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.

中文翻译：

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由 MSH3 功能障碍引起的炎症相关微卫星改变在溃疡性结肠炎中普遍存在，并随着肿瘤进展而增加。

炎症相关微卫星改变（也称为选定四核苷酸重复序列升高的微卫星改变 [EMAST]）是由 IL-6 诱导的 DNA 错配修复 (MMR) 蛋白 MSH3 的核向胞质置换引起的，允许二核苷酸或DNA 中更长的微卫星。MSH3 还参与同源重组以修复双链断裂 (DSB)，使 MSH3 缺乏导致 EMAST 和 DSB。在癌症中观察到 EMAST，但鉴于其起源于细胞因子，它可能存在于非肿瘤性炎症状况中。我们检查了溃疡性结肠炎 (UC)，这是一种炎症持续时间延长的癌前疾病。方法 我们评估了 70 例无肿瘤的 UC 结肠、5 例不典型增生的 UC 样本、14 例 UC 衍生的结直肠癌 (CRC)、和 19 个早期散发性 CRC，通过能够同时检测 MSI-H、MSI-L 和 EMAST 的多重聚合酶链反应检测微卫星不稳定性 (MSI)。我们通过免疫组织化学评估了 UC 标本的 MSH3 表达。结果 UC、不典型增生的 UC 和 UC 衍生的 CRC 表现出二核苷酸或更长的微卫星移码，UC 表现出核​​ MSH3 表达同时减少。没有 UC 标本，无论有或没有瘤形成，都显示出单核苷酸移码。UC 衍生的 CRC 中的 EMAST 频率高于 UC（71.4% 对 31.4%，P = 0.0045），高于早期散发性 CRC（66.7% 对 26.3%，P = 0.0426）。与 ≤8 年相比，UC 持续时间 >8 年的 EMAST 频率更高（40% 对 16%，P = 0.0459）。讨论 炎症相关的微卫星改变/EMAST 在 UC 中很普遍，并且在没有瘤形成的情况下表示基因组突变。疾病持续时间和进展为瘤形成增加了 EMAST 的频率。MSH3 功能障碍是 UC 肿瘤形成的潜在促成途径，可以通过治疗干预来靶向。