K-raj Mutation is an Early Event in Pancreatic Duct Carcinogenesis in the Syrian Golden Hamster1

K-ra.v oncogene mutation has been shown to be a frequent event in pancreatic ductal adenocarcinomas induced by the carcinogen V-nitroso-bis(2-oxopropyl)amine in the hamster. The present study exam ines the mutational status of the K-r«.v oncogene in lesions that precede the appearance of invasive ductal adenocarcinomas. Syrian golden ham sters (80-100 g) received 12 weekly doses of 15 mg/kg A'-nitroso-bis(2-oxopropyl)amine and were serially sacrificed at 8, 12, 14, 16, or 24 weeks following the initiation of treatment. Ten ¿im-thick sections of formalin-fixed paraffin-embedded pancreas were examined for hyperplasia, papillary hyperplasia, carcinoma in situ, and invasive and metastatic ductal carcinoma. Marked lesions of interest were scraped from the slide, subjected to polymerase chain reaction-mediated amplification of the first exon of the K-ras gene, and probed by oligonucleotidespecific hybridization for mutations at codon either 12 or 13. Of 186 samples assayed, K-ras codon 12 mutations were detected in 26% of hyperplasias, 46% of papillary hyperplasias, 76% of carcinoma in situ, 80% of adenocarcinomas, and 43% of lymph node métastases. Codon 12 mutations were exclusively G to A changes at the second position. Codon 13 mutations were only detected in 9 of 168 samples. These results suggest that K-ras activation is an early event in W-nitroso-bis(2-oxopropyl)amine-induced pancreatic carcinogenesis in the hamster.