Relationship between K-ras mutation and the expression of p21WAF1/CIP1 and p53 in chronic pancreatitis and pancreatic adenocarcinoma

Abstract

Overexpression of p21WAF1/CIP1 was recently described as an early event in the development of pancreatic intraepithelial neoplasia. Since activating K-ras mutations are described in more than 80% of pancreatic cancers and are known to increase intracellular levels of p21WAF1/CIP1 in experimental models, the possible role of activating K-ras mutations in an induction of the p21WAF1/CIP1 expression was investigated in our study. We examined 71 surgical specimens, 29 of chronic pancreatitis and 42 of invasive ductal adenocarcinoma both having a large spectrum of PanIN (pancreatic intraepithelial neoplasia) lesions. Expression of p53 and p21WAF1/CIP1 was examined immunohistochemically and codon 12 K-ras mutational analysis was performed using the very sensitive mutant-enriched PCR-RFLP (polymerase chain reaction-restriction fragment length polymorphism) analysis. Our study demonstrated the overexpression of p21WAF1/CIP1 as an early event in the development of pancreatic intraepithelial neoplasia in the group of chronic pancreatitis and invasive adenocarcinoma as well. Overexpression of p21WAF1/CIP1 increased progressively from normal ducts through the spectrum of PanIN lesions to invasive carcinomas. The p53 overexpression increased again progressively according to the severity of the lesion and seems to be a later event in the development of pancreatic intraepithelial neoplasia if compared to p21WAF1/CIP1 expression. Our results confirmed also the possible p53 independent p21WAF1/CIP1 expression in some PanIN2, PanIN3 lesions and invasive carcinomas. K-ras mutations were not revealed in samples with only low grade PanIN lesions (PanIN1a and PanIN1b). K-ras mutations were detected in 69,4% adenocarcinomas and in only one case of chronic pancreatitis. Two codon 12 K-ras positive pancreatic carcinomas showed K-ras mutations in the surrounding normal pancreatic tissue. In adenocarcinomas, no statistically significant correlation was found between K-ras mutational status and p21WAF1/CIP1 and p53 expression, respectively. The possible role of activating K-ras mutations in an induction of p21WAF1/CIP1 expression was not confirmed in this study.