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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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. |
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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.</description><identifier>ISSN: 1949-2553</identifier><identifier>EISSN: 1949-2553</identifier><identifier>DOI: 10.18632/oncotarget.4674</identifier><identifier>PMID: 26305418</identifier><language>eng</language><publisher>United States: Impact Journals LLC</publisher><subject>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</subject><ispartof>Oncotarget, 2015-09, Vol.6 (28), p.26129-26141</ispartof><rights>Copyright: © 2015 Lionetti et al. 2015</rights><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c420t-559cd6adff947c42a906d8bc128cc2dea1a5fcb6986bdbce5221fb82ad5dbb283</citedby><cites>FETCH-LOGICAL-c420t-559cd6adff947c42a906d8bc128cc2dea1a5fcb6986bdbce5221fb82ad5dbb283</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC4694891/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC4694891/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,315,729,782,786,887,27931,27932,53798,53800</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/26305418$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Lionetti, Marta</creatorcontrib><creatorcontrib>Barbieri, Marzia</creatorcontrib><creatorcontrib>Todoerti, Katia</creatorcontrib><creatorcontrib>Agnelli, Luca</creatorcontrib><creatorcontrib>Fabris, Sonia</creatorcontrib><creatorcontrib>Tonon, Giovanni</creatorcontrib><creatorcontrib>Segalla, Simona</creatorcontrib><creatorcontrib>Cifola, Ingrid</creatorcontrib><creatorcontrib>Pinatel, Eva</creatorcontrib><creatorcontrib>Tassone, Pierfrancesco</creatorcontrib><creatorcontrib>Musto, Pellegrino</creatorcontrib><creatorcontrib>Baldini, Luca</creatorcontrib><creatorcontrib>Neri, Antonino</creatorcontrib><title>A compendium of DIS3 mutations and associated transcriptional signatures in plasma cell dyscrasias</title><title>Oncotarget</title><addtitle>Oncotarget</addtitle><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.</description><subject>Adult</subject><subject>Aged</subject><subject>Aged, 80 and over</subject><subject>Amino Acid Sequence</subject><subject>Cell Line, Tumor</subject><subject>Disease Progression</subject><subject>Exosome Multienzyme Ribonuclease Complex - genetics</subject><subject>Female</subject><subject>Gene Expression Profiling</subject><subject>Gene Ontology</subject><subject>High-Throughput Nucleotide Sequencing - methods</subject><subject>Humans</subject><subject>Male</subject><subject>Middle Aged</subject><subject>Molecular Sequence Data</subject><subject>Multiple Myeloma - genetics</subject><subject>Multiple Myeloma - pathology</subject><subject>Mutation</subject><subject>Paraproteinemias - genetics</subject><subject>Paraproteinemias - pathology</subject><subject>Prognosis</subject><subject>Research Paper</subject><subject>Sequence Homology, Amino Acid</subject><issn>1949-2553</issn><issn>1949-2553</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2015</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpVUU1PHDEMjapWgOjeOaEcuSydZCazyQUJ0ZYiIfVQOEfOx2yDZpIhziDx75stC6W-2LGfX2w_Qk5Yc85k3_IvKdpUIG99Oe_6TfeBHDHVqTUXov34Lj4kK8SHpproNpKrA3LI-7Y-mDwi5pLaNM0-urBMNA30682vlk5LgRJSRArRUUBMNkDxjpYMEW0O864KI8WwjVCW7JGGSOcRcAJq_ThS91xxgAHwM_k0wIh-tffH5P77t7urH-vbn9c3V5e3a9vxpqyFUNb14IZBdZuaAtX0ThrLuLSWOw8MxGBNr2RvnLFecM4GIzk44Yzhsj0mFy-882Im76yPddpRzzlMkJ91gqD_r8TwW2_Tk-561UnFKsHZniCnx8Vj0VPA3TIQfVpQs029KW8Fbyu0eYHanBCzH96-YY3-q47-p47eqVNbTt-P99bwqkX7B9wLkfI</recordid><startdate>20150922</startdate><enddate>20150922</enddate><creator>Lionetti, Marta</creator><creator>Barbieri, Marzia</creator><creator>Todoerti, Katia</creator><creator>Agnelli, Luca</creator><creator>Fabris, Sonia</creator><creator>Tonon, Giovanni</creator><creator>Segalla, Simona</creator><creator>Cifola, Ingrid</creator><creator>Pinatel, Eva</creator><creator>Tassone, Pierfrancesco</creator><creator>Musto, Pellegrino</creator><creator>Baldini, Luca</creator><creator>Neri, Antonino</creator><general>Impact