RNF43 Mutation Frequently Occurs With GNAS Mutation and Mucin Hypersecretion in Intraductal Papillary Neoplasms of the Bile Duct.

RNF43 is a tumor suppressor gene that is frequently mutated in intraductal papillary mucinous neoplasms of the pancreas (IPMN). RNF43 suppresses the Wnt/β-catenin signaling pathway. We conducted mutation analysis of RNF43 in intraductal papillary neoplasms of the bile duct (IPNBs) and identified RNF43 mutation in 6 (12%) out of 50 IPNBs. RNF43 mutation was more frequent in the intestinal subtype of IPNB (17%) than in the gastric/pancreatobiliary subtype (5%). There were a strong association of RNF43 mutation with GNAS (P = .007) mutation and a borderline correlation with KRAS (P = .074) mutation. The presence of macroscopic mucin hypersecretion was closely related to RNF43 (P = .024) and GNAS mutation (P < .001). A two-step clustering analysis algorithm successfully categorized IPNBs into 2 subgroups by using the clinicopathological and molecular features of IPNBs. One subgroup of IPNB represented "the biliary counterpart of the pancreatic IPMN" (biliary-IPMN) and exhibited unique features reminiscent of IPMN, such as macroscopic and microscopic mucin hypersecretion, intestinal cell lineage, the presence of GNAS mutation, and RNF43 mutation. The biliary-IPMN significantly associated with high expression for CK20, MUC2, and CDX2 immunostains (P = .032, .001, and .026, respectively) with a borderline association with low expression for CK7 (P = .063). Using this splitting algorithm, RNF43 mutations were identified in 36% of the "biliary-IPMN". 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 using Wnt pathway inhibitors. This article is protected by copyright. All rights reserved.