Stepwise deletions of PolyA sequences in mismatch repair-deficient colorectal cancers

PolyA simple repeat sequence deletions are common in tumors with microsatel lite instability (MSI+). Such deletions occur one base at a time in DNA mis match repair (MMR)-deficient yeast suggesting larger deletions in human. MS I+ tumors represent multiple sequential stepwise losses, Sum total deletion s in four polyA repeats were variable (between -17 to -45 bp) in 20 sporadi c MSI+ colorectal cancers, progressive but less extensive total deletions ( maximum of -12 bp) occurred in similar polyA sequences in MMR-deficient mic e (mlh1-/-) up to 478 days old. PolyA repeat lengths were relatively stable but already shortened in the MMR-deficient cell Line HCT116. A transgene w ith 26 A's transfected into HCT116 shortened an average of 3.8 bases pairs after 469 days in culture, less than average deletions of BAT25 (-5.3) or B AT26 (-9.0) in MSI+ cancers. These findings further suggest that extensive polyA deletions common in MSI+ tumors likely reflect multiple stepwise smal ler deletions that accumulate more than hundreds of divisions after loss of MMR.