Clinicopathological significance of abnormalities in Gadd45 expression and its relationship to p53 in human pancreatic cancer.

PURPOSE The growth arrest and DNA damage-inducible 45 gene (GADD45a) is one of the downstream mediators of the p53 gene that stimulates DNA excision repair. The present study was designed to assess the clinicopathological significance of GADD45a and p53 in resectable invasive ductal carcinomas (IDCs) of the pancreas. EXPERIMENTAL DESIGN This study included 72 pancreatic IDC patients who received surgery between 1982 and 2001. Point mutations in exons 1 and 4 of GADD45a and the expression of the GADD45a gene product (Gadd45) and p53 protein were analyzed by direct DNA sequencing and immunohistochemistry. RESULTS Point mutations were found in exon 4 of GADD45a in eight cases (13.6%). Gadd45 and p53 were expressed in 54.2% (39 of 72) and 47.2% (34 of 72) of the patients. The expression of Gadd45 did not necessarily correlate with that of p53. However, Gadd45 expression correlated significantly with the grade of the pT factor of the tumors. Coexpression analysis of Gadd45 and p53 indicated that in patients with p53(+) IDC, the Gadd45(+) group had a significantly lower survival rate than the Gadd45(-) group. Furthermore, Gadd45 expression had no effect on the efficacy of the adjuvant chemotherapy. Multivariate analysis indicated that pTNM (tumor-node-metastasis) stage, grade, and adjuvant chemotherapy were significant variables for survival. Furthermore, in the p53(-) group, there were no significant variables. In contrast, in the p53(+) group, pTNM stage, histological grade, and Gadd45 expression were significant variables. CONCLUSIONS The frequency of GADD45a mutation is appreciable in human pancreatic IDC, and the expression of Gadd45, combined with that of p53, significantly affects the survival of patients with resectable IDCs of the pancreas.