Evolution of instability at coding and non-coding repeat sequences in human MSI-H colorectal cancers

A number of human genes containing coding mononucleotide repeat sequences a re particularly prone to mutations in tumors with defects in mismatch repai r (MMR) genes (MSI-H cancers). In a large series of MSI-H colorectal tumors , we looked for mutations in 25 coding repeats contained in eight genes alr eady known to be mutated in these cancers or in 17 other genes with an expe cted role in carcinogenesis. Mutations were found in 19 of the 25 candidate genes. Using a maximum likelihood statistical method, they were separated into two different groups that differed significantly in their mutation fre quencies, and were likely to represent mutations that do or do not provide selective pressures during MSI-H tumoral progression, respectively. Three n ew target genes were found (GRB-14, RHAMM, RAD50). Our results provide evid ence that MSI-H tumoral progression involves the cumulative mutations of a large number of genes. For each MSI-H tumor we calculated indexes represent ing the number of mutations found in genes of these groups. We also evaluat ed a shortening index at both the Bat-25 and Bat-26 non-coding mononucleoti de tracts that are known to be almost always unstable in MSI-H cancers. A s ignificant correlation was observed between instability at both coding and non-coding repeats, suggesting that Bat-25 and Bat-26 could be used as simp le phenotypical markers of the tumoral evolution. A preferential order of m utations was deduced. During this process, hMSH3 alterations, a target gene encoding for a MMR protein, was found to play an important role by increas ing the instability phenomenon characterizing these cancers.