Genomic instability and target gene mutations in colon cancers with different degrees of allelic shifts

Two grades (high and low) of microsatellite instability (MSI) are known, depending on the number of mutated markers and the amount of allelic shifts. Forty-two colorectal tumors, previously found to have high-degree MSI at dinucleotidic repeat loci, were revisited with BAT26, a mononucleotide marker, and the number of shifted bases were counted. Seven tumors, all with local stages at diagnosis, had less than or equal to 6-bp deletions and consistently displayed shorter shifts also with other intronic mononucleotide markers. Analysis of mononucleotide tracts in the coding regions of MSH3, MSH6, BAX, and TGF beta R11 in the groups with large (>6 bp) and short (less than or equal to 6 bp) allelic shifts showed specific patterns of involvement for the individual genes: TGF beta R11 displayed a uniformly high rate of mutations, while MSH3, MSH6, and BAX were less frequently altered in tumors with short shifts. Our findings suggest that microsatellite instability arises gradually, evenly involving loci with similar features of length and repetition. However, target genes have a specific timing of mutation in this process: TGF beta R11 is involved in the early phases, while BAX and MSH6 are frequently associated with big size shifts and tumors with more advanced stages. (C) 2000 Wiley-Liss, Inc.