Genetic instability caused by loss of MutS homologue 3 in human colorectal cancer.
Genetic instability caused by loss of MutS homologue 3 in human colorectal cancer.
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DOI：
10.1158/0008-5472.can-08-0002
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发表时间：
2008-10-15
期刊：
影响因子：
11.2
通讯作者：
Koi M
中科院分区：
文献类型：
--
作者：
Haugen AC;Goel A;Yamada K;Marra G;Nguyen TP;Nagasaka T;Kanazawa S;Koike J;Kikuchi Y;Zhong X;Arita M;Shibuya K;Oshimura M;Hemmi H;Boland CR;Koi M
微卫星不稳定性（MSI）是错配修复缺陷的标志。结直肠癌（CRC）中单核苷酸和二核苷酸重复序列处的高水平MSI归因于错配修复基因hMLH 1和hMSH 2的失活。存在低水平MSI（MSI-L）的CRC;但其分子基础尚不清楚。还有另一种类型的MSI -“在选定的四核苷酸重复序列处升高的微卫星改变”-（EMAST），其中含有[AAAG]n或[ATAG]n重复序列的基因座不稳定。EMAST常见于非结直肠癌;然而，EMAST在CRC中的发病率及其原因尚不清楚。在这里，我们报告说，MSH 3敲低或MSH 3缺陷的细胞表现出EMAST表型和低水平的突变在二核苷酸重复。117例散发性CRC病例中约60%表现为EMAST。所有被定义为MSI-H的病例（16例）均表现出高水平的EMAST。在101例非MSI-H病例中，19例MSI-L和82例MSS中的35例均显示EMAST。尽管非MSI-H CRC组织含有占总肿瘤细胞群2-50%的MSH 3阴性肿瘤细胞，但表现出EMAST的组织含有比未表现出EMAST的组织（8.4%）更多的MSH 3阴性细胞（平均31.5%）。综上所述，我们的研究结果支持这样的想法，即MSH 3缺陷导致EMAST或EMAST与低水平的MSI的位点与CRC中的二核苷酸重复。
Microsatellite instability (MSI) is a hallmark of mismatch repair deficiency. High levels of MSI at mono- and dinucleotide repeats in colorectal cancer (CRC) are attributed to inactivation of the mismatch repair genes, hMLH1 and hMSH2. CRC with low levels of MSI (MSI-L) exists; however its molecular basis is unclear. There is another type of MSI - “elevated microsatellite alterations at selected tetranucleotide repeats” - (EMAST) where loci containing [AAAG]n or [ATAG]n repeats are unstable. EMAST is frequent in non-colorectal cancers; however the incidence of EMAST and its cause in CRC is not known. Here, we report that MSH3-knock-down or MSH3-deficient cells exhibit the EMAST phenotype and low levels of mutations at dinucleotide repeats. About 60% of 117 sporadic CRC cases exhibit EMAST. All of the cases defined as MSI-H (16 cases) exhibited high levels of EMAST. Among 101 non-MSI-H cases, all 19 cases of MSI-L and 35 of 82 cases of MSS exhibited EMAST. Although non-MSI-H CRC tissues contained MSH3-negative tumor cells ranging from 2-50% of the total tumor cell population, the tissues exhibiting EMAST contained more MSH3-negative cells (average 31.5%) than did the tissues not exhibiting EMAST (8.4%). Taken together, our results support the idea that MSH3-deficiency causes EMAST or EMAST with low levels of MSI at the loci with dinucleotide repeats in CRC.