Intraclonal heterogeneity and distinct molecular mechanisms characterize the development of t(4;14) and t(11;14) myeloma.

B.A. Walker, C.P. Wardell, L. Melchor, S. Hulkki, N.E. Potter, D.C. Johnson, K. Fenwick, I. Kozarewa, D. Gonzalez, C.J. Lord, A. Ashworth, F.E. Davies, G.J. Morgan

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198 Citations (Scopus)


We have used whole exome sequencing to compare a group of presentation t(4;14) with t(11;14) cases of myeloma to define the mutational landscape. Each case was characterized by a median of 24.5 exonic nonsynonymous single-nucleotide variations, and there was a consistently higher number of mutations in the t(4;14) group, but this number did not reach statistical significance. We show that the transition and transversion rates in the 2 subgroups are similar, suggesting that there was no specific mechanism leading to mutation differentiating the 2 groups. Only 3% of mutations were seen in both groups, and recurrently mutated genes include NRAS, KRAS, BRAF, and DIS3 as well as DNAH5, a member of the axonemal dynein family. The pattern of mutation in each group was distinct, with the t(4;14) group being characterized by deregulation of chromatin organization, actin filament, and microfilament movement. Recurrent RAS pathway mutations identified subclonal heterogeneity at a mutational level in both groups, with mutations being present as either dominant or minor subclones. The presence of subclonal diversity was confirmed at a single-cell level using other tumor-acquired mutations. These results are consistent with a distinct molecular pathogenesis underlying each subgroup and have important impacts on targeted treatment strategies. The Medical Research Council Myeloma IX trial is registered under ISRCTN68454111.
Original languageEnglish
Pages (from-to)1077-1086
Number of pages10
Issue number5
Publication statusPublished - 02 Aug 2012


  • Chromosomes, Human, Pair 11
  • Chromosomes, Human, Pair 14
  • Chromosomes, Human, Pair 4
  • Clinical Trials as Topic
  • Clonal Evolution
  • Female
  • Gene Dosage
  • Gene Expression Profiling
  • Genetic Heterogeneity
  • Humans
  • Loss of Heterozygosity
  • Male
  • Microarray Analysis
  • Models, Biological
  • Multiple Myeloma
  • Mutation
  • Signal Transduction
  • Translocation, Genetic
  • Validation Studies as Topic


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