AIM: To clarify the relations between tumor differentiation phenotype and tumor invasion or geneticalterations in gastric differentiated-type tumors.METHODS: We examined the tumor differentiation phenotype, the presence of mutations in APC and p53,and the microsatellite instability (MSI) status in 48 gastric adenomas and 171 differentiated-type carcinomas.The tumor differentiation phenotype was determined by examining the expression of human gastric mucin (HGM), MUC6, MUC2 and CD10. The tumors were then classified into gastric- (G-), gastric and intestinal mixed(GI-), or intestinal- (I-) phenotypes, according to the immunopositivity of the above markers. The presence of mutations in APC and p53 and the MSI status were also investigated in all the tumors.RESULTS: Gastric adenomas were significantly associated with CD10 expression, I-phenotype tumors and the presence of APC mutations, compared with carcinomas (66.7％ vs 25.1％, P ＜ 0.0001; 56.3％ vs 14.6％, P ＜0.0001; 39.6％ vs 14.0％, P ＜ 0.0001, respectively) and inversely associated with expressions of HGM and MUC6 and the presence of p53 mutations (10.4％ vs 62.6％,P ＜ 0.0001; 39.6％ vs 64.3％, P = 0.003; 2.0％ vs 26.3％, P = 0.001, respectively). The frequency of APC mutations was significantly higher in HGM-negative tumors, MUC6-negative tumors, CD10-positive tumors and I-phenotype tumors than in HGM-positive tumors, MUC6-positive tumors, CD10-negative tumors and G-phenotyp etumors (32.7％ vs 7.1％, P ＜ 0.0001; 27.8％ vs 14.0％, P = 0.0182; 37.3％ vs 10.4％, P ＜ 0.0001; and 38.5％ vs 9.5％, P = 0.0017, respectively). The frequency of MSI was significantly higher in MUC6-positive tumors, CD10-negative tumors and G-phenotype tumors than in MUC6-negative tumors, CD10-positive tumors and I-phenotype tumors (24.8％ vs 6.7％, P = 0.0009; 22.2％ vs 8.0％,P = 0.0143; and 28.6％ vs 9.6％, P = 0.0353, respectively).CONCLUSION: The tumor differentiation phenotype is closely related to tumor invasion and genetic alterations in gastric differentiated-type tumors.