TP53 mutations and mdm2 protein overexpression in cholangiocarcinomas

Tumor suppressor protein p53 is a positive regulator of MDM2 gene expressio n and the mdm2 protein can bind to p53, pre venting the transactivation of p53 responsive genes, thus mimicking TP53 mutation. The authors looked for alterations that could affect. directly and indirectly, p53 function in 13 patients with extrahepatic cholangiocarcinoma. Molecular analysis by single strand conformation polymorphism and DNA sequencing revealed that TP53 gen e mutations occurred in only 2 of 13 cholangiocarcinomas. High levels of md m2 protein were found, by immunohistochemical staining, in 61% of the chola ngiocarcinomas and in almost all specimens (70%) displaying stabilized p53 protein in the absence and in the presence of TP53 mutations. The finding o f co-overexpressed mdm2 and p53 proteins in cholangiocarcinomas indicates t hat they can upregulate the expression of mdm2 protein to a level sufficien t for binding and accumulating p53 in a presumably inactive complexed form. The presence of TP53 mutations or upregulation of MDM2 gene expression in 9 of the 13 cholangiocarcinomas strongly supports that the impairment of th e p53 pathway is an important and specific step in cholangiocarcinoma patho genesis. At variance with other authors, no alteration of p16(ink4)/CDKN2 g ene was observed in all 13 cholangiocarcinomas.