Two modes of microsatellite instability in human cancer: differential connection of defective DNA mismatch repair to dinucleotide repeat instability.
Two modes of microsatellite instability in human cancer: differential connection of defective DNA mismatch repair to dinucleotide repeat instability.
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人类癌症中微卫星不稳定性的两种模式：有缺陷的DNA不匹配修复与二核苷酸重复不稳定性的差异连接。
DOI：
10.1093/nar/gki303
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发表时间：
2005
影响因子：
14.9
通讯作者：
Yoshida, MA
中科院分区：
文献类型：
--
作者：
Oda, S;Maehara, Y;Ikeda, Y;Oki, E;Egashira, A;Okamura, Y;Takahashi, I;Kakeji, Y;Sumiyoshi, Y;Miyashita, K;Yamada, Y;Zhao, Y;Hattori, H;Taguchi, K;Ikeuchi, T;Tsuzuki, T;Sekiguchi, M;Karran, P;Yoshida, MA
微卫星不稳定性（MSI）与多种人类恶性肿瘤中DNA错配修复缺陷相关。使用一种独特的荧光技术，我们观察到两种不同的模式，在人类结直肠癌的二核苷酸微卫星改变。A型改变定义为≤6 bp的长度变化。B型变化更剧烈，涉及≥8 bp的修饰。我们在这里表明，有缺陷的错配修复是必要的和足够的A型变化。这些变化在细胞系和错配修复基因敲除小鼠的肿瘤中观察到。在这些细胞或肿瘤中未观察到B型不稳定性。在一组人结直肠肿瘤中，观察到A型MSI和B型不稳定性。两种类型的MSI均与hMSH2或hMLH1错配修复基因的改变有关。有趣的是，p53突变通常被认为在MSI+表型的人类肿瘤中不常见，但经常与A型不稳定性相关，而在B型不稳定性肿瘤中没有发现，这反映了流行的观点。对已发表数据的检查显示，在各种恶性肿瘤中观察到的微卫星不稳定性主要是B型，包括与遗传性非息肉病性结直肠癌（HNPCC）相关的那些。我们的研究结果表明，B型不稳定性并不是修复缺陷的简单反映。我们认为，在人类结直肠癌中至少有两种不同的二核苷酸MSI模式，不同的分子机制可能是这些模式的MSI的基础。MSI和错配修复缺陷之间的关系可能比迄今所怀疑的更为复杂。
Microsatellite instability (MSI) is associated with defective DNA mismatch repair in various human malignancies. Using a unique fluorescent technique, we have observed two distinct modes of dinucleotide microsatellite alterations in human colorectal cancer. Type A alterations are defined as length changes of ≤6 bp. Type B changes are more drastic and involve modifications of ≥8 bp. We show here that defective mismatch repair is necessary and sufficient for Type A changes. These changes were observed in cell lines and in tumours from mismatch repair gene-knockout mice. No Type B instability was seen in these cells or tumours. In a panel of human colorectal tumours, both Type A MSI and Type B instability were observed. Both types of MSI were associated with hMSH2 or hMLH1 mismatch repair gene alterations. Intriguingly, p53 mutations, which are generally regarded as uncommon in human tumours of the MSI+ phenotype, were frequently associated with Type A instability, whereas none was found in tumours with Type B instability, reflecting the prevailing viewpoint. Inspection of published data reveals that the microsatellite instability that has been observed in various malignancies, including those associated with Hereditary Non-Polyposis Colorectal Cancer (HNPCC), is predominantly Type B. Our findings indicate that Type B instability is not a simple reflection of a repair defect. We suggest that there are at least two qualitatively distinct modes of dinucleotide MSI in human colorectal cancer, and that different molecular mechanisms may underlie these modes of MSI. The relationship between MSI and defective mismatch repair may be more complex than hitherto suspected.
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影响因子：
64.5
作者：
FISHEL, R;LESCOE, MK;KOLODNER, R
通讯作者：
KOLODNER, R
影响因子：
30.8
作者：
LIU, B;NICOLAIDES, NC;VOGELSTEIN, B
通讯作者：
VOGELSTEIN, B
影响因子：
64.5
作者：
BAKER, SM;BRONNER, CE;LISKAY, RM
通讯作者：
LISKAY, RM
影响因子：
4
作者：
Froggatt, NJ;Brassett, C;Maher, ER
通讯作者：
Maher, ER
影响因子：
64.5
作者：
DEWIND, N;DEKKER, M;RIELE, HT
通讯作者：
RIELE, HT