title: RNF43 mutation frequently occurs with GNAS mutation and mucin hypersecretion in intraductal papillary neoplasms of the bile duct.
abstract: OBJECTIVE
  RNF43 is a tumour suppressor gene that suppresses the Wnt-β-catenin signalling pathway. We investigated the role of RNF43 in intraductal papillary neoplasm of the bile duct (IPNB).
  
  
  RESULTS
  We conducted mutation analysis of RNF43 in 50 IPNBs, and identified six (12%) RNF43 mutations. RNF43 mutation was more frequent in the intestinal subtype of IPNB (17%) than in the gastric/pancreatobiliary subtype (5%). There was a strong association of RNF43 mutation with GNAS (P = 0.007) mutation, and a borderline correlation with KRAS (P = 0.074) mutation. The presence of macroscopic mucin hypersecretion was closely related to RNF43 (P = 0.024) and GNAS (P < 0.001) mutations. A two-step clustering analysis algorithm successfully categorized IPNBs into two subgroups by using the clinicopathological and molecular features of IPNBs. One subgroup of IPNB represented the 'biliary counterpart of intraductal papillary mucinous neoplasm of the pancreas' (biliary-IPMN), and showed unique features reminiscent of IPMN, such as macroscopic and microscopic mucin hypersecretion, an intestinal cell lineage, GNAS mutation, and RNF43 mutation. Biliary-IPMNs were significantly associated with high expression of cytokeratin (CK) 20, mucin 2 (MUC2), and CDX2, as shown by immunostaining (P = 0.032, P = 0.001, and P = 0.026, respectively), and had a borderline association with low expression of CK7 (P = 0.063). With the use of this splitting algorithm, RNF43 mutations were identified in 36% of the biliary-IPMNs.
  
  
  CONCLUSIONS
  The identification of RNF43 mutations in a distinct subset of IPNBs revealed a new molecular role in the pathogenesis of IPNB, and provided a potential application for cancer therapeutics by the use of Wnt pathway inhibitors.
authors.affiliation: Department of Pathology, National Taiwan University Hospital, Taipei, Taiwan.|Graduate Institute of Pathology, College of Medicine, Taipei, Taiwan.
authors.forename: Jia-Huei
authors.initials: JH
authors.lastname: Tsai
authors.affiliation: Department of Pathology, National Taiwan University Hospital, Taipei, Taiwan.|Graduate Institute of Pathology, College of Medicine, Taipei, Taiwan.
authors.forename: Jau-Yu
authors.initials: JY
authors.lastname: Liau
authors.affiliation: Department of Pathology, National Taiwan University Hospital, Taipei, Taiwan.
authors.forename: Chang-Tsu
authors.initials: CT
authors.lastname: Yuan
authors.affiliation: Department of Pathology, National Taiwan University Hospital, Taipei, Taiwan.
authors.forename: Mei-Ling
authors.initials: ML
authors.lastname: Cheng
authors.affiliation: Department of Surgery, National Taiwan University Hospital, Taipei, Taiwan.
authors.forename: Ray-Hwang
authors.initials: RH
authors.lastname: Yuan
authors.affiliation: Department of Pathology, National Taiwan University Hospital, Taipei, Taiwan.|Graduate Institute of Pathology, College of Medicine, Taipei, Taiwan.
authors.forename: Yung-Ming
authors.initials: YM
authors.lastname: Jeng
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000465:Algorithms; D001650:Bile Duct Neoplasms / Q000235:genetics* / Q000473:pathology; D044584:Carcinoma, Ductal / Q000235:genetics* / Q000473:pathology; D002291:Carcinoma, Papillary / Q000235:genetics* / Q000473:pathology; D002864:Chromogranins / Q000235:genetics*; D016000:Cluster Analysis; D004252:DNA Mutational Analysis; D004268:DNA-Binding Proteins / Q000235:genetics*; D005260:Female; D019205:GTP-Binding Protein alpha Subunits, Gs / Q000235:genetics*; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D008875:Middle Aged; D009077:Mucins / Q000378:metabolism; D009154:Mutation; D015513:Oncogene Proteins / Q000235:genetics*; D016133:Polymerase Chain Reaction; D044767:Ubiquitin-Protein Ligases
chemical_list: D002864:Chromogranins; D004268:DNA-Binding Proteins; D009077:Mucins; D015513:Oncogene Proteins; C496945:RNF43 protein, human; D044767:Ubiquitin-Protein Ligases; C406732:GNAS protein, human; D019205:GTP-Binding Protein alpha Subunits, Gs
keywords: GNAS; RNF43; intraductal papillary neoplasm of the bile duct; mucin hypersecretion