Inflammation-Associated Microsatellite Alterations Caused by MSH3 Dysfunction Are Prevalent in Ulcerative Colitis and Increase With Neoplastic Advancement
Inflammation-Associated Microsatellite Alterations Caused by MSH3 Dysfunction Are Prevalent in Ulcerative Colitis and Increase With Neoplastic Advancement
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DOI：
10.14309/ctg.0000000000000105
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发表时间：
2019-12-01
影响因子：
3.6
通讯作者：
Carethers, John M.
中科院分区：
文献类型：
--
作者：
Munakata, Koji;Koi, Minoru;Carethers, John M.
目的：炎症相关微卫星改变(也称为特定四核苷酸重复序列[EMAST]的升高微卫星改变)是由于IL-6诱导DNA错配修复(MMR)蛋白MSH3的核浆置换，使DNA内二核苷酸或更长的微卫星发生移码。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。EMAST在癌症中观察到，但鉴于其由细胞因子引起，它可能存在于非肿瘤性炎症条件下。方法：采用多重聚合酶链式反应同时检测70例非肿瘤UC、5例不典型增生UC、14例UC起源的结直肠癌和19例早期散发性结直肠癌的微卫星不稳定性。结果：UC、伴异型增生的UC和UC来源的CRC均表现为二核苷酸或更长的微卫星移位，UC表现为核MSH3表达的降低。UC标本，无论有没有肿瘤，都没有显示出单核苷酸移码。UC来源癌的EMAST频率高于UC(71.4%比31.4%，P=0.0045)，也高于早期散发性癌(66.7%比26.3%，P=0.0426)。EMAST频率随UC病程的延长和8年的增加而增加
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