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 singlenucleotide 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

Reduced intensity-conditioned allogeneic stem cell transplantation for multiple myeloma relapsing or progressing after autologous transplantation: a study by the European Group for Blood and Marrow Transplantation

“…11,[36][37][38] Furthermore, recent evidence for clonal competition with alternating dominance of tumour subclones during disease progression suggests that the presence of genetic features at diagnosis may not allow conclusions to be made about their presence or absence at a later time during the disease course. [39][40][41] The database also fails to provide stringent information about treatment with novel agents. However, given that patients transplanted in the years 2004-2008 had the same outcome as patients transplanted in 1999-2003 (Supplementary Table 1), novel treatment modalities are unlikely to have had a major impact.…”

Collaborative Control of Cell Cycle Progression by the RNA Exonuclease Dis3 and Ras Is Conserved Across Species

“…In multiple myeloma, a malignancy of plasma B cells, whole genome sequencing approaches uncover dis3 as one of the most frequently mutated genes in this cancer (Chapman et al 2011;Walker et al 2012;Lohr et al 2014). Essentially all multiple myeloma-specific dis3 mutations are missense mutations that cluster in its RNB domain and appear to reduce but not eliminate dis3 function in the tumor cells: dis3 mutations that are associated with loss of heterozygosity appear to simply reduce Dis3 exonuclease activity, whereas those mutations found associated with a wild-type copy of dis3 in the tumor appear to largely eliminate exonuclease activity for the variant allele product (Chapman et al 2011;Walker et al 2012;Lohr et al 2014;Tomecki et al 2014). Within multiple myeloma tumors, dis3 mutations have been found simultaneously clonal with activating mutations in k-ras (Lohr et al 2014).…”

Functional characterization of a chr13q22.1 pancreatic cancer risk locus reveals long-range interaction and allele-specific effects onDIS3expression

“…While the effects of DIS3 in the context of cancer have not previously been explored in depth, mutations in DIS3 have been observed in several cancer types (15)(16)(17)(18)(19)(20). Perhaps the most striking example is multiple myeloma (MM), which shows a 10-18.5% somatic mutation rate in different studies (15,16,20,21). DIS3 ribonuclease II (RNB) domain mutations observed in MM were shown to be synthetic lethal with catalytic mutations in the PIN domain, suggesting a possible drug target (22).…”