P16 AND K-RAS GENE-MUTATIONS IN THE INTRADUCTAL PRECURSORS OF HUMAN PANCREATIC ADENOCARCINOMA

Pancreatic adenocarcinoma is thought to arise from a noninvasive neopl astic precursor, the pancreatic intraductal lesion (PIL), Mutations of the K-ras gene are known to occur in PILs, but their high prevalence among Fns within the general population probably limit the use of K-ra s as a marker of eventual clinical risk. In search of genetic constell ations that might indicate the progression of some PILs toward an inva sive phenotype, mutations at both the It-ms and p16 genes were sought within Pns of 10 pancreata resected for adenocarcinoma, K-ins mutation s were present in most Pns and in nearly all Pns having nuclear atypia . In half of the patients, two or more unique K-ras mutations were ide ntified among distinct. Pns, which is evidence for the separate clonal evolution of multiple pancreatic neoplasms within individual patients , pld alterations (one homozygous deletion and three point mutations) were found in 4 of the 10 carcinomas; these four pancreata harbored p1 6 alterations in three of nine PILs, of which one was a ''histological ly early'' lesion. ,Two patients had p16 alterations in PILs matching those of the associated carcinomas. p16 mutations were not found in PI Ls of pancreata having wild-type p16 in the carcinoma, nor were they F ound in ducts having normal histology. It is suggested that alteration s of the pld gene affect a subset of PILs that contain mutations of th e K-ras gene and that these mutations might identify high-risk precurs ors of the invasive malignancy.