title: Intraclonal heterogeneity and distinct molecular mechanisms characterize the development of t(4;14) and t(11;14) myeloma.
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.
authors.affiliation: Haemato-Oncology Research Unit, Division of Molecular Pathology, The Institute of Cancer Research, London, UK.
authors.forename: Brian A
authors.initials: BA
authors.lastname: Walker
authors.forename: Christopher P
authors.initials: CP
authors.lastname: Wardell
authors.forename: Lorenzo
authors.initials: L
authors.lastname: Melchor
authors.forename: Sanna
authors.initials: S
authors.lastname: Hulkki
authors.forename: Nicola E
authors.initials: NE
authors.lastname: Potter
authors.forename: David C
authors.initials: DC
authors.lastname: Johnson
authors.forename: Kerry
authors.initials: K
authors.lastname: Fenwick
authors.forename: Iwanka
authors.initials: I
authors.lastname: Kozarewa
authors.forename: David
authors.initials: D
authors.lastname: Gonzalez
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Lord
authors.forename: Alan
authors.initials: A
authors.lastname: Ashworth
authors.forename: Faith E
authors.initials: FE
authors.lastname: Davies
authors.forename: Gareth J
authors.initials: GJ
authors.lastname: Morgan
mesh_terms: D002880:Chromosomes, Human, Pair 11 / Q000235:genetics; D002883:Chromosomes, Human, Pair 14 / Q000235:genetics; D002894:Chromosomes, Human, Pair 4 / Q000235:genetics; D002986:Clinical Trials as Topic; D060965:Clonal Evolution / Q000235:genetics* / Q000502:physiology; D005260:Female; D018628:Gene Dosage; D020869:Gene Expression Profiling; D018740:Genetic Heterogeneity; D006801:Humans; D019656:Loss of Heterozygosity / Q000235:genetics; D008297:Male; D046228:Microarray Analysis; D008954:Models, Biological; D009101:Multiple Myeloma / Q000235:genetics*; D009154:Mutation / Q000502:physiology; D015398:Signal Transduction / Q000235:genetics; D014178:Translocation, Genetic / Q000235:genetics*; D054928:Validation Studies as Topic