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

• Published in: Blood 2012-08, Vol.120 (5), p.1077-1086
• Main Authors: Walker, Brian A., Wardell, Christopher P., Melchor, Lorenzo, Hulkki, Sanna, Potter, Nicola E., Johnson, David C., Fenwick, Kerry, Kozarewa, Iwanka, Gonzalez, David, Lord, Christopher J., Ashworth, Alan, Davies, Faith E., Morgan, Gareth J.
• Format: Article
• Language: English
• Subjects: Biological and medical sciences; Chromosome aberrations; Chromosomes, Human, Pair 11 - genetics; Chromosomes, Human, Pair 14 - genetics; Chromosomes, Human, Pair 4 - genetics; Clinical Trials as Topic; Clonal Evolution - genetics; Clonal Evolution - physiology; Female; Gene Dosage; Gene Expression Profiling; Genetic Heterogeneity; Hematologic and hematopoietic diseases; Humans; Immunodeficiencies. Immunoglobulinopathies; Immunoglobulinopathies; Immunopathology; Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis; Loss of Heterozygosity - genetics; Male; Medical genetics; Medical sciences; Microarray Analysis; Models, Biological; Multiple Myeloma - genetics; Mutation - physiology; Signal Transduction - genetics; Translocation, Genetic - genetics; Validation Studies as Topic
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2012-03-412981

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.