Frameshift Mutations at Mononucleotide Repeats inRAD50Recombinational DNA Repair Gene in Colorectal Cancers with Microsatellite Instability

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Abstract
To identify additional genes targeted for microsatellite instability (MSI), we search for human genes which contain mononucleotide repeats in their coding region, selected 7 genes (RAD50, DNA‐PKcs, FLASH, Apaf‐1, XPG, CtIP, and MLSN1), and analyzed frameshift mutations in them. Here we report that 60% (3 out of 5) of human colorectal cancer cell lines exhibiting a high frequency of MSI (MSI‐H) and 46% (6 out of 13) of MSI‐H primary colorectal tumors 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‐negative colorectal cancer cell lines, 8 colorectal tumors exhibiting a low frequency 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 cancers. These results suggest that RAD50 frameshift mutations may play a role in the tumorigenesis of MSI‐H colorectal cancers.