K-ras gene mutations in intrahepatic bile duct tumors of Syrian golden hamsters

Abstract

Background and Objectives In our laboratory, we have developed a new model of carcinoma of the bile duct in Syrian golden hamsters, using N‐nitrosobis(2‐oxopropyl)amine (BOP). Morphologic and biologic characteristics of the carcinoma induced in this model are similar to those seen in humans. In order to examine the gene‐related carcinogenesis of intrahepatic bile duct carcinoma, we investigated mutations in the K‐ras gene in various early hyperplastic and neoplastic lesions of these hamsters, according to the original sites of the lesions. Methods Inbred female hamsters were given a subcutaneous injection of N‐nitrosobis(2‐oxopropyl)amine (BOP) following dissection of the extrahepatic bile duct on the distal end of the common duct and preparation of a cholecystoduodenostomy (CDDB) or simple laparotomy (SL). Neoplastic lesions arising from the intrahepatic bile duct were histologically examined, and K‐ras mutations were investigated. Results Mutations of K‐ras codon 12 were evident in 12% of tubular hyperplasias, 19% of tubular adenocarcinomas, 15% of papillary hyperplasias and 36% of papillary adenocarcinomas. In papillary adenocarcinoma arising from a large bile duct, K‐ras mutations occurred more frequently than in tubular adenocarcinoma arising from ductule or ductular proliferation. K‐ras mutations were present even in a hyperplasia; the positive rates of the mutations increased in the presence of a carcinoma. Genetic changes in carcinoma of the intrahepatic bile duct varied based on sites of the duct and the histological type. Conclusions A part of the hyperplastic lesions of the intrahepatic bile duct presented K‐ras gene mutation. This suggests that K‐ras gene mutation is an early event in the carcinogenic process. In carcinoma of the intrahepatic bile duct, the lesion arising from a large bile duct of the hepatic hilum tended to exhibit a higher frequency of K‐ras gene mutation than did a tubular lesion arising from ductule or ductal proliferation. This hamster model is useful to examine the carcinogenesis of human intrahepatic bile duct carcinoma. J. Surg. Oncol. 1997;66:97–103. © 1997 Wiley‐Liss, Inc.

Sulindac Prevents Carcinogen-Induced Intrahepatic Cholangiocarcinoma Formation In Vivo

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An intraductal papillary component is associated with prolonged survival after hepatic resection for intrahepatic cholangiocarcinoma

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