Abstract
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 language | English |
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Pages (from-to) | 1077-1086 |
Number of pages | 10 |
Journal | Blood |
Volume | 120 |
Issue number | 5 |
DOIs | |
Publication status | Published - 02 Aug 2012 |
Keywords
- 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