DETECTION OF K-RAS MUTATIONS IN MUCINOUS PANCREATIC DUCT HYPERPLASIA FROM A PATIENT WITH A FAMILY HISTORY OF PANCREATIC-CARCINOMA

Mutations in the K-ras oncogene and in the p53 tumor suppressor gene a re commonly identified in sporadic cases of pancreatic adenocarcinoma. Although these genes might serve as useful markers for early diagnosi s of pancreatic carcinoma inpatients at risk for the development of th is disease, familial pancreatic carcinomas have not been studied for t hese mutations. We recently had the opportunity to examine a pancreas prophylactically removed from a patient with a strong family history o f pancreatic carcinoma. This gave us the unique opportunity to study t he early events ia the development of familial adenocarcinoma of the p ancreas. Histopathological examination of the pancreas revealed multif ocal papillary and nonpapillary mucinous duct hyperplasia. Seven of th ese foci were microdissected and analyzed for K-ras and p53 mutations. The K-ras mutations were detected by combined mutant-enriched polymer ase chain reaction-restriction fragment length polymorphism analysis a nd characterized further by allele-specific oligonucleotide hybridizat ion. Five of the seven duct lesions harbored activating point mutation s in codon 12 of K-ras; a G to A transition was found in four and a G to C transversion in one. Is contrast, these lesions did not harbor de tectable p53 mutations as determined by denaturing gradient gel electr ophoresis of exons 5 to 8, nor was there overexpression of the p53 pro tein as determined by immunohistochemistry. These findings suggest tha t mutations in K-ras represent an early event in the pathogenesis of p ancreatic carcinoma. In addition, monitoring of patients with a strong family history of pancreatic carcinoma for K-ras mutations may identi fy patients at risk for the development of invasive carcinoma.