3'-UTR poly(T/U) tract deletions and altered expression of EWSR1 are a hallmark of mismatch repair-deficient cancers

Cancer Res. 2014 Jan 1;74(1):224-34. doi: 10.1158/0008-5472.CAN-13-2100. Epub 2013 Oct 24.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 3' Untranslated Regions*
  • Calmodulin-Binding Proteins / biosynthesis*
  • Calmodulin-Binding Proteins / genetics
  • Colorectal Neoplasms / genetics*
  • Colorectal Neoplasms, Hereditary Nonpolyposis / genetics
  • DNA Mismatch Repair*
  • DNA Repair-Deficiency Disorders*
  • HCT116 Cells
  • HT29 Cells
  • HeLa Cells
  • Humans
  • Microsatellite Instability
  • RNA, Messenger / biosynthesis
  • RNA, Messenger / genetics
  • RNA-Binding Protein EWS
  • RNA-Binding Proteins / biosynthesis*
  • RNA-Binding Proteins / genetics
  • Transfection

Substances

  • 3' Untranslated Regions
  • Calmodulin-Binding Proteins
  • EWSR1 protein, human
  • RNA, Messenger
  • RNA-Binding Protein EWS
  • RNA-Binding Proteins