K-ras mutations and allelic loss at 5q and 18q in the development of human pancreatic cancers

Conclusion. Our findings have implications for early diagnosis and for the identification of patients at increased risk. Background. Invasive cancers of the pancreas frequently are preceded by and associated with a spectrum of preneoplastic changes. We investigated the presence of K-ras mutations and allelic loss at 5q and 18q loci in preneoplastic lesions associated with nine cases of invasive pancreatic ductal carcinomas. Methods. We precisely microdissected 115 loci of normal, preinvasive, and invasive loci from paraffin-embedded sections. Results. 1. K-ras mutations occur early in the pathogenesis of pancreatic adenocarcinoma. Mutations were identified in multiple preneoplastic foci associated with all six cases in which ras mutations were present in the corresponding invasive cancers, including nearly all foci of mucous cell and atypical hyperplasia, in some cases of papillary hyperplasia (40%), and in one example of morphologically normal epithelium. 2. Ras mutations in preneoplastic loci are widespread, occur distant from the invasive tumor, and may present multiple mutations. Two, and in one case three, different types of K-ras mutations were found in separate preneoplastic foci from three individual cases. 3. Evidence for a 'second hit' in the ras gene (i.e., loss of wild-type allele or amplication of the mutant allele) was present in some tumors and may be associated with the invasive process. 4. In contrast to ras mutations, limited data suggest that loss of heterozygosity (LOH) at 5q and 18q are relatively late events.