Journals LLC</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope><scope>5PM</scope></search><sort><creationdate>20150922</creationdate><title>A compendium of DIS3 mutations and associated transcriptional signatures in plasma cell dyscrasias</title><author>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</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c420t-559cd6adff947c42a906d8bc128cc2dea1a5fcb6986bdbce5221fb82ad5dbb283</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2015</creationdate><topic>Adult</topic><topic>Aged</topic><topic>Aged, 80 and over</topic><topic>Amino Acid Sequence</topic><topic>Cell Line, Tumor</topic><topic>Disease Progression</topic><topic>Exosome Multienzyme Ribonuclease Complex - genetics</topic><topic>Female</topic><topic>Gene Expression Profiling</topic><topic>Gene Ontology</topic><topic>High-Throughput Nucleotide Sequencing - methods</topic><topic>Humans</topic><topic>Male</topic><topic>Middle Aged</topic><topic>Molecular Sequence Data</topic><topic>Multiple Myeloma - genetics</topic><topic>Multiple Myeloma - pathology</topic><topic>Mutation</topic><topic>Paraproteinemias - genetics</topic><topic>Paraproteinemias - pathology</topic><topic>Prognosis</topic><topic>Research Paper</topic><topic>Sequence Homology, Amino Acid</topic><toplevel>online_resources</toplevel><creatorcontrib>Lionetti, Marta</creatorcontrib><creatorcontrib>Barbieri, Marzia</creatorcontrib><creatorcontrib>Todoerti, Katia</creatorcontrib><creatorcontrib>Agnelli, Luca</creatorcontrib><creatorcontrib>Fabris, Sonia</creatorcontrib><creatorcontrib>Tonon, Giovanni</creatorcontrib><creatorcontrib>Segalla, Simona</creatorcontrib><creatorcontrib>Cifola, Ingrid</creatorcontrib><creatorcontrib>Pinatel, Eva</creatorcontrib><creatorcontrib>Tassone, Pierfrancesco</creatorcontrib><creatorcontrib>Musto, Pellegrino</creatorcontrib><creatorcontrib>Baldini, Luca</creatorcontrib><creatorcontrib>Neri, Antonino</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Oncotarget</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Lionetti, Marta</au><au>Barbieri, Marzia</au><au>Todoerti, Katia</au><au>Agnelli, Luca</au><au>Fabris, Sonia</au><au>Tonon, Giovanni</au><au>Segalla, Simona</au><au>Cifola, Ingrid</au><au>Pinatel, Eva</au><au>Tassone, Pierfrancesco</au><au>Musto, Pellegrino</au><au>Baldini, Luca</au><au>Neri, Antonino</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>A compendium of DIS3 mutations and associated transcriptional signatures in plasma cell dyscrasias</atitle><jtitle>Oncotarget</jtitle><addtitle>Oncotarget</addtitle><date>2015-09-22</date><risdate>2015</risdate><volume>6</volume><issue>28</issue><spage>26129</spage><epage>26141</epage><pages>26129-26141</pages><issn>1949-2553</issn><eissn>1949-2553</eissn><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.</abstract><cop>United States</cop><pub>Impact Journals LLC</pub><pmid>26305418</pmid><doi>10.18632/oncotarget.4674</doi><tpages>13</tpages><oa>free_for_read</oa></addata></record> |
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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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