title: Heterogeneity of genomic evolution and mutational profiles in multiple myeloma.
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.
authors.affiliation: 1] Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton CB10 1SA, UK [2] Department of Haematology, University of Cambridge, CIMR, Cambridge CB2 0XY, UK.
authors.forename: Niccolo
authors.initials: N
authors.lastname: Bolli
authors.affiliation: 1] Unité de Génomique du Myélome, CHU Rangueil, Toulouse 31059, France [2] CRCT, INSERM U1037, Toulouse 31400, France.
authors.forename: Hervé
authors.initials: H
authors.lastname: Avet-Loiseau
authors.affiliation: Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton CB10 1SA, UK.
authors.forename: David C
authors.initials: DC
authors.lastname: Wedge
authors.affiliation: 1] Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton CB10 1SA, UK [2] Department of Human Genetics, VIB and University of Leuven, Leuven 3000, Belgium.
authors.forename: Peter
authors.initials: P
authors.lastname: Van Loo
authors.affiliation: Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton CB10 1SA, UK.
authors.forename: Ludmil B
authors.initials: LB
authors.lastname: Alexandrov
authors.affiliation: Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton CB10 1SA, UK.
authors.forename: Inigo
authors.initials: I
authors.lastname: Martincorena
authors.affiliation: Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton CB10 1SA, UK.
authors.forename: Kevin J
authors.initials: KJ
authors.lastname: Dawson
authors.affiliation: 1] Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton CB10 1SA, UK [2] European Molecular Biology Laboratory-European Bioinformatics Institute, Hinxton CB10 1SA, UK.
authors.forename: Francesco
authors.initials: F
authors.lastname: Iorio
authors.affiliation: 1] Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton CB10 1SA, UK [2] Department of Medical Genetics, Addenbrooke's Hospital NHS Trust, Cambridge CB2 0QQ, UK.
authors.forename: Serena
authors.initials: S
authors.lastname: Nik-Zainal
authors.affiliation: Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton CB10 1SA, UK.
authors.forename: Graham R
authors.initials: GR
authors.lastname: Bignell
authors.affiliation: Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton CB10 1SA, UK.
authors.forename: Jonathan W
authors.initials: JW
authors.lastname: Hinton
authors.affiliation: Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton CB10 1SA, UK.
authors.forename: Yilong
authors.initials: Y
authors.lastname: Li
authors.affiliation: Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton CB10 1SA, UK.
authors.forename: Jose M C
authors.initials: JM
authors.lastname: Tubio
authors.affiliation: Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton CB10 1SA, UK.
authors.forename: Stuart
authors.initials: S
authors.lastname: McLaren
authors.affiliation: Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton CB10 1SA, UK.
authors.forename: Sarah
authors.initials: S
authors.lastname: O' Meara
authors.affiliation: Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton CB10 1SA, UK.
authors.forename: Adam P
authors.initials: AP
authors.lastname: Butler
authors.affiliation: Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton CB10 1SA, UK.
authors.forename: Jon W
authors.initials: JW
authors.lastname: Teague
authors.affiliation: Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton CB10 1SA, UK.
authors.forename: Laura
authors.initials: L
authors.lastname: Mudie
authors.affiliation: Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton CB10 1SA, UK.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Anderson
authors.affiliation: Lebow Institute of Myeloma Therapeutics and Jerome Lipper Multiple Myeloma Center, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02115, USA.
authors.forename: Naim
authors.initials: N
authors.lastname: Rashid
authors.affiliation: Lebow Institute of Myeloma Therapeutics and Jerome Lipper Multiple Myeloma Center, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02115, USA.
authors.forename: Yu-Tzu
authors.initials: YT
authors.lastname: Tai
authors.affiliation: 1] Lebow Institute of Myeloma Therapeutics and Jerome Lipper Multiple Myeloma Center, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02115, USA [2] Boston Veterans Administration Healthcare System, West Roxbury, Massachusetts 02132, USA.
authors.forename: Masood A
authors.initials: MA
authors.lastname: Shammas
authors.affiliation: Lebow Institute of Myeloma Therapeutics and Jerome Lipper Multiple Myeloma Center, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02115, USA.
