Heterogeneity of genomic evolution and mutational profiles in multiple myeloma

Nat Commun. 2014;5:2997. doi: 10.1038/ncomms3997.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Adult
  • Aged
  • Antigens, Nuclear
  • Cohort Studies
  • DNA Copy Number Variations
  • Early Growth Response Protein 1
  • Evolution, Molecular
  • Exome*
  • GTP Phosphohydrolases
  • Genetic Heterogeneity
  • Humans
  • Lymphotoxin-beta
  • Membrane Proteins
  • Middle Aged
  • Multiple Myeloma / genetics*
  • Mutation
  • Mutation, Missense
  • Nerve Tissue Proteins
  • Proto-Oncogene Proteins
  • Proto-Oncogene Proteins B-raf
  • Proto-Oncogene Proteins p21(ras)
  • Receptors, Immunologic
  • Sequence Analysis, DNA
  • Transcription Factors
  • Tumor Suppressor Protein p53
  • ras Proteins

Substances

  • Antigens, Nuclear
  • EGR1 protein, human
  • Early Growth Response Protein 1
  • KRAS protein, human
  • LTB protein, human
  • Lymphotoxin-beta
  • Membrane Proteins
  • Nerve Tissue Proteins
  • Proto-Oncogene Proteins
  • Receptors, Immunologic
  • SP140 protein, human
  • TP53 protein, human
  • Transcription Factors
  • Tumor Suppressor Protein p53
  • roundabout protein
  • BRAF protein, human
  • Proto-Oncogene Proteins B-raf
  • GTP Phosphohydrolases
  • NRAS protein, human
  • Proto-Oncogene Proteins p21(ras)
  • ras Proteins