56
views
0
recommends
+1 Recommend
0 collections
    0
    shares
      • Record: found
      • Abstract: found
      • Article: found
      Is Open Access

      The repertoire of mutational signatures in human cancer

      research-article

      Read this article at

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

          Abstract

          Somatic mutations in cancer genomes are caused by multiple mutational processes, each of which generates a characteristic mutational signature 1 . Here, as part of the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium 2 of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA), we characterized mutational signatures using 84,729,690 somatic mutations from 4,645 whole-genome and 19,184 exome sequences that encompass most types of cancer. We identified 49 single-base-substitution, 11 doublet-base-substitution, 4 clustered-base-substitution and 17 small insertion-and-deletion signatures. The substantial size of our dataset, compared with previous analyses 315 , enabled the discovery of new signatures, the separation of overlapping signatures and the decomposition of signatures into components that may represent associated—but distinct—DNA damage, repair and/or replication mechanisms. By estimating the contribution of each signature to the mutational catalogues of individual cancer genomes, we revealed associations of signatures to exogenous or endogenous exposures, as well as to defective DNA-maintenance processes. However, many signatures are of unknown cause. This analysis provides a systematic perspective on the repertoire of mutational processes that contribute to the development of human cancer.

          Abstract

          The characterization of 4,645 whole-genome and 19,184 exome sequences, covering most types of cancer, identifies 81 single-base substitution, doublet-base substitution and small-insertion-and-deletion mutational signatures, providing a systematic overview of the mutational processes that contribute to cancer development.

          Related collections

          Most cited references41

          • Record: found
          • Abstract: found
          • Article: found
          Is Open Access

          The evolutionary history of 2,658 cancers

          Cancer develops through a process of somatic evolution 1,2 . Sequencing data from a single biopsy represent a snapshot of this process that can reveal the timing of specific genomic aberrations and the changing influence of mutational processes 3 . Here, by whole-genome sequencing analysis of 2,658 cancers as part of the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA) 4 , we reconstruct the life history and evolution of mutational processes and driver mutation sequences of 38 types of cancer. Early oncogenesis is characterized by mutations in a constrained set of driver genes, and specific copy number gains, such as trisomy 7 in glioblastoma and isochromosome 17q in medulloblastoma. The mutational spectrum changes significantly throughout tumour evolution in 40% of samples. A nearly fourfold diversification of driver genes and increased genomic instability are features of later stages. Copy number alterations often occur in mitotic crises, and lead to simultaneous gains of chromosomal segments. Timing analyses suggest that driver mutations often precede diagnosis by many years, if not decades. Together, these results determine the evolutionary trajectories of cancer, and highlight opportunities for early cancer detection.
            Bookmark
            • Record: found
            • Abstract: found
            • Article: found
            Is Open Access

            Patterns of somatic structural variation in human cancer genomes

            A key mutational process in cancer is structural variation, in which rearrangements delete, amplify or reorder genomic segments that range in size from kilobases to whole chromosomes 1–7 . Here we develop methods to group, classify and describe somatic structural variants, using data from the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA), which aggregated whole-genome sequencing data from 2,658 cancers across 38 tumour types 8 . Sixteen signatures of structural variation emerged. Deletions have a multimodal size distribution, assort unevenly across tumour types and patients, are enriched in late-replicating regions and correlate with inversions. Tandem duplications also have a multimodal size distribution, but are enriched in early-replicating regions—as are unbalanced translocations. Replication-based mechanisms of rearrangement generate varied chromosomal structures with low-level copy-number gains and frequent inverted rearrangements. One prominent structure consists of 2–7 templates copied from distinct regions of the genome strung together within one locus. Such cycles of templated insertions correlate with tandem duplications, and—in liver cancer—frequently activate the telomerase gene TERT. A wide variety of rearrangement processes are active in cancer, which generate complex configurations of the genome upon which selection can act.
              Bookmark
              • Record: found
              • Abstract: found
              • Article: not found

              A mutational signature reveals alterations underlying deficient homologous recombination repair in breast cancer

              Paz Polak, Jaegil Kim, Lior Z. Braunstein and colleagues have identified patterns of genome-wide mutation in certain breast cancers that can be used to identify those with DNA-repair deficiencies that make the tumor more likely to respond to therapies based on PARP inhibitors or platinum. In contrast, oncogenic mutations in several other DNA-repair genes do not generate these patterns.
                Bookmark

