| Objective:To examine the expression of CyclinA1 and ATPase family AAA domain containing2(ATAD2)in different gastric epithelial lesions,especially the clinical diagnostic value of their separate or combined expression in the differential diagnosis of high-grade intraepithelial neoplasia and well-differentiated gastric adenocarcinoma;Meanwhile,the relationship between their expression and clinicopathological characteristics,including survival of patients,were also investigated in advanced gastric adenocarcinoma patients.Methods:The tissue microarrays(TMA)consisted of 173 pairs advanced gastric adenocarcinoma tissues and corresponding non-neoplastic gastric tissues,30 low-grade intraepithelial neoplasia,30 high-grade intraepithelial neoplasia,27 well-differentiated gastric adenocarcinoma obtained from endoscopic submucosal dissection(ESD)or endoscopic mucosal resection(EMR),and 16 well-differentiated gastric adenocarcinoma biopsy specimens confirmed by surgical specimens were detected by immunohistochemical method respectively.The expression levels of CyclinA1 and ATAD2 in these cases were observed and the expressive difference of both in different gastric epithelial lesions were analyzed.The receiver operating characteristic curve was used to analyze the clinical value in the differential diagnosis of high-grade intraepithelial neoplasia and well differentiated gastric adenocarcinoma.Meanwhile,in 173 cases advanced gastric adenocarcinoma patients,the chi-squared test was performed to analyze the correlation between CyclinA1 and ATAD2 expression and clinicopathological parameters,the Kaplan-Meier method was used for survival curve,survival data were evaluated by using univariate and multivariate Cox regression analyses,the correlation between the expression of CyclinA1 and ATAD2 was analyzed using Spearman method.SPSS 23.0 software and Med Calc 19.0 software were used to analyze the data.Results:1.The average expressive level of CyclinA1 in non-neoplastic gastric tissue,lowgrade intraepithelial neoplasia,high-grade intraepithelial neoplasia and gastric adenocarcinoma(mucosal exfoliation and TMA specimens)was 0.532±1.627%,2.370±2.942%,14.000±8.137%,47.790±25.089% respectively,and it of ATAD2 in the above lesions was 0.197±0.797%,1.770±2.208%,7.070±5.681% and 20.675±19.123%respectively.The differences were statistically significant(both P < 0.001).There were statistically significant differences in low-grade intraepithelial neoplasia and high-grade intraepithelial neoplasia,as well as high-grade intraepithelial neoplasia and gastric adenocarcinoma(mucosal exfoliation and TMA specimens)tissues(all P < 0.05),while there were no statistically significant differences both between non-neoplastic gastric tissues and low-grade intraepithelial neoplasia tissues(P = 0.434,P = 0.259).2.The average expressive level of CyclinA1 in high-grade intraepithelial neoplasia,well-differentiated gastric adenocarcinoma(mucosal exfoliation specimens)and welldifferentiated gastric adenocarcinoma(biopsy specimens)was 14.000±8.137%,45.741±27.759%,49.688±16.680% respectively,and it of ATAD2 in the above lesions was7.070±5.681%,20.740±16.954%,21.250±11.328% respectively.The difference was statistically significant(both P < 0.001).There was statistically significant difference between high-grade intraepithelial neoplasia and well-differentiated gastric adenocarcinoma(mucosal exfoliation specimens),as well as between high-grade intraepithelial neoplasia and well-differentiated gastric adenocarcinoma(biopsy specimens)(all P < 0.01),while there was no statistically significant difference between mucosal exfoliation specimens and biopsy specimens in well-differentiated gastric adenocarcinoma(both P > 0.05).3.30 high-grade intraepithelial neoplasia and 27 well-differentiated gastric adenocarcinoma(mucosal exfoliation specimens)were chosen,the ROC curve of CyclinA1 and ATAD2 alone or combined was drawn,and the area under curve(AUC)was calculated.When the cut-off value of CyclinA1 expressive level was 20%,the maximal Youden index was 0.570,the AUC was 0.847,the sensitivity and the specificity were 70.370% and 86.670%to distinguish high-grade intraepithelial neoplasia from well-differentiated gastric adenocarcinoma respectively.That was,when the expressive level of CyclinA1 was above20%,it suggested that the lesion might be well-differentiated gastric adenocarcinoma.When the cut-off value of ATAD2 was 10%,the maximal Youden index was 0.419,the AUC was 0.760,the sensitivity and the specificity were 51.850% and 90.000% respectively.In other words,when the expressive level of ATAD2 was above 10%,it suggested that the lesion might be well-differentiated gastric adenocarcinoma.The sensitivity and the specificity of the joint detection to distinguish high-grade intraepithelial neoplasia from well-differentiated gastric adenocarcinoma were 88.890% and 90.000%,and the AUC was0.942.There was no significant difference in the diagnostic value of CyclinA1 and ATAD2(P = 0.332),and the diagnostic value of the joint detection was better than that of single detection of CyclinA1(P = 0.039)or ATAD2(P = 0.001).4.In 173 advanced gastric adenocarcinoma patients,the expression of CyclinA1 was higher in patient with poorly differentiation(P = 0.022),≥ 5cm tumor(P = 0.019),vascular invasion(P = 0.006),lymph node metastasis(P = 0.014)and clinical stage Ⅲ-Ⅳ(P =0.010).ATAD2 was also highly expressed in patient with poorly differentiation(P = 0.024),≥ 5cm tumor(P = 0.033)and clinical stage Ⅲ-Ⅳ(P = 0.026).There was a significant positive correlation between the expression of CyclinA1 and ATAD2 in the advanced gastric adenocarcinoma by Spearman correlation analysis(P < 0.001).5.The overall survival(OS)and disease-free survival(DFS)of both CyclinA1 and ATAD2 high expression were shorter than those of both protein low expression simultaneously,and the difference was statistically significant(P < 0.05).The expression both of CyclinA1 and ATAD2,vascular invasion and clinical stage were independent prognostic factors of OS and DFS in advanced gastric adenocarcinoma patients by cox regression analysis(all P < 0.05).Conclusion:CyclinA1 and ATAD2 may play important roles in the occurrence and development of gastric adenocarcinoma.The combined detection of the two may reveal some hints and provide certain reference values in identification of high-grade intraepithelial neoplasia and well-differentiated gastric adenocarcinoma.The expression of CyclinA1 and ATAD2 is independent prognostic factors for advanced gastric adenocarcinoma patients,which may suggest that both of the two can be used as important prognostic indicators,and may become potential targets of molecular targeted therapy. |
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