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Inflammation-Associated Microsatellite Alterations Caused by MSH3 Dysfunction Are Prevalent in Ulcerative Colitis and
Koji Munakata1, Minoru Koi1, Takahito Kitajima1
1Division of Gastroenterology, Departments of Internal Medicine and Human Genetics, Rogel Cancer Center, University of Michigan, Ann Arbor, Michigan, USA.
Objectives:
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 MSH3 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.
Methods:
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.
Results:
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%, P = 0.0045) and higher than early-stage sporadic CRCs (66.7% vs 26.3%, P = 0.0426). EMAST frequency was higher with UC duration >8 years compared with ≤8 years (40% vs 16%, P = 0.0459).
Discussion:
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.
Insights
Inflammation-associated microsatellite alterations (EMAST) are common in ulcerative colitis (UC), indicating genomic mutations even without cancer. MSH3 protein dysfunction may drive UC toward neoplasia.
Area of Science:
- Genomic instability and DNA repair mechanisms
- Gastroenterology and oncology
- Inflammatory and preneoplastic conditions
Background:
- Inflammation-associated microsatellite alterations (EMAST) arise from MSH3 protein displacement, impacting DNA repair.
- MSH3 deficiency contributes to both EMAST and DNA double-strand breaks.
- EMAST is found in cancers and potentially in non-neoplastic inflammatory conditions like ulcerative colitis (UC).
Purpose of the Study:
- To investigate the prevalence and characteristics of EMAST in ulcerative colitis (UC).
- To assess the relationship between UC duration, neoplasia, and EMAST.
- To evaluate the role of MSH3 expression in UC-associated genomic alterations.
Main Methods:
- Analyzed 70 non-neoplastic UC colons, 5 UC with dysplasia, 14 UC-derived colorectal cancers (CRCs), and 19 sporadic CRCs.
- Utilized multiplexed PCR to detect microsatellite instability (MSI-H, MSI-L) and EMAST.
- Assessed MSH3 expression in UC specimens using immunohistochemistry.
Main Results:
- UC, UC with dysplasia, and UC-derived CRCs showed microsatellite frameshifts, with reduced nuclear MSH3 in UC.
- EMAST frequency was significantly higher in UC-derived CRCs compared to UC and early-stage sporadic CRCs.
- EMAST frequency increased with UC duration exceeding 8 years.
Conclusions:
- EMAST is prevalent in UC, signifying genomic mutations independent of neoplasia.
- Disease duration and progression to neoplasia correlate with increased EMAST frequency.
- MSH3 dysfunction represents a potential therapeutic target in UC-related neoplasia.
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