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, de pending on the number of mutated markers and the amount of allelic shifts. Forty-two colorectal tumors, previously found to have high-degree MSI at di nucleotidic repeat loci, were revisited with BAT26, a mononucleotide marker , and the number of shifted bases were counted. Seven tumors, all with loca l stages at diagnosis, had less than or equal to 6-bp deletions and consist ently displayed shorter shifts also with other intronic mononucleotide mark ers. 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 tha n 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 m utations, while MSH3, MSH6, and BAX were less frequently altered in tumors with short shifts. Our findings suggest that microsatellite instability ari ses gradually, evenly involving loci with similar features of length and re petition. 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 a re frequently associated with big size shifts and tumors with more advanced stages. (C) 2000 Wiley-Liss, Inc.