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AIM: To investigate the differences in biological features of gastric dysplasia (Dys), indefinite dysplasia (IDys) and reactive hyperplasia (RH) by studying the biomarker alterations in cell proliferation, cell differentiation, cell cycle control and the expression of house-keeping genes, and further to search for markers which could be used in guiding the pathological diagnosis of three lesions. METHODS: Expressions of MUC5AC, MUC6, adenomatous polyposis coli (APC), p53, Ki-67, proliferation cell nuclear antigen (PCNA) and EGFR were studied by immunohistochemistry with a standard Envision technique in formalinfixed and paraffin-embedded specimens from 43 RH, 35 IDys, 35 Dys and 36 intestinal type gastric carcinomas (IGC). In addition, Bayes discriminant analysis was used to investigate the value of markers studied in differential diagnosis of RH, IDys, Dys and IGC. RESULTS: The MUC5AC and MUC6 antigen expressions in RH, IDys, Dys and IGC decreased gradually (MUC5AC:86.04%, 77.14%, 28.57%, 6.67%; MUC6: 65.15%, 54.29%, 20.00%, 25.00%, respectively). The expressions of the two markers had no significant difference between RH and IDys, but were all significantly higher than those ofthe other two lesions (MUC5AC: x2 = 27.607, 38.027 and 17.33, 26.092; MUC6: x2= 16.54, 12.665 and 9.282, 6.737, P＜0.01). There was no significant differencebetween RH and IDys, Dys and IGC in MUC6 expression. The APC gene expression in the four lesions had a similar decreasing tendency (RH 69.76%, IDys 68.57%, Dys39.39%, IGC 22.86%), and it was significantly higher in the first two lesions than in the last two (x2 = 7.011,16.995 and 14.737, 19.817, P＜0.05). The p53 expressionin RH, IDys, Dys and IGC was 6.98%, 20%, 57.14% and 50%, respectively. There was no significant differencebetween RH and IDys or Dys and IGC, but the p53 expression in RH and IDys was significantly lower than that in Dys and IGC (x2 = 7.011, 16.995 and 14.737, 19.817, P＜0.01).The Ki-67 label index was significantly different among four lesions (RH: 0.298±8.92%, IDys: 0.358±9.25%,Dys: 0.498±9.03%, IGC: 0.620±10.8%, P＜0.001). Positive immunostaining of PCNA was though observed in all specimens, significant differences were detected among four lesions (F= 95.318, P＜0.01). In addition, we used Bayes discriminant analysis to investigate molecular pathological classification of the lesions, and obtained the best result with the combination of MUC5AC, Ki-67 and PCNA. The overall rate of correct classification was67.4% (RH), 68.6% (IDys), 70.6% (Dys) and 84.8% (IGC), respectively.CONCLUSION: Dys has neoplastic biological characteristics, while RH and IDys display hyperplastic characteristics. MUC5AC and proliferation-related biomarkers (Ki-67, PCNA) are more specific in distinguishing Dys from RH and IDys.