DIS3 mutations in multiple myeloma impact the transcriptional signature and clinical outcome

Abstract

DIS3 gene mutations (DIS3mts) occur in roughly 10% of multiple myeloma (MM) patients; furthermore, DIS3 expression could be affected by monosomy 13 or del(13q), which occur in approximately 40% of MM cases. Despite several reports on the prevalence of DIS3mts, their contribution to the pathobiology of MM remains largely unknown. We took advantage of the large public CoMMpass dataset to investigate the spectrum of DIS3mts in MM and its impact on the transcriptome and clinical outcome. We found that DIS3mts clinical relevance strictly depended on del(13q) co-occurrence. In particular, bi-allelic DIS3 lesions significantly affected PFS, independently from other predictors of poor clinical outcome, while mono-allelic events mostly impacted OS. As expected, DIS3mts affect MM transcriptome involving cellular processes and signaling pathways associated with RNA metabolism, and the deregulation of a large number of lncRNAs, among which we identified five distinct transcripts as independent predictors of poorer OS and nine of worse PFS, some of which (AC015982.2 and AL445228.3) predicting both. These findings strongly prompt further studies investigating the relevance of these lncRNAs in MM.

Transcription/Replication Conflicts in Tumorigenesis and Their Potential Role as Novel Therapeutic Targets in Multiple Myeloma

“…DIS3 mutations are involved in MM progression [90]. Indeed, DIS3 mutations are associated with a poor prognosis and are associated with significant transcriptional changes [91,92]. Moreover, germline variants in DIS3 were identified in familial MM [93].…”

DIS3: The Enigmatic Gene in Multiple Myeloma

“…In addition to the heterozygous deletion of this gene, Chapman et al identified DIS3 mutations in MM using whole-genome and whole-exome sequencing in 2011 [ 49 ]. Subsequent studies have confirmed that DIS3 mutations are recurrent and present in approximately 10% of patients with MM [ 4 , 50 , 51 , 52 , 53 , 54 ]. Germline mutations in DIS3 have also been reported in familial MM, suggesting the pathological relevance of DIS3 mutations in MM [ 55 ].…”

“…Germline mutations in DIS3 have also been reported in familial MM, suggesting the pathological relevance of DIS3 mutations in MM [ 55 ]. In the Multiple Myeloma Research Foundation (MMRF) CoMMpass cohort, which included 930 patients with MM, the variant allele frequency (VAF) ranged from 5.3 to 100% (mean: 48%; median: 43%), indicating the presence of DIS3 mutations in both major and minor subclones [ 54 ]. Most of the DIS3 mutations observed in MM are missense mutations, and nonsense mutations are barely observed [ 4 , 49 , 50 , 51 , 52 , 53 , 54 ].…”

“…In the Multiple Myeloma Research Foundation (MMRF) CoMMpass cohort, which included 930 patients with MM, the variant allele frequency (VAF) ranged from 5.3 to 100% (mean: 48%; median: 43%), indicating the presence of DIS3 mutations in both major and minor subclones [ 54 ]. Most of the DIS3 mutations observed in MM are missense mutations, and nonsense mutations are barely observed [ 4 , 49 , 50 , 51 , 52 , 53 , 54 ]. Notably, DIS3 mutations are primarily present in the catalytic domains of this protein; about 70% of the mutations are located in the RNB domain, and about 10–20% are located in the PIN domain, suggesting the functional relevance of these mutations [ 52 , 53 , 54 ].…”

Dissecting the Biological Relevance and Clinical Impact of lncRNA MIAT in Multiple Myeloma

“…MM is characterized by a profound genomic instability resulting in structural and numerical chromosomal aberrations, some of which, i.e., chromosomal translocations involving the immunoglobulin heavy chain (IGH) locus at chromosome 14q32 with an extensive array of putative proto-oncogenes, or trisomies involving odd chromosomes, are thought to represent early and specific events in myelomagenesis [ 3 ]. More recently, mutations affecting several genes, such as KRAS , NRAS , TP53 , BRAF , TRAF3 , FAM46C , and DIS3 , have been identified and extensively characterized [ 4 , 5 , 6 , 7 , 8 , 9 , 10 ]. Overall, these events may have a profound impact on the biology and clinical outcome of the disease.…”