                Author and article information

                Contributors
                steverozen@gmail.com
                mrs@sanger.ac.uk
                Journal
                Nature
                Nature
                Nature
                Nature Publishing Group UK (London )
                0028-0836
                1476-4687
                5 February 2020
                5 February 2020
                2020
                : 578
                : 7793
                : 94-101
                Affiliations
                [1 ]ISNI 0000 0001 2107 4242, GRID grid.266100.3, Department of Cellular and Molecular Medicine, Department of Bioengineering, Moores Cancer Center, , University of California, ; San Diego, CA USA
                [2 ]GRID grid.66859.34, Broad Institute of MIT and Harvard, ; Cambridge, MA USA
                [3 ]ISNI 0000 0004 0386 9924, GRID grid.32224.35, Center for Cancer Research, , Massachusetts General Hospital, ; Boston, MA USA
                [4 ]ISNI 0000 0004 0385 0924, GRID grid.428397.3, Programme in Cancer & Stem Cell Biology, , Duke-NUS Medical School, ; Singapore, Singapore
                [5 ]ISNI 0000 0004 0385 0924, GRID grid.428397.3, Centre for Computational Biology, , Duke-NUS Medical School, ; Singapore, Singapore
                [6 ]ISNI 0000 0001 2160 926X, GRID grid.39382.33, Human Genome Sequencing Center, , Baylor College of Medicine, ; Houston, TX USA
                [7 ]ISNI 0000 0001 2160 926X, GRID grid.39382.33, Dan L. Duncan Cancer Center, , Baylor College of Medicine, ; Houston, TX USA
                [8 ]ISNI 0000 0001 2110 5790, GRID grid.280664.e, Genome Integrity and Structural Biology Laboratory, , National Institute of Environmental Health Sciences (NIEHS), ; Durham, NC USA
                [9 ]GRID grid.473715.3, Institute for Research in Biomedicine (IRB Barcelona), , The Barcelona Institute of Science and Technology, ; Barcelona, Spain
                [10 ]ISNI 0000 0001 2172 2676, GRID grid.5612.0, Research Program on Biomedical Informatics, , Universitat Pompeu Fabra, ; Barcelona, Spain
                [11 ]ISNI 0000 0000 9601 989X, GRID grid.425902.8, Institució Catalana de Recerca i Estudis Avançats (ICREA), ; Barcelona, Spain
                [12 ]ISNI 0000 0001 2110 5790, GRID grid.280664.e, Integrative Bioinformatics Support Group, , National Institute of Environmental Health Sciences (NIEHS), ; Durham, NC USA
                [13 ]ISNI 0000 0004 0606 5382, GRID grid.10306.34, Wellcome Sanger Institute, ; Hinxton, UK
                [14 ]ISNI 0000 0004 0502 9283, GRID grid.22401.35, National Centre for Biological Sciences, Tata Institute of Fundamental Research, ; Bangalore, India
                [15 ]ISNI 0000 0001 1811 6966, GRID grid.7722.0, Institute for Research in Biomedicine (IRB Barcelona), ; Barcelona, Spain
                [16 ]ISNI 0000 0001 2160 926X, GRID grid.39382.33, Department of Molecular and Human Genetics, , Baylor College of Medicine, ; Houston, TX USA
                [17 ]ISNI 0000 0004 0410 2071, GRID grid.7737.4, Department of Computer Science, , University of Helsinki, ; Helsinki, Finland
                [18 ]ISNI 0000 0004 0410 2071, GRID grid.7737.4, Organismal and Evolutionary Biology Research Programme, , University of Helsinki, ; Helsinki, Finland
                [19 ]ISNI 0000 0004 0410 2071, GRID grid.7737.4, Institute of Biotechnology, , University of Helsinki, ; Helsinki, Finland
                [21 ]ISNI 0000 0004 0386 9924, GRID grid.32224.35, Department of Pathology, , Massachusetts General Hospital, ; Boston, MA USA
                [22 ]ISNI 000000041936754X, GRID grid.38142.3c, Harvard Medical School, ; Boston, MA USA
                [23 ]ISNI 0000 0004 0620 9905, GRID grid.419385.2, SingHealth, Duke-NUS Institute of Precision Medicine, , National Heart Centre Singapore, ; Singapore, Singapore
                [27 ]ISNI 0000 0001 2157 2938, GRID grid.17063.33, Department of Medical Biophysics, , University of Toronto, ; Toronto, Ontario Canada
