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

// Marta Lionetti 1, 2 * , Marzia Barbieri 2 * , Katia Todoerti 3 , Luca Agnelli 1, 2 , Sonia Fabris 2 , Giovanni Tonon 4 , Simona Segalla 4 , Ingrid Cifola 5 , Eva Pinatel 5 , Pierfrancesco Tassone 6 , Pellegrino Musto 3 , Luca Baldini 1, 2 and Antonino Neri 1, 2 1 Department of Clinical Sciences and Community Health, University of Milano, Milan, Italy 2 Hematology Unit, Fondazione IRCCS Ca’ Granda, Ospedale Maggiore Policlinico, Milan, Italy 3 Laboratory of Pre-Clinical and Translational Research, IRCCS-CROB, Referral Cancer Center of Basilicata, Rionero in Vulture (PZ), Italy 4 Functional Genomics of Cancer Unit, Division of Experimental Oncology, IRCCS San Raffaele Scientific Institute, Milan, Italy 5 Institute for Biomedical Technologies, National Research Council, Milan, Italy 6 Department of Experimental and Clinical Medicine, Magna Graecia University, Catanzaro, Italy * These authors have contributed equally to this work Correspondence to: Antonino Neri, e-mail: antonino.neri@unimi.it Marta Lionetti, e-mail: marta.lionetti@unimi.it Keywords: multiple myeloma, plasma cell leukemia, DIS3, next-generation sequencing Received: May 08, 2015      Accepted: July 06, 2015      Published: July 20, 2015 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.