title: 3'-UTR poly(T/U) tract deletions and altered expression of EWSR1 are a hallmark of mismatch repair-deficient cancers.
abstract: The genome-wide accumulation of DNA replication errors known as microsatellite instability (MSI) is the hallmark lesion of DNA mismatch repair (MMR)-deficient cancers. Although testing for MSI is widely used to guide clinical management, the contribution of MSI at distinct genic loci to the phenotype remains largely unexplored. Here, we report that a mononucleotide (T/U)16 tract located in the 3' untranslated region (3'-UTR) of the Ewing sarcoma breakpoint region 1 (EWSR1) gene is a novel MSI target locus that shows perfect sensitivity and specificity in detecting mismatch repair-deficient cancers in two independent populations. We further found a striking relocalization of the EWSR1 protein from nucleus to cytoplasm in MMR-deficient cancers and that the nonprotein-coding MSI target locus itself has a modulatory effect on EWSR1 gene expression through alternative 3' end processing of the EWSR1 gene. Our results point to a MSI target gene-specific effect in MMR-deficient cancers.
authors.affiliation: Authors' Affiliations: Biozentrum, University of Basel; Research Group Human Genetics, Dept of Biomedicine, University of Basel, and Division of Medical Genetics, University Hospital Basel; Institute for Surgical Research and Hospital Management and Department of Biomedicine, University of Basel; Institute of Pathology, University Hospital of Basel, Basel; Pathologie Laenggasse Bern, Bern; Institute of Molecular Cancer Research, University of Zurich, Zurich, Switzerland; Department of Medical Genetics, Haartman Institute, University of Helsinki, Helsinki, Finland; and Paterson Institute for Cancer Research, University of Manchester, Manchester, United Kingdom.
authors.forename: Shivendra
authors.initials: S
authors.lastname: Kishore
authors.forename: Salvatore
authors.initials: S
authors.lastname: Piscuoglio
authors.forename: Michal B
authors.initials: MB
authors.lastname: Kovac
authors.forename: Annette
authors.initials: A
authors.lastname: Gylling
authors.forename: Friedel
authors.initials: F
authors.lastname: Wenzel
authors.forename: Francesca
authors.initials: F
authors.lastname: Trapani
authors.forename: Hans Joerg
authors.initials: HJ
authors.lastname: Altermatt
authors.forename: Valentina
authors.initials: V
authors.lastname: Mele
authors.forename: Giancarlo
authors.initials: G
authors.lastname: Marra
authors.forename: Päivi
authors.initials: P
authors.lastname: Peltomäki
authors.forename: Luigi
authors.initials: L
authors.lastname: Terracciano
authors.forename: Mihaela
authors.initials: M
authors.lastname: Zavolan
authors.forename: Karl
authors.initials: K
authors.lastname: Heinimann
mesh_terms: D020413:3' Untranslated Regions; D002148:Calmodulin-Binding Proteins / Q000096:biosynthesis* / Q000235:genetics; D015179:Colorectal Neoplasms / Q000235:genetics*; D003123:Colorectal Neoplasms, Hereditary Nonpolyposis / Q000235:genetics; D053843:DNA Mismatch Repair; D049914:DNA Repair-Deficiency Disorders; D045325:HCT116 Cells; D019073:HT29 Cells; D006367:HeLa Cells; D006801:Humans; D053842:Microsatellite Instability; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D034802:RNA-Binding Protein EWS; D016601:RNA-Binding Proteins / Q000096:biosynthesis* / Q000235:genetics; D014162:Transfection
chemical_list: D020413:3' Untranslated Regions; D002148:Calmodulin-Binding Proteins; C500986:EWSR1 protein, human; D012333:RNA, Messenger; D034802:RNA-Binding Protein EWS; D016601:RNA-Binding Proteins