Frameshift mutations at mononucleotide repeats in RAD50 recombinational DNA repair gene in colorectal cancers with microsatellite instability

To identify additional genes targeted for microsatellite instability (MSI), we search for human genes which contain mononucleotide repeats in their co ding region, selected 7 genes (RAD50, DNA-PKcs, FLASH, Apaf-1, XPG, CtIP, a nd MLSN1), and analyzed frameshift mutations in them. Here we report that 6 0% (3 out of 5) of human colorectal cancer cell lines exhibiting a high fre quency of MSI (MSI-H) and 46% (6 out of 13) of MSI-H primary colorectal tum ors had mutations in the (A)9 repeat of RAD50 recombinational repair gene. In contrast, no frameshift mutations were found in any of the 5 MSI-negativ e colorectal cancer cell lines, 8 colorectal tumors exhibiting a low freque ncy of MSI (MSI-L), or 28 MSI-negative colorectal tumors. No mutations were found in the mononucleotide repeats of 6 other genes, even in MSI-H cancer s. These results suggest that RAD50 frameshift mutations may play a role in the tumorigenesis of MSI-H colorectal cancers.