The molecular spectrum and clinical impact of DIS3 mutations in multiple myeloma

Abstract

SummaryMultiple myeloma (MM) is a plasma cell neoplasm that presents with a major biological and clinical heterogeneity. We here investigated the spectrum of clonal and subclonal mutations of DIS3, an active part of the exosome complex, that may play a role in the development or progression of MM. The whole coding sequence of DIS3 was subjected to deep sequencing in 81 uniformly-treated MM patients and 12 MM cell lines and the overall occurrence of DIS3 mutations as well as the presence of DIS3 mutations in minor and major subclones were correlated with cytogenetic alterations and clinical parameters. Our study identified DIS3 mutations in 9/81 patients that were associated with 13q14 deletions and IGH translocations on the cytogenetic level. Specifically, we detected seven novel somatic DIS3 single nucleotide variants (SNVs) and defined three hot spot mutations within the RNB domain. Lastly, we found a trend towards a shorter median overall survival for patients with DIS3 mutations, and patients carrying DIS3 mutations in minor subclones of their tumours showed a significantly worse response to therapy compared to patients with DIS3 mutations in the major subclone.

The RNA Exosome Channeling and Direct Access Conformations Have Distinct In Vivo Functions

“…Our results raise the possibility that defects in the two different conformations cause different human diseases. Specifically, multiple myeloma genomes often contain mutations in the Rrp44 exonuclease domain, but not in other RNA exosome subunits (Weissbach et al, 2015). In contrast, pontocerebellar hypoplasia is caused by point mutations in the exo-9 core (EXOSC3 and EXOSC8; Boczonadi et al, 2014; Wan et al, 2012).…”

“…These molecular functions are best defined in yeast, but many are conserved in human cells (Staals and Pruijn, 2011). In human patients, different mutations that affect RNA exosome activity are associated with distinct human diseases: multiple myeloma (Weissbach et al, 2015), pontocerebellar hypoplasia (Boczonadi et al, 2014; Wan et al, 2012), trichohepatoenteric syndrome (Fabre et al, 2012; Hartley et al, 2010), and most recently, a distinct disorder that has not yet been named (Di Donato et al, 2016). A thorough investigation of the structure and function of the RNA exosome is essential to understand how the RNA exosome carries out all of these functions, and how RNA exosome defects cause these very diverse diseases.…”

DIS3 shapes the RNA polymerase II transcriptome in humans by degrading a variety of unwanted transcripts

“…Human DIS3 attracted our attention because it is essential for the survival of vertebrate cells (Tomecki et al 2014). Interestingly, DIS3 is frequently mutated in multiple myeloma and other cancers (Chapman et al 2011;Walker et al 2012;Weißbach et al 2014). Approximately 10%-15% of multiple myeloma cases have specific hemizygous or homozygous mutations in the DIS3 RNB domain, which leads to DIS3 dysfunction, but not complete inactivation (Tomecki 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).…”

“…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). Furthermore, a trend towards shorter survival was observed in MM patients with DIS3 mutations (16). Other studies have shown DIS3 missense mutations in acute myeloid leukaemia, somatic deletions in breast cancer and loss of heterozygosity in superficial spreading melanoma (17)(18)(19).…”