Inflammation-Associated Microsatellite Alterations Caused by MSH3 Dysfunction Are Prevalent in Ulcerative Colitis and Increase With Neoplastic Advancement

  • Koji Munakata
    Division of Gastroenterology, Departments of Internal Medicine and Human Genetics, Rogel Cancer Center, University of Michigan, Ann Arbor, Michigan, USA;
  • Minoru Koi
    Division of Gastroenterology, Departments of Internal Medicine and Human Genetics, Rogel Cancer Center, University of Michigan, Ann Arbor, Michigan, USA;
  • Takahito Kitajima
    Division of Gastroenterology, Departments of Internal Medicine and Human Genetics, Rogel Cancer Center, University of Michigan, Ann Arbor, Michigan, USA;
  • Stephanie Tseng-Rogenski
    Division of Gastroenterology, Departments of Internal Medicine and Human Genetics, Rogel Cancer Center, University of Michigan, Ann Arbor, Michigan, USA;
  • Mamoru Uemura
    Department of Surgery, National Hospital Organization, Osaka National Hospital, Osaka, Japan;
  • Hiroshi Matsuno
    Department of Gastroenterological Surgery, Osaka University, Osaka, Japan;
  • Kenji Kawai
    Department of Gastroenterological Surgery, Osaka University, Osaka, Japan;
  • Yuki Sekido
    Department of Gastroenterological Surgery, Osaka University, Osaka, Japan;
  • Tsunekazu Mizushima
    Department of Gastroenterological Surgery, Osaka University, Osaka, Japan;
  • Yuji Toiyama
    Department of Gastrointestinal and Pediatric Surgery, Mie University, Tsu, Japan;
  • Takuya Yamada
    Department of Gastroenterology and Hepatology, National Hospital Organization, Osaka National Hospital, Osaka, Japan;
  • Masayuki Mano
    Department of Pathology, National Hospital Organization, Osaka National Hospital, Osaka, Japan.
  • Eiji Mita
    Department of Gastroenterology and Hepatology, National Hospital Organization, Osaka National Hospital, Osaka, Japan;
  • Masato Kusunoki
    Department of Gastrointestinal and Pediatric Surgery, Mie University, Tsu, Japan;
  • Masaki Mori
    Department of Gastroenterological Surgery, Osaka University, Osaka, Japan;
  • John M. Carethers
    Division of Gastroenterology, Departments of Internal Medicine and Human Genetics, Rogel Cancer Center, University of Michigan, Ann Arbor, Michigan, USA;

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<jats:sec> <jats:title>OBJECTIVES:</jats:title> <jats:p>Inflammation-associated microsatellite alterations (also known as elevated microsatellite alterations at selected tetranucleotide repeats [EMAST]) result from IL-6–induced nuclear-to-cytosolic displacement of the DNA mismatch repair (MMR) protein MSH3, allowing frameshifts of dinucleotide or longer microsatellites within DNA. MSH3 also engages homologous recombination to repair double-strand breaks (DSBs), making <jats:italic toggle="yes">MSH3</jats:italic> deficiency contributory to both EMAST and DSBs. EMAST is observed in cancers, but given its genesis by cytokines, it may be present in non-neoplastic inflammatory conditions. We examined ulcerative colitis (UC), a preneoplastic condition from prolonged inflammatory duration.</jats:p> </jats:sec> <jats:sec> <jats:title>METHODS:</jats:title> <jats:p>We assessed 70 UC colons without neoplasia, 5 UC specimens with dysplasia, 14 UC-derived colorectal cancers (CRCs), and 19 early-stage sporadic CRCs for microsatellite instability (MSI) via multiplexed polymerase chain reaction capable of simultaneous detection of MSI-H, MSI-L, and EMAST. We evaluated UC specimens for MSH3 expression via immunohistochemistry.</jats:p> </jats:sec> <jats:sec> <jats:title>RESULTS:</jats:title> <jats:p>UC, UC with dysplasia, and UC-derived CRCs demonstrated dinucleotide or longer microsatellite frameshifts, with UC showing coincident reduction of nuclear MSH3 expression. No UC specimen, with or without neoplasia, demonstrated mononucleotide frameshifts. EMAST frequency was higher in UC-derived CRCs than UC (71.4% vs 31.4%, <jats:italic toggle="yes">P</jats:italic> = 0.0045) and higher than early-stage sporadic CRCs (66.7% vs 26.3%, <jats:italic toggle="yes">P</jats:italic> = 0.0426). EMAST frequency was higher with UC duration >8 years compared with ≤8 years (40% vs 16%, <jats:italic toggle="yes">P</jats:italic> = 0.0459).</jats:p> </jats:sec> <jats:sec> <jats:title>DISCUSSION:</jats:title> <jats:p>Inflammation-associated microsatellite alterations/EMAST are prevalent in UC and signify genomic mutations in the absence of neoplasia. Duration of disease and advancement to neoplasia increases frequency of EMAST. MSH3 dysfunction is a potential contributory pathway toward neoplasia in UC that could be targeted by therapeutic intervention.</jats:p> </jats:sec>

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