Mononucleotide Repeat Sequence Variability in Mismatch Repair-deficient Cancers 1

Mismatch repair-deficient cancers are characterized by widespread insertions and deletions in microsatellite sequences, including those comprised of mononucleotide repeats. Such alterations have been observed in relatively short mononucleotide tracts in several genes and often are interpreted to indicate that the affected genes normally act as tumor suppressors. To aid in the interpretation of such changes, we have systematically assessed their frequency within transcribed regions of the genome that are unlikely to play a tumorigenic role. The advent of the complete human genomic sequences of chromosome 22 allowed us to select 29 genes for this analysis, spaced at ;1-Mb intervals. Each of the selected genes had an (A) 8 or a (G)8 tract deep within intronic sequences that was not included in the processed transcript. Surprisingly, we found that there was substantial variation in the prevalence of mutations among these tracts. Some tracts were altered in<5% of the mismatch repair-deficient cancers studied, whereas other tracts were altered in nearly half of the cancers. In particular, (G)8 tracts were considerably more prone to mutation than (A)8 tracts, and the sequences or chromatin structures surrounding the mononucleotide tracts seemed to affect their mutability significantly.