Accumulated frameshift mutations at coding nucleotide repeats during the progression of gastric carcinoma with microsatellite instability

Microsatellite instability (MSI) and frameshift mutations in genes containi ng nucleotide repeats have been reported in a subset of gastric carcinomas, but the mutational profiles in precancerous lesions have not been characte rized. To characterize the genetic events during gastric carcinogenesis, we analyzed DNA from 56 gastric adenomas and 167 gastric carcinomas for MSI u sing five microsatellite markers and for frameshift mutations at coding nuc leotide repeats of the type II transforming growth factor beta receptor, BA X, hMSH3, hMSH6, IGF II receptor, and E2F-4 genes. On the basis of the numb er of markers displaying instability per tumor, the tumors were divided int o three groups: those with two or more of the five markers showing instabil ity (high MSI [MSI-H]), those with one of the five markers showing instabil ity (low MSI [MSI-L]), and those with no instability. MSI-H was found in 8 adenomas (14%) and 19 carcinomas (11%), and MSI-L was found in 8 adenomas ( 14%) and 9 carcinomas (5%). These groups were tested for correlations with several clinicopathologic parameters. MSI-H gastric adenomas were related t o the high histologic grade of composing dysplastic glands (rho = 0.004), a nd MSI-H gastric carcinomas were associated with exophytic tumor growth (rh o = 0.005). We found 48 frameshift mutations at coding nucleotide repeats o f the six genes, and all mutations except one were found in MSI-H gastric t umors. Only one of the 17 MSI-L tumors showed frameshift mutations at codin g nucleotide repeats of the transforming growth factor beta receptor II gen e. Compared with MSI-H gastric carcinomas, MSI-H adenomas had no mutations in the hMSH6 and the IGF II receptor genes, less frequent mutations in the transforming growth factor beta receptor II (38% versus 63%), BAX (13% vers us 37%), and hMSH3 (13% versus 37%) genes, and more frequent mutations in t he E2F-4 (50% versus 37%) gene. Our findings suggest that MSI and E2F-4 mut ations are early genetic events and that mutations of the other five genes are accumulated during the progression of gastric carcinomas with MSI.