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

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.