title: Prevalence of activating K-ras mutations in the evolutionary stages of neoplasia in intraductal papillary mucinous tumors of the pancreas.
abstract: 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.
authors.affiliation: Department of Surgery, Massachusetts General Hospital and Harvard Medical School, Boston 02114, USA.
authors.forename: K
authors.initials: K
authors.lastname: Z'graggen
authors.forename: J A
authors.initials: JA
authors.lastname: Rivera
authors.forename: C C
authors.initials: CC
authors.lastname: Compton
authors.forename: M
authors.initials: M
authors.lastname: Pins
authors.forename: J
authors.initials: J
authors.lastname: Werner
authors.forename: C
authors.initials: C
authors.lastname: Fernández-del Castillo
authors.forename: D W
authors.initials: DW
authors.lastname: Rattner
authors.forename: K B
authors.initials: KB
authors.lastname: Lewandrowski
authors.forename: A K
authors.initials: AK
authors.lastname: Rustgi
authors.forename: A L
authors.initials: AL
authors.lastname: Warshaw
mesh_terms: 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
chemical_list: D017931:DNA Primers; D004273:DNA, Neoplasm