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      Heterogeneity of genomic evolution and mutational profiles in multiple myeloma

        1 , 2 , 3 , 4 , 1 , 1 , 5 , 1 , 1 , 1 , 1 , 6 , 1 , 7 , 1 , 1 , 1 , 1 , 1 , 1 , 1 , 1 , 1 , 1 , 8 , 8 , 8 , 9 , 8 , 8 , 8 , 10 , 11 , 12 , 11 , 12 , 13 , 14 , 15 , 1 , 16 , 8 , a , 1 , 2 , b , 8 , 9

      Nature Communications

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

          Abstract

          Multiple myeloma is an incurable plasma cell malignancy with a complex and incompletely understood molecular pathogenesis. Here we use whole-exome sequencing, copy-number profiling and cytogenetics to analyse 84 myeloma samples. Most cases have a complex subclonal structure and show clusters of subclonal variants, including subclonal driver mutations. Serial sampling reveals diverse patterns of clonal evolution, including linear evolution, differential clonal response and branching evolution. Diverse processes contribute to the mutational repertoire, including kataegis and somatic hypermutation, and their relative contribution changes over time. We find heterogeneity of mutational spectrum across samples, with few recurrent genes. We identify new candidate genes, including truncations of SP140, LTB, ROBO1 and clustered missense mutations in EGR1. The myeloma genome is heterogeneous across the cohort, and exhibits diversity in clonal admixture and in dynamics of evolution, which may impact prognostic stratification, therapeutic approaches and assessment of disease response to treatment.

          Abstract

          Multiple myeloma is a malignant plasma cell disorder with a complex molecular pathogenesis. Here, the authors perform whole-exome sequencing, copy-number profiling and cytogenetic analysis in 84 myeloma samples and highlight the diversity and evolution of the mutational profile underlying the disease.

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          Most cited references 25

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          Class switch recombination and hypermutation require activation-induced cytidine deaminase (AID), a potential RNA editing enzyme.

          Induced overexpression of AID in CH12F3-2 B lymphoma cells augmented class switching from IgM to IgA without cytokine stimulation. AID deficiency caused a complete defect in class switching and showed a hyper-IgM phenotype with enlarged germinal centers containing strongly activated B cells before or after immunization. AID-/- spleen cells stimulated in vitro with LPS and cytokines failed to undergo class switch recombination although they expressed germline transcripts. Immunization of AID-/- chimera with 4-hydroxy-3-nitrophenylacetyl (NP) chicken gamma-globulin induced neither accumulation of mutations in the NP-specific variable region gene nor class switching. These results suggest that AID may be involved in regulation or catalysis of the DNA modification step of both class switching and somatic hypermutation.
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            Understanding multiple myeloma pathogenesis in the bone marrow to identify new therapeutic targets.

            Multiple myeloma is a plasma cell malignancy characterized by complex heterogeneous cytogenetic abnormalities. The bone marrow microenvironment promotes multiple myeloma cell growth and resistance to conventional therapies. Although multiple myeloma remains incurable, novel targeted agents, used alone or in combination, have shown great promise to overcome conventional drug resistance and improve patient outcome. Recent oncogenomic studies have further advanced our understanding of the molecular pathogenesis of multiple myeloma, providing the framework for new prognostic classification and identifying new therapeutic targets.
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              Bayesian Markov chain Monte Carlo sequence analysis reveals varying neutral substitution patterns in mammalian evolution.

               D. Hwang,  Phil Green (2004)
              We describe a model of neutral DNA evolution that allows substitution rates at a site to depend on the two flanking nucleotides ("context"), the branch of the phylogenetic tree, and position within the sequence and implement it by using a flexible and computationally efficient Bayesian Markov chain Monte Carlo approach. We then apply this approach to characterize phylogenetic variation in context-dependent substitution patterns in a 1.7-megabase genomic region in 19 mammalian species. In contrast to other substitution types, CpG transition substitutions have accumulated in a relatively clock-like fashion. More broadly, our results support the notion that context-dependent DNA replication errors, cytosine deamination, and biased gene conversion are major sources of naturally occurring mutations whose relative contributions have varied in mammalian evolution as a result of changes in generation times, effective population sizes, and recombination rates.
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                Author and article information

                Journal
                Nat Commun
                Nat Commun
                Nature Communications
                Nature Pub. Group
                2041-1723
                16 January 2014
                : 5
                Affiliations
                [1 ]Cancer Genome Project, Wellcome Trust Sanger Institute , Hinxton CB10 1SA, UK
                [2 ]Department of Haematology, University of Cambridge, CIMR , Cambridge CB2 0XY, UK
                [3 ]Unité de Génomique du Myélome, CHU Rangueil , Toulouse 31059, France
                [4 ]CRCT, INSERM U1037 , Toulouse 31400, France
                [5 ]Department of Human Genetics, VIB and University of Leuven , Leuven 3000, Belgium
                [6 ]European Molecular Biology Laboratory—European Bioinformatics Institute , Hinxton CB10 1SA, UK
                [7 ]Department of Medical Genetics, Addenbrooke’s Hospital NHS Trust , Cambridge CB2 0QQ, UK
                [8 ]Lebow Institute of Myeloma Therapeutics and Jerome Lipper Multiple Myeloma Center, Dana–Farber Cancer Institute, Harvard Medical School , Boston, Massachusetts 02115, USA
                [9 ]Boston Veterans Administration Healthcare System , West Roxbury, Massachusetts 02132, USA
                [10 ]Dana–Farber Cancer Institute and Harvard School of Public Health , Boston, Massachusetts 02115, USA
                [11 ]Center for Cancer Research Nantes-Angers, UMR 892 Inserm-6299 CNRS-University of Nantes , IRS-UN, Nantes 4407, France
                [12 ]UMGC, University Hospital , Nantes 44093, France
                [13 ]Department of Hematology, University Hospital , Nantes 44093, France
                [14 ]Department of Hematology, University Hospital and CRCT, INSERM U1037 , Toulouse 31400, France
                [15 ]Department of Hematology, University Hospital , Lille 59045, France
                [16 ]Present address: MD Anderson Cancer Center, Houston, Texas, USA
                Author notes
                Article
                ncomms3997
                10.1038/ncomms3997
                3905727
                24429703
                Copyright © 2014, Nature Publishing Group, a division of Macmillan Publishers Limited. All Rights Reserved.

                This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivs 3.0 Unported License. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-nd/3.0/

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