title: A compendium of DIS3 mutations and associated transcriptional signatures in plasma cell dyscrasias.
abstract: DIS3 is a catalytic subunit of the human exosome complex, containing exonucleolytic (RNB) and endonucleolytic (PIN) domains, recently found mutated in multiple myeloma (MM), a clinically and genetically heterogeneous form of plasma cell (PC) dyscrasia. We analyzed by next-generation sequencing (NGS) the DIS3 PIN and RNB domains in purified bone marrow PCs from 164 representative patients, including 130 cases with MM, 24 with primary PC leukemia and 10 with secondary PC leukemia. DIS3 mutations were found respectively in 18.5%, 25% and 30% of cases. Identified variants were predominantly missense mutations localized in the RNB domain, and were often detected at low allele frequency. DIS3 mutations were preferentially carried by IGH-translocated/nonhyperdiploid patients. Sequential analysis at diagnosis and relapse in a subset of cases highlighted some instances of increasing DIS3 mutation burden during disease progression. NGS also revealed that the majority of DIS3 variants in mutated cases were comparably detectable at transcriptional level. Furthermore, gene expression profiling analysis in DIS3-mutated patients identified a transcriptional signature suggestive for impaired RNA exosome function. In conclusion, these data further support the pathological relevance of DIS3 mutations in plasma cell dyscrasias and suggest that DIS3 may represent a potential tumor suppressor gene in such disorders.
authors: Department of Clinical Sciences and Community Health, University of Milano, Milan, Italy.|Hematology Unit, Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico, Milan, Italy.
authors: Marta
authors: M
authors: Lionetti
authors: Hematology Unit, Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico, Milan, Italy.
authors: Marzia
authors: M
authors: Barbieri
authors: Laboratory of Pre-Clinical and Translational Research, IRCCS-CROB, Referral Cancer Center of Basilicata, Rionero in Vulture, Italy.
authors: Katia
authors: K
authors: Todoerti
authors: Department of Clinical Sciences and Community Health, University of Milano, Milan, Italy.|Hematology Unit, Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico, Milan, Italy.
authors: Luca
authors: L
authors: Agnelli
authors: Hematology Unit, Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico, Milan, Italy.
authors: Sonia
authors: S
authors: Fabris
authors: Functional Genomics of Cancer Unit, Division of Experimental Oncology, IRCCS San Raffaele Scientific Institute, Milan, Italy.
authors: Giovanni
authors: G
authors: Tonon
authors: Functional Genomics of Cancer Unit, Division of Experimental Oncology, IRCCS San Raffaele Scientific Institute, Milan, Italy.
authors: Simona
authors: S
authors: Segalla
authors: Institute for Biomedical Technologies, National Research Council, Milan, Italy.
authors: Ingrid
authors: I
authors: Cifola
authors: Institute for Biomedical Technologies, National Research Council, Milan, Italy.
authors: Eva
authors: E
authors: Pinatel
authors: Department of Experimental and Clinical Medicine, Magna Graecia University, Catanzaro, Italy.
authors: Pierfrancesco
authors: P
authors: Tassone
authors: Laboratory of Pre-Clinical and Translational Research, IRCCS-CROB, Referral Cancer Center of Basilicata, Rionero in Vulture, Italy.
authors: Pellegrino
authors: P
authors: Musto
authors: Department of Clinical Sciences and Community Health, University of Milano, Milan, Italy.|Hematology Unit, Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico, Milan, Italy.
authors: Luca
authors: L
authors: Baldini
authors: Department of Clinical Sciences and Community Health, University of Milano, Milan, Italy.|Hematology Unit, Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico, Milan, Italy.
authors: Antonino
authors: A
authors: Neri
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000595:Amino Acid Sequence; D045744:Cell Line, Tumor; D018450:Disease Progression; D063326:Exosome Multienzyme Ribonuclease Complex / Q000235:genetics*; D005260:Female; D020869:Gene Expression Profiling; D063990:Gene Ontology; D059014:High-Throughput Nucleotide Sequencing / Q000379:methods; D006801:Humans; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D009101:Multiple Myeloma / Q000235:genetics / Q000473:pathology; D009154:Mutation; D010265:Paraproteinemias / Q000235:genetics* / Q000473:pathology; D011379:Prognosis; D017386:Sequence Homology, Amino Acid
chemical_list: D063326:Exosome Multienzyme Ribonuclease Complex; C551543:DIS3 protein, human
keywords: DIS3; multiple myeloma; next-generation sequencing; plasma cell leukemia