RIS1, a gene with trinucleotide repeats, is a target in the mutator pathway of colorectal carcinogenesis

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• 作者：Daniel Iglesias ; Antonia M. Ferná ; ndez-Peralta ; Nargisse Nejda ; Lidia Daimiel ; Mariano Moreno Azcoita ; Soledad Oliart and Juan J. Gonzá ; lez-Aguilera
• 刊名：Cancer Genetics and Cytogenetics
• 出版年：2006
• 出版时间：June 2006
• 年：2006
• 卷：167
• 期：2
• 页码：138-144
• 全文大小：206 K

文摘

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.