The K-ras mutation pattern in pancreatic ductal adenocarcinoma usually is identical to that in associated normal, hyperplastic, and metaplastic ductal epithelium

BACKGROUND. Hyperplastic ductal lesions of the pancreas are believed to represent precursors of ductal adenocarcinoma. The most frequent mutation in manifest ductal carcinoma of the pancreas is the K-ras mutation at codon 12. The frequency and significance of this mutation in precursor lesions are a matter of controversy. METHODS. The study included 35 resection specimens of ductal adenocarcinoma of the head of the pancreas and 3 noncancerous, noninflammatory pancreases. Ductal lesions were classified according to established criteria. Single cells from these lesions were microdissected and analyzed by the denaturing gradient gel electrophoresis polymerase chain reaction method. RESULTS. All primary adenocarcinomas showed a K-ras mutation at codon 12 (25 cases with GAT, 7 cases with GTT, and 3 cases with CGT). One hundred and six of 364 ductal lesions were positive for the mutation. The highest relative percentage (53%) occurred in adenomatoid hyperplasia, followed by 36% in papillary hyperplasia, 26% in mucinous hypertrophy, and 14% in squamous metaplasia. With only two exceptions the mutation pattern of the ductal lesions and that of the corresponding primary tumor were identical. Twenty-one samples from normal ducts (17%) also harbored the K- ras mutation, as did 3 lesions from noncancerous specimens. CONCLUSIONS. K- ras mutations are common events in normal, hyperplastic, metaplastic, and neoplastic pancreatic ductal cells. Because K-ras mutations frequently, although not exclusively, are related to mucinous differentiation of pancreatic cells, this mutation may not cause but only promote mucinous differentiation. The prevalence of a certain mutation pattern in nonneoplastic and neoplastic ductal cells in an individual pancreas suggests the dominance of one carcinogenic factor.