EVIDENCE OF GENETIC PROGRESSION IN HUMAN GASTRIC CARCINOMAS WITH MICROSATELLITE INSTABILITY

Mutator phenotype tumors provide unique opportunities to unravel malig nant progression because of various gene alterations acquired during c lonal tumor evolution, Gastric carcinomas, which have been known to sh ow frequent genetic instability, would be composed of initial gene alt erations shared by most tumor areas and subsequent alterations restric ted to particular tumor sites, To analyse the timing of genetic events , we examined separate sites of tumor tissue obtained from a given gas tric carcinoma patient with microsatellite instability (MSI), Our stud y included 95 normal/tumor area pairs from 25 patients, Six of the 25 patients (24%) demonstrated various levels of MSI ranging from 7% (two of 30) to 97% (28 of 29) of markers tested in multiple tumor sites. O f the six patients, five manifested frameshift mutations in a tract of ten deoxyadenosines within transforming growth factor beta receptor t ype II and four demonstrated frameshift mutations in a tract of eight deoxyguanosines within BAX. These mutations were common to all tumor s ites regardless of the various level of MSI phenotype, indicating init ial events, Two of the six patients exhibited frameshift mutations in mononucleotide repeats of mismatch repair genes, hMSH3 and hMSH6, and the insulin-like growth factor II receptor in restricted tumor areas, indicating additional alterations. Insulin-like growth factor II recep tor mutations appear to be caused by hMSH3 and hMSH6 mutations because the former mutations were confined to tumor portions with the latter two mismatch repair lesions, These results provide genetic progression evidence for gastric carcinomas of the mutator pathway, In this pathw ay, mismatch repair insufficiency initially targets mononucleotide tra cts of transforming growth factor beta receptor type II and BAX. Durin g tumorigenesis, primary mismatch repair failure may give rise to the secondary mismatch repair lesions, frameshift mutations of hMSH3 and h MSH6, which result in another tumorigenic mutation in the insulin-like growth factor II receptor.