A compendium of DIS3 mutations and associated transcriptional signatures in plasma cell dyscrasias

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)...

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Veröffentlicht in:Oncotarget 2015-09, Vol.6 (28), p.26129-26141
Hauptverfasser: Lionetti, Marta, Barbieri, Marzia, Todoerti, Katia, Agnelli, Luca, Fabris, Sonia, Tonon, Giovanni, Segalla, Simona, Cifola, Ingrid, Pinatel, Eva, Tassone, Pierfrancesco, Musto, Pellegrino, Baldini, Luca, Neri, Antonino
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container_end_page 26141
container_issue 28
container_start_page 26129
container_title Oncotarget
container_volume 6
creator Lionetti, Marta
Barbieri, Marzia
Todoerti, Katia
Agnelli, Luca
Fabris, Sonia
Tonon, Giovanni
Segalla, Simona
Cifola, Ingrid
Pinatel, Eva
Tassone, Pierfrancesco
Musto, Pellegrino
Baldini, Luca
Neri, Antonino
description 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.
doi_str_mv 10.18632/oncotarget.4674
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source Freely Accessible Journals; MEDLINE; PubMed Central Open Access; EZB-FREE-00999 freely available EZB journals; PubMed Central
subjects Adult
Aged
Aged, 80 and over
Amino Acid Sequence
Cell Line, Tumor
Disease Progression
Exosome Multienzyme Ribonuclease Complex - genetics
Female
Gene Expression Profiling
Gene Ontology
High-Throughput Nucleotide Sequencing - methods
Humans
Male
Middle Aged
Molecular Sequence Data
Multiple Myeloma - genetics
Multiple Myeloma - pathology
Mutation
Paraproteinemias - genetics
Paraproteinemias - pathology
Prognosis
Research Paper
Sequence Homology, Amino Acid
title A compendium of DIS3 mutations and associated transcriptional signatures in plasma cell dyscrasias
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