Jia-Huei Tsai1,2, Jau-Yu Liau1,2, Chang-Tsu Yuan1, Mei-Ling Cheng1, Ray-Hwang Yuan3, Yung-Ming Jeng1,2. 1. Department of Pathology, National Taiwan University Hospital, Taipei, Taiwan. 2. Graduate Institute of Pathology, College of Medicine, Taipei, Taiwan. 3. Department of Surgery, National Taiwan University Hospital, Taipei, Taiwan.
Abstract
AIMS: 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). METHODS AND 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.
AIMS: 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). METHODS AND 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.