title: KRAS and GNAS mutations and p53 overexpression in biliary intraepithelial neoplasia and intrahepatic cholangiocarcinomas.
abstract: BACKGROUND
  Similar to the pancreatic intraepithelial neoplasia (PanIN)-pancreatic carcinoma sequence model, intrahepatic cholangiocarcinoma (ICC) also reportedly follows a stepwise carcinogenesis process through the a precursor lesion: biliary intraepithelial neoplasia (BilIN). For this study, the authors investigated the status of v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS) and GNAS complex locus (GNAS) mutations and tumor protein 53 (p53) overexpression in the stepwise process of cholangiocarcinogenesis.
  
  
  METHODS
  Thirty patients with hepatolithiasis were surveyed, and their lesions were categorized as follows: non-neoplastic large bile duct (LBD) (n = 12), peribiliary gland (PBG) (n = 9), BilIN-1 (low-grade dysplasia; n = 12), BilIN-2 (high-grade dysplasia; n = 16), and BilIN-3 (noninvasive or in situ carcinoma; n = 10). KRAS mutation at codons 12 and 13 and GNAS mutations at codon 201 were analyzed using genomic DNA extracted from isolated lesions by laser capture microdissection [corrected]. Immunohistochemical expression of p53 also was evaluated in BilIN lesions, ICCs, and extrahepatic cholangiocarcinomas (ExCCs).
  
  
  RESULTS
  A prevalence of KRAS mutations was identified in patients with ICC (31.5%), BilIN-3 (30%), and BilIN-2 (43.8%) compared with BilIN-1 (25%). Furthermore, KRAS mutations were detected in LBD lesions (41.7%) and PBG lesions (44.4%), and these mutations were observed with greater frequency in patients who had BilIN with KRAS mutations. GNAS mutations were not identified in any of the ICCs or other lesions examined. The overexpression of p53 was not identified in BilIN lesions and was less frequent in ICCs (18.2%) compared with ExCCs (38.1%) and gallbladder carcinomas (61.5%).
  
  
  CONCLUSIONS
  KRAS mutations, which were present in approximately 33% of BilIN lesions, occurred as an early molecular event during the progression of BilIN to ICC, whereas p53 overexpression was identified as a late molecular event. Furthermore, the current results indicted that BilIN also may arise from LBD and PBG lesions in patients who have hepatolithiasis with KRAS mutations.
authors: Department of Human Pathology, Kanazawa University Graduate School of Medicine, Kanazawa, Japan.
authors: Maylee
authors: M
authors: Hsu
authors: Motoko
authors: M
authors: Sasaki
authors: Saya
authors: S
authors: Igarashi
authors: Yasunori
authors: Y
authors: Sato
authors: Yasuni
authors: Y
authors: Nakanuma
mesh_terms: D001483:Base Sequence; D001650:Bile Duct Neoplasms; D001653:Bile Ducts, Intrahepatic; D001661:Biliary Tract Neoplasms / Q000235:genetics*; D018281:Cholangiocarcinoma / Q000235:genetics*; D002864:Chromogranins; D017931:DNA Primers; D019205:GTP-Binding Protein alpha Subunits, Gs / Q000235:genetics*; D016158:Genes, p53; D011905:Genes, ras; D006801:Humans; D007150:Immunohistochemistry; D008113:Liver Neoplasms / Q000235:genetics*; D009154:Mutation; D016133:Polymerase Chain Reaction
chemical_list: D002864:Chromogranins; D017931:DNA Primers; C406732:GNAS protein, human; D019205:GTP-Binding Protein alpha Subunits, Gs