Microsatellite alterations in differentiated-type adenocarcinomas and precancerous lesions of the stomach with special reference to cellular phenotype

To elucidate the relationship between genetic alterations and cellular phen otype of differentiated-type adenocarcinomas and precancerous lesions of th e stomach, we phenotyped 61 gastric tumors consisting of 33 noninvasive les ions and 28 submucosal invasive carcinomas by histochemical and immunohisto chemical techniques, including analysis of mucin expression. We then analyz ed loss of heterozygosity (LOH) at tumor suppressor loci, examined microsat ellite instability (MSI), and compared the results according to cellular ph enotype. Of the 61 gastric rumors studied, 7% (4 of 61) were classified as tumors with a gastric foveolar epithelial phenotype (foveolar-type), 8% (5 of 61) as tumors with a complete-type intestinal metaplastic phenotype (CIM -type), and the remaining 85% (52 of 61) as tumors with an ordinary phenoty pe (ordinary-type). Forty-two percent (26 of 61) of the tumors showed LOH o n at least 1 chromosomal arm. Although LOH was rare in foveolar-type tumors , it was present at variable frequencies at each tumor suppressor loci in t umors with other cellular phenotypes. p53 overexpression was observed in 0% (0 of 4) of foveolar-type, 48% (25 of 52) of ordinary-type, and 80% (4 of 5) of CIM-type tumors. With regard to MSI, all (4 of 4) of the foveolar-typ e tumors were classified as having high-rate MSI (MSI-H), whereas all (5 of 5) of the CIM-type tumors were microsatellite stable (MSS). Of 52 ordinary -type tumors, 19% (10 of 52) were classified as MSI-H, 12% (6 of 52) as low -rate MSI (MSI-L), and 69% (36 of 52) as MSS. The incidence of MSI-H was fo und to be significantly higher in foveolar-type tumors (100%; 4 of 4) than in ordinary-type (19%; 10 of 52) or CIM-type tumors (0%; 0 of 5) (P < .01). An inverse correlation between MSI-H and p53 overexpression was also notic ed (P < .01). Results suggested that each cellular phenotype followed a dif ferent genetic pathway; foveolar-type tumors followed the "mutator" pathway , characterized by MSI, CIM-type tumors followed the "suppressor" pathway, characterized by LOH of tumor suppressor loci and p53 overexpression, and o rdinary-type tumors appeared to show mixed genetic alterations of both type s. Copyright (C) 2000 by W.B. Saunders Company.