Cholangiocarcinoma in primary sclerosing cholangitis: K-ras mutations and Tp53 dysfunction are implicated in the neoplastic development

Background/Aim Cholangiocarcinoma is a feared complication of primary scler osing cholangitis (PSC), Neoplastic bile duct strictures may be difficult t o differentiate cholangiographically from the non-neoplastic bile duct irre gularities characteristic of this disorder, and the diagnosis of cholangioc arcinoma may be difficult to establish with certainty, even in tissue sampl es, Thus, new methods which can improve the diagnostic accuracy of cholangi ocarcinoma in PSC are needed. Methods: We investigated the occurrence of IC-Mcs codon 12 and 13 mutations , p53 protein accumulation, and Ki-67 expression in tumor tissue from PSC p atients (n=33) who had developed cholangiocarcinoma, using bile duct specim ens exised at Liver transplantation of PSC patients without cholangiocarcin oma (n=15) as controls, Results: K-ras mutations were present in 11 (33%) of the cholangiocarcinoma samples and significantly more frequent in females, Nine tumors carried a codon 12 mutation, and 2 had a codon 13 mutation, The most frequent substit utions in codon 12 were GGT --> GAT (n=5) and GGT --> TGT (n=3). None of th e control bile ducts had K-ras mutations. p53 protein was accumulated in 10 (31%) of the tumors, as opposed to negative findings in all the control sa mples, Sixteen (48%) tumors revealed either K-ras mutation or p53 accumulat ion, Ki-67 positivity was significantly higher in cholangiocarcinomas than in the non-neoplastic bile duets (median 29% vs 12%, respectively; p=0.011) . Conclusion: We conclude that R-vas mutations and p53 dysfunction are implic ated in tumorigenesis of cholangiocarcinomas arising in PSC patients and th at these abnormalities together with increased Ki-67 index may indicate neo plastic progression of bile ducts in these patients.