K-ras gene mutations and loss of heterozygosity at the p53 gene locus relative to histological characteristics of mucin-producing tumors of the pancreas

Mucin-producing tumors (MPTs) of the pancreas accompanied by carcinomas usu ally include various grades of dysplasia in the ductal epithelium, and inva sive areas are histologically similar to those of common invasive ductal ca rcinomas, suggesting that MPTs provide a good tool to investigate early sta ges of pancreatic carcinogenesis. Thus, to clarify genetic alterations in t he early stage of pancreatic carcinogenesis, we analyzed K-ras gene mutatio ns and loss of heterozygosity (LON) at the p53 gene locus using 37 cases of MPTs harboring dysplastic epithelium. Further, we conducted an extended, m ultifocal microdissection analysis focusing on the histological features of ductal epithelium and the distribution of genetic alterations for S cases of MPT positive for LOW of the p53 gene to determine the relation to tumor progression. K-ras gene mutations were detected with high frequency in 50% or more cases of the adenomas (14 of 19), borderline tumors (4 of 7), and c arcinomas (8 of 11), whereas LOH of the p53 gene was limited to carcinomas (S of 5 informative cases, 60%) and always accompanied by K-ras gene mutati on. Investigation of a total of 126 microdissection sites from 3 cases show ed the presence of K-ras gene mutations in mild dysplasia and all (100%) re gions of moderate or more marked dysplasia, whereas LOH of the p53 gene sho wed more gradual tendency to increase with grade from moderate dysplasia. I n addition, the multifocal genetic analysis showed K-ras gene mutations to be widely distributed throughout tumors, whereas LOH of the p53 gene was lo calized to I or a few areas. Further, topographically delimited areas with the same histology in the same tumor did not always show the same genetic a lteration. In conclusion, we could confirm that both the K-ras and P53 gene alterations occur in the intraductal stage of MPT, and the latter is super imposed on the former during the course of tumor progression. However, the pattern of association of histological features with genetic alteration dif fers from tumor to tumor. Copyright (C) 2000 by W.B. Saunders Company.