K-RAS MUTATION IN FOCAL PROLIFERATIVE LESIONS OF HUMAN PANCREAS

The K-ras gene is mutated in greater than or equal to 75% of human pan creatic adenocarcinomas and in a number of hyperplastic ductal lesions from noncarcinoma patients, In this study, the incidence of K-ras mut ation was determined in a spectrum of focal proliferative pancreatic l esions to evaluate their preneoplastic significance, PCR-based mutatio n-enriched RFLP analysis was used to identify mutations in codon 12, I mmunostaining for Ki67 and p53 was also performed, Forty-seven % of in traductal nonpapillary hyperplasias (8 of 17) contained codon 12 mutat ions, as did 55% of adenomatoid hyperplasias (6 of 11). This rate incr eased to 61% in papillary hyperplasias (27 of 44) and to 78% when ther e was severe dysplasia (7 of 9), The fraction of cells staining for th e Ki67 proliferation marker showed a general correlation with the rate of K-ras mutation. Nuclear staining for p53 protein was seen only in two ductal lesions with severe dysplasia, No mutations were found in n ormal acinar tissue (n = 38), squamous metaplasia (n = 13), ductal com plexes (n = 8), or focal acinar cell dysplasia (n = 5), There seemed t o be a general correlation of proliferative potential with the presenc e of K-ras mutation in ductal lesions. However, because of the high pr evalence of lesions with K-ras mutations, we conclude that this mutati on alone cannot be taken as proof of significant risk for progression to carcinoma. Efforts to use the presence of K-ras mutations in DNA ha rvested from pancreatic juice or duodenal aspirates as an approach for diagnosis of occult pancreatic carcinoma seem vulnerable to a high fa lse-positive rate.