MUTATOR PHENOTYPES IN HUMAN COLORECTAL-CARCINOMA CELL-LINES

Recent studies have revealed that tumors in patients with hereditary n onpolyposis colon cancer are associated with high frequency alteration s of microsatellite sequences. To investigate the mechanisms and conse quences of this form of genetic instability, we identified three color ectal carcinoma cell lines that express dinucleotide-repeat instabilit y like that found in hereditary nonpolyposis felon cancer tumors and s how increased rates of spontaneous mutation at selectable loci. Howeve r, the pattern of hypermutation in these cell lines differed significa ntly. In one line (HCT116), microsatellite mutations occurred at a rem arkably high rate (approximate to 10-2 mutations per cell per generati on), whereas this rate was considerably lower in the two other lines ( DLD-1 and HCT15). The rate of mutation at the locus encoding hypoxanth ine guanine phosphoribosyltransferase was substantially elevated (200- to 600-fold) in all three tumor cell lines, yet the types of mutation s arising differed. A specific frame-shift hotspot accounted for 24% o f hypoxanthine guanine phosphoribosyltransferase mutations in HCT116. The frequency of mutations at this site was reduced significantly in D LD-1 and HCT15 lines. These data suggest that the mutator phenotypes i n the colorectal carcinoma cell lines could be the consequence of muta tor genes affecting different repair or error-avoidance pathways.