Prevalence of activating K-ras mutations in the evolutionary stages of neoplasia in intraductal papillary mucinous tumors of the pancreas.
OBJECTIVE
The purpose of the study was to determine the prevalence of activating K-ras mutations in the pancreas of patients with intraductal papillary mucinous tumors (IPMT) and to analyze their relation to the degree of site-specific histopathologic abnormality.


BACKGROUND
Intraductal papillary mucinous tumors of the pancreas have a biologic behavior that is significantly different from pancreatic ductal adenocarcinoma. Activating K-ras mutations, which may be important events in a multistage process of carcinogenesis, have been reported in IPMT.


METHODS
Forty-six different histologic specimens (comprising normal pancreatic ducts, hyperplasia, low-grade dysplasia, high-grade dysplasia-carcinoma in situ, and carcinoma) from 16 patients with IPMT and 9 specimens from patients with pancreatic ductal adenocarcinomas were designated by a pathologist. Genomic DNA was extracted from paraffin-embedded tissue sections after microdissection. The K-ras gene was amplified by polymerase chain reaction and subjected to DNA sequencing.


RESULTS
The K-ras mutations were detected in at least one specimen in 13 (81.2%) of 16 patients with IPMT. All mutations were found in codon 12. No codon 13 mutations were detected. The relative frequency of K-ras mutations in the different stages of IPMT was 16.7% in normal epithelium and papillary hyperplasia, 28.6% in low-grade dysplasia, and 57.1% in high-grade dysplasia-carcinoma in situ and invasive carcinoma. The K-ras mutations were detected in 6 (66%) of 9 pancreatic ductal adenocarcinomas.


CONCLUSIONS
The K-ras codon 12 point mutations are as frequent in IPMT as in ductal adenocarcinoma. A stepwise increase in the frequency of codon 12 mutations correlated with the stage of neoplastic evolution to cancer. This finding is consistent with an important role of K-ras gene mutations in the transformation from normal epithelium to invasive carcinoma in the majority of patients with IPMT.
Z'graggen
K
K
Department of Surgery, Massachusetts General Hospital and Harvard Medical School, Boston 02114, USA.
Rivera
J A
JA
Compton
C C
CC
Pins
M
M
Werner
J
J
Fernández-del Castillo
C
C
Rattner
D W
DW
Lewandrowski
K B
KB
Rustgi
A K
AK
Warshaw
A L
AL
D018270:Carcinoma, Ductal, Breast / Q000235:genetics*; D018291:Cystadenoma, Mucinous / Q000235:genetics*; D017931:DNA Primers; D004273:DNA, Neoplasm / Q000235:genetics; D011905:Genes, ras / Q000235:genetics*; D006801:Humans; D010190:Pancreatic Neoplasms / Q000235:genetics*; D017354:Point Mutation; D016133:Polymerase Chain Reaction; D015995:Prevalence
D017931:DNA Primers; D004273:DNA, Neoplasm