Sequential accumulation of K-ras mutations and p53 overexpression in the progression of pancreatic mucinous cystic neoplasms to malignancy

Citation
Re. Jimenez et al., Sequential accumulation of K-ras mutations and p53 overexpression in the progression of pancreatic mucinous cystic neoplasms to malignancy, ANN SURG, 230(4), 1999, pp. 501-509
Citations number
50
Language
INGLESE
art.tipo
Article
Categorie Soggetti
Surgery,"Medical Research Diagnosis & Treatment
Journal title
ANNALS OF SURGERY
ISSN journal
0003-4932 → ACNP
Volume
230
Issue
4
Year of publication
1999
Pages
501 - 509
Database
ISI
SICI code
0003-4932(199910)230:4<501:SAOKMA>2.0.ZU;2-H
Abstract
Objective Pancreatic mucinous cystic neoplasms (MCNs) provide a spectrum of neoplastic changes ranging from benign to malignant. The authors have corr elated K-ras mutations and p53 overexpression with the evolution of these t umors. Methods Areas of mild, moderate, or severe dysplasia were microdissected fr om paraffin-embedded tissue sections of 28 different MCNs (10 benign, 9 bor derline, 9 malignant). Nonneoplastic pancreatic ducts were also microdissec ted from tissues adjacent to the tumors. Ten serous cystadenomas served as negative controls. K-ras codon 12 mutations were identified by a mutant-enr iched nested polymerase chain reaction-restriction fragment length polymorp hism assay acid confirmed by sequencing, p53 overexpression was demonstrate d by immunohistochemistry. Results K-ras mutations were detected in 20% of benign, 33% of borderline, and 89% of malignant MCNs. Histologically, mutations were found in 26% (7/2 7) of MCN epithelia with mild dysplasia, 38% (5/13) of MCN epithelia with m oderate dysplasia, and 89% (8/9) of MCN epithelia with severe dysplasia or carcinoma. Ten percent (4/39) of nonneoplastic pancreatic ducts at the marg ins of MCN harbored mutations, all associated with borderline or malignant tumors. Overexpression of p53 occurred in none of the benign or borderline MCNs but in 44% (4/9) of the malignant tumors (p = 0.006 benign/borderline vs. malignant). p53 immunoreactivity was concentrated in areas of severe dy splasia/carcinoma or invasion, where K-ras mutation had been detected. Conclusion These findings demonstrate a sequential accumulation of genetic changes in the carcinogenesis of MCN, K-ras mutations appear early and incr ease in proportion with increasing dysplasia. Overexpression of p53 is a la te finding observed only in carcinomas, and in combination with mutated K-r as genes. The presence of K-ras mutations in nonneoplastic ducts supports f ormal pancreatic resection over enucleation for treatment. Mucinous cystic neoplasms may be a useful model to study the evolution of pancreatic ductal adenocarcinomas, in which precursor lesions remain unknown.