title: Cholangiocarcinoma in primary sclerosing cholangitis: K-ras mutations and Tp53 dysfunction are implicated in the neoplastic development.
abstract: OBJECTIVE
  Cholangiocarcinoma is a feared complication of primary sclerosing cholangitis (PSC). Neoplastic bile duct strictures may be difficult to differentiate cholangiographically from the non-neoplastic bile duct irregularities characteristic of this disorder, and the diagnosis of cholangiocarcinoma may be difficult to establish with certainty, even in tissue samples. Thus, new methods which can improve the diagnostic accuracy of cholangiocarcinoma in PSC are needed.
  
  
  METHODS
  We investigated the occurrence of K-ras codon 12 and 13 mutations, p53 protein accumulation, and Ki-67 expression in tumor tissue from PSC patients (n=33) who had developed cholangiocarcinoma, using bile duct specimens exised at liver transplantation of PSC patients without cholangiocarcinoma (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 substitutions in codon 12 were GGT-->GAT (n=5) and GGT-->TGT (n=3). None of the 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 samples. Sixteen (48%) tumors revealed either K-ras mutation or p53 accumulation. Ki-67 positivity was significantly higher in cholangiocarcinomas than in the non-neoplastic bile ducts (median 29% vs 12%, respectively; p=0.011).
  
  
  CONCLUSIONS
  We conclude that K-ras mutations and p53 dysfunction are implicated in tumorigenesis of cholangiocarcinomas arising in PSC patients and that these abnormalities together with increased Ki-67 index may indicate neoplastic progression of bile ducts in these patients.
authors.affiliation: Medical Department, Rikshospitalet, Oslo, Norway.
authors.forename: K M
authors.initials: KM
authors.lastname: Boberg
authors.forename: E
authors.initials: E
authors.lastname: Schrumpf
authors.forename: A
authors.initials: A
authors.lastname: Bergquist
authors.forename: U
authors.initials: U
authors.lastname: Broomé
authors.forename: A
authors.initials: A
authors.lastname: Pares
authors.forename: H
authors.initials: H
authors.lastname: Remotti
authors.forename: A
authors.initials: A
authors.lastname: Schjölberg
authors.forename: A
authors.initials: A
authors.lastname: Spurkland
authors.forename: O P
authors.initials: OP
authors.lastname: Clausen
mesh_terms: D000293:Adolescent; D000328:Adult; D001650:Bile Duct Neoplasms / Q000209:etiology* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D018281:Cholangiocarcinoma / Q000209:etiology* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D015209:Cholangitis, Sclerosing / Q000150:complications*; D018450:Disease Progression; D005260:Female; D011905:Genes, ras / Q000502:physiology*; D006801:Humans; D007150:Immunohistochemistry; D019394:Ki-67 Antigen / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000502:physiology; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism / Q000502:physiology
chemical_list: D019394:Ki-67 Antigen; D016159:Tumor Suppressor Protein p53