Division of Gastroenterology, Departments of Internal Medicine and Human Genetics, Rogel Cancer Center, University of Michigan, Ann Arbor, Michigan, USA.
Department of Surgery, National Hospital Organization, Osaka National Hospital, Osaka, Japan.
Clin Transl Gastroenterol. 2019 Dec;10(12):e00105. doi: 10.14309/ctg.0000000000000105.
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.
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.
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).
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.
炎症相关的微卫星改变（也称为选定四核苷酸重复序列中升高的微卫星改变[EMAST]）是由白细胞介素 6（IL-6）诱导的 DNA 错配修复（MMR）蛋白 MSH3 的核质易位引起的，导致 DNA 中双核苷酸或更长微卫星的移码。MSH3 还参与同源重组以修复双链断裂（DSB），因此 MSH3 缺陷与 EMAST 和 DSB 均有关。EMAST 见于癌症，但由于其由细胞因子引起，因此可能存在于非肿瘤性炎症性疾病中。我们检查了溃疡性结肠炎（UC），这是一种长期炎症导致的癌前状态。
我们评估了 70 例无肿瘤的 UC 结肠、5 例伴有异型增生的 UC 标本、14 例 UC 衍生的结直肠癌（CRC）和 19 例早期散发性 CRC，通过可同时检测 MSI-H、MSI-L 和 EMAST 的多重聚合酶链反应评估微卫星不稳定性（MSI）。我们通过免疫组织化学评估 UC 标本中 MSH3 的表达。
UC、伴有异型增生的 UC 和 UC 衍生的 CRC 均显示出双核苷酸或更长的微卫星移码，UC 表现出核 MSH3 表达的同时减少。无论是否有肿瘤，UC 标本均未显示单核苷酸移码。与 UC（71.4%比 31.4%，P = 0.0045）和早期散发性 CRC（66.7%比 26.3%，P = 0.0426）相比，UC 衍生的 CRC 中 EMAST 的频率更高。与≤8 年相比，UC 持续时间>8 年的 EMAST 频率更高（40%比 16%，P = 0.0459）。
炎症相关的微卫星改变/EMAST 在 UC 中很常见，表明在没有肿瘤的情况下存在基因组突变。疾病的持续时间和进展到肿瘤会增加 EMAST 的频率。MSH3 功能障碍是 UC 中肿瘤发生的潜在促成途径，可能成为治疗干预的靶点。
