GRCh38 · COSMIC v92


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Intraclonal heterogeneity and distinct molecular mechanisms characterize the development of t(4;14) and t(11;14) myeloma.
Paper ID
Walker BA, Wardell CP, Melchor L, Hulkki S, Potter NE, Johnson DC, Fenwick K, Kozarewa I, Gonzalez D, Lord CJ, Ashworth A, Davies FE and Morgan GJ
Haemato-Oncology Research Unit, Division of Molecular Pathology, The Institute of Cancer Research, London, United Kingdom;
Blood, 2012
ISSN: 1528-0020
PMID: 22573403 (view at PubMed or Europe PMC)
We have used whole exome sequencing to compare a group of presentation t(4;14) with t(11;14) cases of myeloma in order to define the mutational landscape. Each case was characterized by a median of 24.5 exonic non-synonymous SNVs and there was a consistently higher number of mutations in the t(4;14) group, but this did not reach statistical significance. We show that the transition/transversion rate in the two subgroups is similar suggesting that there was no specific mechanism leading to mutation differentiating the two 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 MRC Myeloma IX trial is registered at under ISRCTN68454111.
Paper Status