Mutations in the K-ras oncogene and in the p53 tumor suppressor gene are 
commonly identified in sporadic cases of pancreatic adenocarcinoma. Although 
these genes might serve as useful markers for early diagnosis of pancreatic 
carcinoma in patients at risk for the development of this disease, familial 
pancreatic carcinomas have not been studied for these mutations. We recently had 
the opportunity to examine a pancreas prophylactically removed from a patient 
with a strong family history of pancreatic carcinoma. This gave us the unique 
opportunity to study the early events in the development of familial 
adenocarcinoma of the pancreas. Histopathological examination of the pancreas 
revealed multifocal papillary and nonpapillary mucinous duct hyperplasia. Seven 
of these foci were microdissected and analyzed for K-ras and p53 mutations. The 
K-ras mutations were detected by combined mutant-enriched polymerase chain 
reaction-restriction fragment length polymorphism analysis and characterized 
further by allele-specific oligonucleotide hybridization. Five of the seven duct 
lesions harbored activating point mutations in codon 12 of K-ras; a G to A 
transition was found in four and a G to C transversion in one. In contrast, 
these lesions did not harbor detectable p53 mutations as determined by 
denaturing gradient gel electrophoresis of exons 5 to 8, nor was there 
overexpression of the p53 protein as determined by immunohistochemistry. These 
findings suggest that mutations in K-ras represent an early event in the 
pathogenesis of pancreatic carcinoma. In addition, monitoring of patients with a 
strong family history of pancreatic carcinoma for K-ras mutations may identify 
patients at risk for the development of invasive carcinoma.