Inflammation-Associated Microsatellite Alterations Caused by MSH3 Dysfunction Are Prevalent in Ulcerative Colitis and...

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.