RIS1, a gene with trinucleotide repeats, is a target in the mutator pathway of colorectal carcinogenesis
RIS1, a gene with trinucleotide repeats, is a target in the mutator pathway of colorectal carcinogenesis
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DOI：
10.1016/j.cancergencyto.2005.12.002
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发表时间：
2006-06-01
影响因子：
--
通讯作者：
González-Aguilera, Juan J.
中科院分区：
文献类型：
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作者：
Iglesias, Daniel;Fernández-Peralta, Antonia M.;González-Aguilera, Juan J.
错配修复系统(MMR)改变导致的微卫星不稳定性(MSI)是结直肠癌发生发展过程中突变子途径的特征。在本研究中，我们分析了RIS1(RAS诱导的衰老1)基因与杂合性丢失(LOH)及其位于3‘-OH端的不完全三核苷酸重复(GCN)的移码突变的关系。此外，我们还将RIS1的状态与一些遗传和临床病理变量进行了比较。RIS1在本系列任何信息性肿瘤中均未显示LOH，但在高频MSI肿瘤(MSI-H)中出现移码突变的比例很高(43.8%)，其变化与两个靶基因Bax和TGFBR2的突变有关。此外，MSI-H肿瘤中RIS1突变与MLH1的表观遗传沉默相关(P=0.04)。最后，RIS1似乎在功能上参与了肿瘤的发展，因为发生RIS1突变的低频率微卫星肿瘤(MSI-L)通常与较差的预后相关：83%的患者发生转移，而MSI-L肿瘤和RIS1突变的患者(占MSI-L的35.3%)均未在术后25个月存活(对数等级P<；0.001)。所有这些结果表明，根据Bethesda标准，RIS1是突变子途径中的一个靶基因。(C)2006 Elsevier Inc.保留所有权利。
Microsatellite instability (MSI) due to mismatch repair system (MMR) alterations characterizes the mutator pathway implied in colorectal cancer development. In the present study, we have analyzed the gene RIS1 (Ras-induced senescence 1) in relation to loss of heterozygosity (LOH) and its frameshift mutations for an imperfect trinucleotide repeat (GCN) located at the 3'-OH end. Additionally, we have compared the status of RIS1 with a number of genetic and clinicopathological variables. RIS1 did not display LOH in any informative tumor of our series, but exhibited frameshift mutations in a high percentage (43.8%) of high-frequency MSI tumors (MSI-H), and its alteration was correlated with mutations in two target genes: BAX and TGFBR2. Moreover, mutations in RIS1 in MSI-H tumors correlated with the epigenetic silencing of MLH1 (P = 0.04). Finally, RIS1 seemed to be functionally involved in tumor development, as low-frequency MSI tumors (MSI-L) with RIS1 mutated usually were associated with a worse prognosis: 83% of them developed metastasis, and no patient with MSI-L tumor and RIS1 mutated (35.3% of MSI-L) survived > 25 months after surgery (log rank P < 0.001). All these results indicate, according to the Bethesda criteria, that RIS1 is a target gene in the mutator pathway. (c) 2006 Elsevier Inc. All rights reserved.