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RNF 43 mutation frequently occurs with GNAS mutation and mucin hypersecretion in intraductal papillary neoplasms of the bile duct
Author(s) -
Tsai JiaHuei,
Liau JauYu,
Yuan ChangTsu,
Cheng MeiLing,
Yuan RayHwang,
Jeng YungMing
Publication year - 2017
Publication title -
histopathology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.626
H-Index - 124
eISSN - 1365-2559
pISSN - 0309-0167
DOI - 10.1111/his.13125
Subject(s) - gnas complex locus , mucin , cdx2 , intraductal papillary mucinous neoplasm , mutation , medicine , bile duct , cancer research , kras , pancreas , mutation testing , pathology , gastroenterology , biology , genetics , cancer , gene , colorectal cancer , gene expression , homeobox
Aims RNF 43 is a tumour suppressor gene that suppresses the Wnt–β‐catenin signalling pathway. We investigated the role of RNF 43 in intraductal papillary neoplasm of the bile duct ( IPNB ). Methods and results We conducted mutation analysis of RNF 43 in 50 IPNB s, and identified six (12%) RNF 43 mutations. RNF 43 mutation was more frequent in the intestinal subtype of IPNB (17%) than in the gastric/pancreatobiliary subtype (5%). There was a strong association of RNF 43 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 RNF 43 ( P = 0.024) and GNAS ( P < 0.001) mutations. A two‐step clustering analysis algorithm successfully categorized IPNB s into two subgroups by using the clinicopathological and molecular features of IPNB s. 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 RNF 43 mutation. Biliary‐ IPMN s were significantly associated with high expression of cytokeratin ( CK ) 20, mucin 2 (MUC2), and CDX 2, as shown by immunostaining ( P = 0.032, P = 0.001, and P = 0.026, respectively), and had a borderline association with low expression of CK 7 ( P = 0.063). With the use of this splitting algorithm, RNF 43 mutations were identified in 36% of the biliary‐ IPMN s. Conclusions The identification of RNF 43 mutations in a distinct subset of IPNB s 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.