                [28 ]ISNI 0000 0000 9632 6718, GRID grid.19006.3e, University of California Los Angeles, ; Los Angeles, CA USA
                [29 ]ISNI 0000 0004 0626 690X, GRID grid.419890.d, Computational Biology Program, , Ontario Institute for Cancer Research, ; Toronto, Ontario Canada
                [30 ]ISNI 0000 0001 2157 2938, GRID grid.17063.33, Department of Pharmacology, , University of Toronto, ; Toronto, Ontario Canada
                [31 ]ISNI 0000 0001 2182 2255, GRID grid.28046.38, Department of Biochemistry, Microbiology and Immunology, Faculty of Medicine, , University of Ottawa, ; Ottawa, Ontario Canada
                [32 ]RIKEN Center for Integrative Medical Sciences, Yokohama, Japan
                [33 ]ISNI 0000 0004 0619 6198, GRID grid.435025.5, A. A. Kharkevich Institute of Information Transmission Problems, ; Moscow, Russia
                [34 ]Dmitry Rogachev National Research Center of Pediatric Hematology, Oncology and Immunology, Moscow, Russia
                [35 ]ISNI 0000 0004 0555 3608, GRID grid.454320.4, Skolkovo Institute of Science and Technology, ; Moscow, Russia
                [36 ]Laboratory for Medical Science Mathematics, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan
                [37 ]ISNI 0000 0004 0386 9924, GRID grid.32224.35, Massachusetts General Hospital, ; Boston, MA USA
                [38 ]ISNI 0000 0001 2157 6568, GRID grid.30064.31, School of Molecular Biosciences, , Washington State University, ; Pullman, WA USA
                [39 ]ISNI 0000 0001 2157 6568, GRID grid.30064.31, Center for Reproductive Biology, , Washington State University, ; Pullman, WA USA
                [40 ]ISNI 0000 0001 2151 536X, GRID grid.26999.3d, Laboratory of Molecular Medicine, Human Genome Center, The Institute of Medical Science, , The University of Tokyo, ; Tokyo, Japan
                [41 ]ISNI 0000 0001 2168 5385, GRID grid.272242.3, Division of Cancer Genomics, , National Cancer Center Research Institute, ; Tokyo, Japan
                [42 ]ISNI 0000 0001 2151 536X, GRID grid.26999.3d, The Institute of Medical Science, , The University of Tokyo, ; Tokyo, Japan
                [43 ]ISNI 0000 0001 2180 6431, GRID grid.4280.e, Cancer Science Institute of Singapore, , National University of Singapore, ; Singapore, Singapore
                [44 ]ISNI 0000 0004 0620 9243, GRID grid.418812.6, Institute of Molecular and Cell Biology, ; Singapore, Singapore
                [45 ]ISNI 0000 0004 0620 9745, GRID grid.410724.4, Laboratory of Cancer Epigenome, Division of Medical Science, , National Cancer Centre Singapore, ; Singapore, Singapore
                [46 ]ISNI 0000 0001 2171 9952, GRID grid.51462.34, Department of Epidemiology and Biostatistics, , Memorial Sloan Kettering Cancer Center, ; New York, NY USA
                [47 ]ISNI 0000000419368729, GRID grid.21729.3f, Department of Statistics, , Columbia University, ; New York, NY USA
                [48 ]ISNI 0000000121885934, GRID grid.5335.0, Department of Applied Mathematics and Theoretical Physics, , Centre for Mathematical Sciences, University of Cambridge, ; Cambridge, UK
                Article
                1943
                10.1038/s41586-020-1943-3
                7054213
                32025018
                cfd964c1-463f-4b1b-9f9b-60158a8a452c
                © The Author(s) 2020

                Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

                History
                : 18 May 2018
                : 18 November 2019
                Categories
                Article
                Custom metadata
                © The Author(s), under exclusive licence to Springer Nature Limited 2020

                Uncategorized
                cancer genetics,mutation
                Uncategorized
                cancer genetics, mutation

                Comments

                Comment on this article