Analysis of K-ras oncogene mutations in chronic pancreatitis with ductal hyperplasia.
BACKGROUND
K-ras oncogene mutations have been identified in up to 95% of pancreatic cancers, implying their critical role in their molecular pathogenesis. However, the earliest stage in which K-ras mutations can be detected in potential precursor lesions of pancreatic cancer remains unclear. This study evaluates pancreatic ductal hyperplasia in the setting of chronic pancreatitis, which predisposes to pancreatic cancer development, for K-ras codon 12 and 13 mutations.


METHODS
Paraffin-embedded surgical specimens from 42 patients with chronic pancreatitis were examined microscopically for the presence of ductal hyperplasia. Both hyperplastic and nonhyperplastic ducts were microdissected from the specimens that contained hyperplasia (11 of 42). Four of the remaining specimens without hyperplasia served as controls. Genomic DNA was extracted, and polymerase chain reaction and amplification of the K-ras oncogene was performed. Polymerase chain reaction products were evaluated by means of hybridization to mutant specific oligonucleotide probes and by means of automated DNA sequencing.


RESULTS
K-ras codon 12 mutations representing glycine to valine substitutions were present in 2 of (18%) 11 patients with ductal hyperplasia. No mutations were found in the controls without ductal hyperplasia.


CONCLUSIONS
Our study supports the premise that K-ras mutations develop in a subset of chronic pancreatitis associated hyperplasia and provides a genetic basis for the potential progression of chronic pancreatitis to pancreatic cancer.
Rivera
J A
JA
Department of Surgery, Massachusetts General Hospital, Boston 02114, USA.
Rall
C J
CJ
Graeme-Cook
F
F
Fernández-del Castillo
C
C
Shu
P
P
Lakey
N
N
Tepper
R
R
Rattner
D W
DW
Warshaw
A L
AL
Rustgi
A K
AK
D000328:Adult; D000368:Aged; D001483:Base Sequence; D002908:Chronic Disease; D004247:DNA / Q000235:genetics; D005260:Female; D011905:Genes, ras; D006801:Humans; D006965:Hyperplasia; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009693:Nucleic Acid Hybridization; D015345:Oligonucleotide Probes; D010183:Pancreatic Ducts / Q000473:pathology*; D010195:Pancreatitis / Q000235:genetics* / Q000473:pathology*; D016133:Polymerase Chain Reaction
D015345:Oligonucleotide Probes; D004247:DNA