GRCh38 · COSMIC v94

Summary

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Reference
Intraclonal heterogeneity and distinct molecular mechanisms characterize the development of t(4;14) and t(11;14) myeloma.
Paper ID
COSP28746
Authors
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
Affiliation
Haemato-Oncology Research Unit, Division of Molecular Pathology, The Institute of Cancer Research, London, United Kingdom;
Journal
Blood, 2012
ISSN: 1528-0020
PMID: 22573403 (view at PubMed or Europe PMC)
Abstract
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 http://isrctn.org under ISRCTN68454111.
Paper Status
Curated