rare and common variants and that low-frequency variants show substantial geographic differentiation, which is further increased by the action of purifying selection. We show that evolutionary conservation and coding consequence are key determinants of the strength of purifying selection, that rare-variant load varies substantially across biological pathways and that each individual harbours hundreds of rare non-coding variants at conserved sites, such as transcription-factor-motif disrupting changes. This resource, which captures up to 98% of accessible SNPs at a frequency of 1% in populations of medical genetics focus, enables analysis of common and low-frequency variants in individuals from diverse, including admixed, populations.
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            Comprehensive Molecular Characterization of Human Colon and Rectal Cancer

            Summary To characterize somatic alterations in colorectal carcinoma (CRC), we conducted genome-scale analysis of 276 samples, analyzing exome sequence, DNA copy number, promoter methylation, mRNA and microRNA expression. A subset (97) underwent low-depth-of-coverage whole-genome sequencing. 16% of CRC have hypermutation, three quarters of which have the expected high microsatellite instability (MSI), usually with hypermethylation and MLH1 silencing, but one quarter has somatic mismatch repair gene mutations. Excluding hypermutated cancers, colon and rectum cancers have remarkably similar patterns of genomic alteration. Twenty-four genes are significantly mutated. In addition to the expected APC, TP53, SMAD4, PIK3CA and KRAS mutations, we found frequent mutations in ARID1A, SOX9, and FAM123B/WTX. Recurrent copy number alterations include potentially drug-targetable amplifications of ERBB2 and newly discovered amplification of IGF2. Recurrent chromosomal translocations include fusion of NAV2 and WNT pathway member TCF7L1. Integrative analyses suggest new markers for aggressive CRC and important role for MYC-directed transcriptional activation and repression.
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              dbSNP: the NCBI database of genetic variation.

               S Sherry (2001)
              In response to a need for a general catalog of genome variation to address the large-scale sampling designs required by association studies, gene mapping and evolutionary biology, the National Center for Biotechnology Information (NCBI) has established the dbSNP database [S.T.Sherry, M.Ward and K. Sirotkin (1999) Genome Res., 9, 677-679]. Submissions to dbSNP will be integrated with other sources of information at NCBI such as GenBank, PubMed, LocusLink and the Human Genome Project data. The complete contents of dbSNP are available to the public at website: The complete contents of dbSNP can also be downloaded in multiple formats via anonymous FTP at

                Author and article information

                9 September 2013
                14 August 2013
                22 August 2013
                22 February 2014
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                [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@

                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.


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