Mutations at coding mononucleotide repeats in gastric cancer with the microsatellite mutator phenotype

We analysed 50 gastric carcinomas (GCs) to verify whether mutations at coding repeats were associated with microsatellite instability (MSI), The tumors included: ten cases with no MSI, 14 cases with MSI=1 locus, 13 cases with MSI=two loci and 13 cases with MSI greater than or equal to 3 loci, We investigated coding repeats within the TGF-beta RII, IGFIIR, BAX, hMSH6, AMSH3 and BRCA2 genes. The TGF-beta RII, IGIIR, BAX, hMSH6 and hMSH3 repeats were altered in 11 (22%), five (10%), four (8%), 16 (32%) and five (10%) cases respectively. Mutations occurred only in MSI-positive (MSI+) tumors and correlated with increasing MSI levels. No alterations of the BRCA2 repeat were found. Mutations in genes other than hMSH6 were strongly associated to kMSH6 mutations, suggesting a key role of this gene. The non-coding BAT-26 and E-Cadherin 3' UTR poly(A)8/(T)15 repeats were analysed in 44 of the 50 cases. Novel tumor-associated alleles were observed only in MSI-positive GCs and were in most cases associated with mutations at coding repeats. Further investigations with BAT-40 confirmed that four cases manifested mononucleotide repeat alterations restricted to hMSH6 and one case to TGF-beta XII. A subset of tumors,vith MSI at two or more dinucleotide loci resulted negative for mutations at coding and non-coding mononucleotide repeats