title: Alteration of the fragile histidine triad gene in intrahepatic cholangiocarcinoma.
abstract: OBJECTIVE
  Intrahepatic cholangiocarcinoma is the second most common intrahepatic neoplasm, accounting for 10-30% of primary liver cancers. Since little is known about the development of this cancer, we searched for alterations to the fragile histidine triad (FHIT) gene, a putative tumour suppressor gene on chromosome 3p14.2. In addition, we investigated oncogenic mutations in beta-catenin, which lead to an activated Wnt signalling pathway and microsatellite instability as a consequence of mismatch repair deficiency.
  
  
  RESULTS
  Loss of heterozygosity at the FHIT/FRA3B locus was detected in two out of ten informative cases (20%) using the marker D3S1300 and in one out of seven informative cases (14%) by marker D3S1234. Furthermore, immunohistochemistry revealed loss of Fhit expression in most of the 19 intrahepatic cholangiocarcinomas analysed, although to varying degrees. Oncogenic mutations were excluded in exon 3 of the beta-catenin gene by restriction enzyme digest and DNA sequence analysis. Microsatellite instability could not be detected in the tumour specimens tested using a validated marker panel. In two out of nine informative cases (22%), loss of heterozygosity was displayed close to the adenomatous polyposis coli (APC) gene.
  
  
  CONCLUSIONS
  Alterations to FHIT/FRA3B were initially detected by allelic losses of genomic DNA in intervening sequences of this tumour suppressor gene. Immunohistochemistry extended this initial observation by demonstrating that seven of the 19 intrahepatic cholangiocarcinomas had entirely lost expression of FHIT. Loss of Fhit protein in only a subpopulation of tumour cells due to oligoclonality may explain the varying portions of negative staining observed in the other tumour samples. Microsatellite instability did not appear to contribute to the development of intrahepatic cholangiocarcinoma in the cohort of tumours we analysed. Furthermore, the Wnt pathway may be constitutively turned on by inactivation of the APC gene due to deletion of genomic DNA but not by oncogenic mutations within exon 3 of the beta-catenin gene.
authors.affiliation: Klinik und Poliklinik f. Innere Medizin I, Sektion Mol. Gast. Onkologie, Martin-Luther-Universität Halle-Wittenberg, Halle, Germany.
authors.forename: Eileen
authors.initials: E
authors.lastname: Koch
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Fiedler
authors.forename: Andrea
authors.initials: A
authors.lastname: Tannapfel
authors.forename: Wolfgang G
authors.initials: WG
authors.lastname: Ballhausen
mesh_terms: D017766:Acid Anhydride Hydrolases; D001653:Bile Ducts, Intrahepatic / Q000502:physiology*; D018281:Cholangiocarcinoma / Q000235:genetics*; D015331:Cohort Studies; D003598:Cytoskeletal Proteins / Q000235:genetics; D004273:DNA, Neoplasm / Q000032:analysis; D005091:Exons / Q000235:genetics; D016147:Genes, Tumor Suppressor / Q000502:physiology*; D005819:Genetic Markers / Q000235:genetics; D006801:Humans; D007150:Immunohistochemistry / Q000379:methods; D019656:Loss of Heterozygosity / Q000235:genetics; D018895:Microsatellite Repeats / Q000235:genetics; D009154:Mutation / Q000235:genetics; D009363:Neoplasm Proteins / Q000235:genetics*; D015534:Trans-Activators / Q000235:genetics; D051176:beta Catenin; D000099170:Bis(5'-adenosyl)triphosphatase
chemical_list: D017766:Acid Anhydride Hydrolases; D003598:Cytoskeletal Proteins; D004273:DNA, Neoplasm; D005819:Genetic Markers; D009363:Neoplasm Proteins; D015534:Trans-Activators; D051176:beta Catenin; D000099170:Bis(5'-adenosyl)triphosphatase; C495270:CTNNB1 protein, human