GNAS and KRAS Mutations are Common in Intraductal Papillary Neoplasms of the Bile Duct

Motoko Sasaki,Yasunori Sato,Yasuni Nakanuma,Takeo Nitta,Andreas-Claudius Hoffmann,Takashi Matsubara

doi:10.1371/journal.pone.0081706

Abstract

Intraductal papillary neoplasms of the bile duct (IPNB) shows favorable prognosis and is regarded as a biliary counterpart of intraductal papillary mucinous neoplasm (IPMN) of the pancreas. Although activating point mutations of GNAS at codon 201 have been detected in approximately two thirds of IPMNs of the pancreas, there have been few studies on GNAS mutations in IPNBs. This study investigates the status of GNAS and KRAS mutations and their association with clinicopathological factors in IPNBs. We examined the status of GNAS mutation at codon 201 and KRAS mutation at codon 12&13, degree of mucin production and immunohistochemical expressions of MUC mucin core proteins in 29 patients (M/F = 15/14) with IPNB in intrahepatic and perihilar bile ducts (perihilar IPNB) and 6 patients (M/F = 5/1) with IPNB in distal bile ducts (distal IPNB). GNAS mutations and KRAS mutations were detected in 50% and 46.2% of IPNBs, respectively. There was no significant correlation between the status of GNAS mutation and clinicopathological factors in IPNBs, whereas, the status of KRAS mutation was significantly inversely correlated with the degree of MUC2 expression in IPNBs (p<0.05). All IPNBs with GNAS mutation only showed high-mucin production. Degree of mucin production was significantly higher in perihilar IPNBs than distal IPNBs (p<0.05). MUC2 and MUC5AC expression was significantly higher in IPNBs with high-mucin production than those with low-mucin production (p<0.01 and p<0.05, respectively). In conclusions, this study firstly disclosed frequent GNAS mutations in IPNBs, similarly to IPMNs. This may suggest a common histopathogenesis of IPNBs and IPMNs. The status of KRAS mutations was inversely correlated to MUC2 expression and this may suggest heterogeneous properties of IPNBs. IPNBs with high-mucin production are characterized by perihilar location and high expression of MUC2 and MUC5AC, irrespective of the status of GNAS and KRAS mutations.

Highlights

Intraductal papillary neoplasm of the bile duct (IPNB) is characterized by dilated intrahepatic bile ducts filled with noninvasive papillary or villous biliary neoplasm covering delicate fibrovascular stalks [1]
Given frequent GNAS mutations in intraductal papillary mucinous neoplasm of the pancreas (IPMN), which are similar to IPNBs, we examined the status of GNAS and Kirsten rat sarcoma viral oncogene homolog (KRAS) mutations
The findings obtained in this study are summarized as follows: 1) GNAS mutations were detected in a half of IPNBs, irrespective of clinicopathological factors; 2) KRAS mutations were detected in about a half of IPNBs and the status of KRAS mutations was inversely correlated with the degree of MUC2 expression; 3) IPNBs with high-mucin production was characterized by perihilar location and high expression of MUC2 and MUC5AC. 4) All

Summary

Introduction

Intraductal papillary neoplasm of the bile duct (IPNB) is characterized by dilated intrahepatic bile ducts filled with noninvasive papillary or villous biliary neoplasm covering delicate fibrovascular stalks [1]. IPNB is regarded as a biliary counterpart of intraductal papillary mucinous neoplasm of the pancreas (IPMN) and shows favorable prognosis [1,2,3]. Some IPNBs show excessive mucin secretion and are described using the terms ‘‘mucin-producing bile duct tumor’’, ‘‘mucinhypersecreting bile duct tumor’’, or ‘‘IPNB with macroscopically mucin-producing biliary tumor’’[4,5,6]. This subset of IPNB is associated with hepatolithiasis [7] and has a tendency to show intestinal differentiation [4,7,8]

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Conclusion