Protein expression and genetic alterations of p53 and ras in intrahepatic cholangiocarcinoma

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Abstract
The significance of molecular and genetic alterations of p53 and ras in the development and progression as well as the histological differentiation of intrahepatic cholangiocarcinoma (ICC) was evaluated. We examined immunohistochemically ras p21 protein and p53-related products (p53 protein, WAF-1 and mdm-2) in 43 cases of ICC. In addition, point mutations of ras and p53 were examined genetically in selected ICC cases by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) and direct sequence analysis. Point mutation of K-ras gene codon 12 was detected in three of 14 cases and one of 15 cases by PCR-RFLP and direct sequence analysis, respectively. Immunoreactivity of ras p21 protein was not detected. Point mutation of p53 was detected in three of 15 cases. p53 protein was immunohistochemically detectable in 33 of 43 cases. Immunoreactivity of p53 was more frequent in well-differentiated and less frequent in poorly differentiated cases. Immunoreactivity of WAF-1 and mdm-2 was seen in 16 and eight of 43 cases, respectively. Both proteins were frequently detected in the cases positive for p53 protein. These results suggest that dysregulation of ras is involved in at least 20% of ICC and expression of p53 protein is more significantly involved in ICC, particularly in the well and moderately differentiated cases. While some cases of p53 expression may be explainable by point mutation of p53, there may be some epigenetic phenomena that stabilize p53 protein in ICC. That is, wild type p53 may be stabilized and then detectable by forming complexes with other molecules of p53 downstream effector genes, such as WAF-1 and mdm-2.