MISMATCH REPAIR GENES AND MONONUCLEOTIDE TRACTS AS MUTATION TARGETS IN COLORECTAL TUMORS WITH DIFFERENT DEGREES OF MICROSATELLITE INSTABILITY

Microsatellite instability occurs in 15% of colorectal carcinomas and may be due to replication errors (RER). The pattern of instability - ' severe' vs 'mild' - and the tumorigenic pathway, as reflected by the i nvolvement of functionally important genes, may vary according to the underlying gene(s), We defined 'mild' RER as mono- or tetranucleotide repeat instability in the absence of widespread instability at dinucle otide repeats and studied 15 colorectal tumors with this phenotype for mutations in the DNA mismatch repair genes MSH2, MLH1, MSH3, and MSH6 . No mutations were found, suggesting that these genes were not implic ated. We then compared colorectal cancers with 'mild' RER (n = 15), an d those with 'severe' RER without (n = 11) or with (n = 22) detectable mutations in MSH2 or MLH1 to assess the involvement of mononucleotide repeats contained in the coding regions of MSH3, MSH6, BAX, and TGF b eta RII, The combined mutation rates of the above mentioned loci varie d significantly between the three groups of tumors, being 0%, 25% and 52%, respectively. Furthermore, the individual genes showed specific p atterns of involvement; for example, among tumors with 'severe' RER, T GF beta RII displayed uniformly high mutation rates while MSH3, MSH6, and BAX were more frequently altered in tumors that also showed MSH2 o r MLH1 mutations. Our findings suggest that different subcategories ex ist among unstable tumors, defined by the RER pattern on the one hand and tumorigenic pathway on the other, and structural changes of MSH2 a nd MLH1 are likely to explain only a proportion of these cases.