title: The molecular spectrum and clinical impact of DIS3 mutations in multiple myeloma.
abstract: Multiple 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.
authors.affiliation: Institute of Pathology, University of Würzburg, Comprehensive Cancer Center Mainfranken (CCC MF), Würzburg, Germany.
authors.forename: Susann
authors.initials: S
authors.lastname: Weißbach
authors.forename: Christian
authors.initials: C
authors.lastname: Langer
authors.forename: Bernhard
authors.initials: B
authors.lastname: Puppe
authors.forename: Theodora
authors.initials: T
authors.lastname: Nedeva
authors.forename: Elisa
authors.initials: E
authors.lastname: Bach
authors.forename: Miriam
authors.initials: M
authors.lastname: Kull
authors.forename: Ralf
authors.initials: R
authors.lastname: Bargou
authors.forename: Hermann
authors.initials: H
authors.lastname: Einsele
authors.forename: Andreas
authors.initials: A
authors.lastname: Rosenwald
authors.forename: Stefan
authors.initials: S
authors.lastname: Knop
authors.forename: Ellen
authors.initials: E
authors.lastname: Leich
mesh_terms: D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage; D045744:Cell Line, Tumor; D002882:Chromosomes, Human, Pair 13 / Q000235:genetics*; D018572:Disease-Free Survival; D063326:Exosome Multienzyme Ribonuclease Complex / Q000235:genetics*; D005260:Female; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D008297:Male; D008875:Middle Aged; D009101:Multiple Myeloma / Q000188:drug therapy / Q000235:genetics* / Q000401:mortality; D009154:Mutation; D009363:Neoplasm Proteins / Q000235:genetics*; D015996:Survival Rate
chemical_list: D009363:Neoplasm Proteins; D063326:Exosome Multienzyme Ribonuclease Complex; C551543:DIS3 protein, human
keywords: DIS3; bortezomib; hot spot mutations; multiple myeloma; ultra-deep amplicon sequencing