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Heterogeneity of genomic evolution and mutational profiles in multiple myeloma

Author

Listed:
  • Niccolo Bolli

    (Cancer Genome Project, Wellcome Trust Sanger Institute
    University of Cambridge, CIMR)

  • Hervé Avet-Loiseau

    (Unité de Génomique du Myélome, CHU Rangueil
    CRCT, INSERM U1037)

  • David C. Wedge

    (Cancer Genome Project, Wellcome Trust Sanger Institute)

  • Peter Van Loo

    (Cancer Genome Project, Wellcome Trust Sanger Institute
    VIB and University of Leuven)

  • Ludmil B. Alexandrov

    (Cancer Genome Project, Wellcome Trust Sanger Institute)

  • Inigo Martincorena

    (Cancer Genome Project, Wellcome Trust Sanger Institute)

  • Kevin J. Dawson

    (Cancer Genome Project, Wellcome Trust Sanger Institute)

  • Francesco Iorio

    (Cancer Genome Project, Wellcome Trust Sanger Institute
    European Molecular Biology Laboratory—European Bioinformatics Institute)

  • Serena Nik-Zainal

    (Cancer Genome Project, Wellcome Trust Sanger Institute
    Addenbrooke’s Hospital NHS Trust)

  • Graham R. Bignell

    (Cancer Genome Project, Wellcome Trust Sanger Institute)

  • Jonathan W. Hinton

    (Cancer Genome Project, Wellcome Trust Sanger Institute)

  • Yilong Li

    (Cancer Genome Project, Wellcome Trust Sanger Institute)

  • Jose M.C. Tubio

    (Cancer Genome Project, Wellcome Trust Sanger Institute)

  • Stuart McLaren

    (Cancer Genome Project, Wellcome Trust Sanger Institute)

  • Sarah O' Meara

    (Cancer Genome Project, Wellcome Trust Sanger Institute)

  • Adam P. Butler

    (Cancer Genome Project, Wellcome Trust Sanger Institute)

  • Jon W. Teague

    (Cancer Genome Project, Wellcome Trust Sanger Institute)

  • Laura Mudie

    (Cancer Genome Project, Wellcome Trust Sanger Institute)

  • Elizabeth Anderson

    (Cancer Genome Project, Wellcome Trust Sanger Institute)

  • Naim Rashid

    (Lebow Institute of Myeloma Therapeutics and Jerome Lipper Multiple Myeloma Center, Dana–Farber Cancer Institute, Harvard Medical School)

  • Yu-Tzu Tai

    (Lebow Institute of Myeloma Therapeutics and Jerome Lipper Multiple Myeloma Center, Dana–Farber Cancer Institute, Harvard Medical School)

  • Masood A. Shammas

    (Lebow Institute of Myeloma Therapeutics and Jerome Lipper Multiple Myeloma Center, Dana–Farber Cancer Institute, Harvard Medical School
    Boston Veterans Administration Healthcare System)

  • Adam S. Sperling

    (Lebow Institute of Myeloma Therapeutics and Jerome Lipper Multiple Myeloma Center, Dana–Farber Cancer Institute, Harvard Medical School)

  • Mariateresa Fulciniti

    (Lebow Institute of Myeloma Therapeutics and Jerome Lipper Multiple Myeloma Center, Dana–Farber Cancer Institute, Harvard Medical School)

  • Paul G. Richardson

    (Lebow Institute of Myeloma Therapeutics and Jerome Lipper Multiple Myeloma Center, Dana–Farber Cancer Institute, Harvard Medical School)

  • Giovanni Parmigiani

    (Dana–Farber Cancer Institute and Harvard School of Public Health)

  • Florence Magrangeas

    (Center for Cancer Research Nantes-Angers, UMR 892 Inserm-6299 CNRS-University of Nantes
    UMGC, University Hospital)

  • Stephane Minvielle

    (Center for Cancer Research Nantes-Angers, UMR 892 Inserm-6299 CNRS-University of Nantes
    UMGC, University Hospital)

  • Philippe Moreau

    (University Hospital)

  • Michel Attal

    (University Hospital and CRCT, INSERM U1037)

  • Thierry Facon

    (University Hospital)

  • P Andrew Futreal

    (Cancer Genome Project, Wellcome Trust Sanger Institute
    Present address: MD Anderson Cancer Center, Houston, Texas, USA)

  • Kenneth C. Anderson

    (Lebow Institute of Myeloma Therapeutics and Jerome Lipper Multiple Myeloma Center, Dana–Farber Cancer Institute, Harvard Medical School)

  • Peter J. Campbell

    (Cancer Genome Project, Wellcome Trust Sanger Institute
    University of Cambridge, CIMR)

  • Nikhil C. Munshi

    (Lebow Institute of Myeloma Therapeutics and Jerome Lipper Multiple Myeloma Center, Dana–Farber Cancer Institute, Harvard Medical School
    Boston Veterans Administration Healthcare System)

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.

Suggested Citation

  • Niccolo Bolli & Hervé Avet-Loiseau & David C. Wedge & Peter Van Loo & Ludmil B. Alexandrov & Inigo Martincorena & Kevin J. Dawson & Francesco Iorio & Serena Nik-Zainal & Graham R. Bignell & Jonathan W, 2014. "Heterogeneity of genomic evolution and mutational profiles in multiple myeloma," Nature Communications, Nature, vol. 5(1), pages 1-13, May.
  • Handle: RePEc:nat:natcom:v:5:y:2014:i:1:d:10.1038_ncomms3997
    DOI: 10.1038/ncomms3997
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    Cited by:

    1. Leo Rasche & Carolina Schinke & Francesco Maura & Michael A. Bauer & Cody Ashby & Shayu Deshpande & Alexandra M. Poos & Maurizio Zangari & Sharmilan Thanendrarajan & Faith E. Davies & Brian A. Walker , 2022. "The spatio-temporal evolution of multiple myeloma from baseline to relapse-refractory states," Nature Communications, Nature, vol. 13(1), pages 1-13, December.
    2. Naser Ansari-Pour & Yonglan Zheng & Toshio F. Yoshimatsu & Ayodele Sanni & Mustapha Ajani & Jean-Baptiste Reynier & Avraam Tapinos & Jason J. Pitt & Stefan Dentro & Anna Woodard & Padma Sheila Rajagop, 2021. "Whole-genome analysis of Nigerian patients with breast cancer reveals ethnic-driven somatic evolution and distinct genomic subtypes," Nature Communications, Nature, vol. 12(1), pages 1-15, December.

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