authors.forename: Adam S
authors.initials: AS
authors.lastname: Sperling
authors.affiliation: Lebow Institute of Myeloma Therapeutics and Jerome Lipper Multiple Myeloma Center, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02115, USA.
authors.forename: Mariateresa
authors.initials: M
authors.lastname: Fulciniti
authors.affiliation: Lebow Institute of Myeloma Therapeutics and Jerome Lipper Multiple Myeloma Center, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02115, USA.
authors.forename: Paul G
authors.initials: PG
authors.lastname: Richardson
authors.affiliation: Dana-Farber Cancer Institute and Harvard School of Public Health, Boston, Massachusetts 02115, USA.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Parmigiani
authors.affiliation: 1] Center for Cancer Research Nantes-Angers, UMR 892 Inserm-6299 CNRS-University of Nantes, IRS-UN, Nantes 4407, France [2] UMGC, University Hospital, Nantes 44093, France.
authors.forename: Florence
authors.initials: F
authors.lastname: Magrangeas
authors.affiliation: 1] Center for Cancer Research Nantes-Angers, UMR 892 Inserm-6299 CNRS-University of Nantes, IRS-UN, Nantes 4407, France [2] UMGC, University Hospital, Nantes 44093, France.
authors.forename: Stephane
authors.initials: S
authors.lastname: Minvielle
authors.affiliation: Department of Hematology, University Hospital, Nantes 44093, France.
authors.forename: Philippe
authors.initials: P
authors.lastname: Moreau
authors.affiliation: Department of Hematology, University Hospital and CRCT, INSERM U1037, Toulouse 31400, France.
authors.forename: Michel
authors.initials: M
authors.lastname: Attal
authors.affiliation: Department of Hematology, University Hospital, Lille 59045, France.
authors.forename: Thierry
authors.initials: T
authors.lastname: Facon
authors.affiliation: 1] Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton CB10 1SA, UK [2].
authors.forename: P Andrew
authors.initials: PA
authors.lastname: Futreal
authors.affiliation: Lebow Institute of Myeloma Therapeutics and Jerome Lipper Multiple Myeloma Center, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02115, USA.
authors.forename: Kenneth C
authors.initials: KC
authors.lastname: Anderson
authors.affiliation: 1] Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton CB10 1SA, UK [2] Department of Haematology, University of Cambridge, CIMR, Cambridge CB2 0XY, UK.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Campbell
authors.affiliation: 1] Lebow Institute of Myeloma Therapeutics and Jerome Lipper Multiple Myeloma Center, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02115, USA [2] Boston Veterans Administration Healthcare System, West Roxbury, Massachusetts 02132, USA.
authors.forename: Nikhil C
authors.initials: NC
authors.lastname: Munshi
mesh_terms: D000328:Adult; D000368:Aged; D034961:Antigens, Nuclear; D015331:Cohort Studies; D056915:DNA Copy Number Variations; D051766:Early Growth Response Protein 1; D019143:Evolution, Molecular; D059472:Exome; D020558:GTP Phosphohydrolases; D018740:Genetic Heterogeneity; D006801:Humans; D053308:Lymphotoxin-beta; D008565:Membrane Proteins; D008875:Middle Aged; D009101:Multiple Myeloma / Q000235:genetics*; D009154:Mutation; D020125:Mutation, Missense; D009419:Nerve Tissue Proteins; D011518:Proto-Oncogene Proteins; D048493:Proto-Oncogene Proteins B-raf; D016283:Proto-Oncogene Proteins p21(ras); D011971:Receptors, Immunologic; D017422:Sequence Analysis, DNA; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53; D018631:ras Proteins; D000097905:Roundabout Proteins
chemical_list: D034961:Antigens, Nuclear; D051766:Early Growth Response Protein 1; D020558:GTP Phosphohydrolases; D053308:Lymphotoxin-beta; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; D011518:Proto-Oncogene Proteins; D048493:Proto-Oncogene Proteins B-raf; D016283:Proto-Oncogene Proteins p21(ras); D011971:Receptors, Immunologic; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53; D018631:ras Proteins; D000097905:Roundabout Proteins; C497325:EGR1 protein, human; C117307:KRAS protein, human; C505886:LTB protein, human; C102470:SP140 protein, human; C495901:TP53 protein, human; C482119:BRAF protein, human; C579846:NRAS protein, human