The tumor suppressor genes p53, retinoblastoma (RB), p16, and p15 encode proteins that regulate the cell cycle cooperatively by controlling the transition from G1 to S phase and may play an important role in cell growth and differentiation. To screen for abnormalities in these genes in cancer, we performed genetic analysis in six human pancreatic cancer and five hepatoma cell lines, by single-strand conformation polymorphism (SSCP) analysis, direct sequencing, and the reverse transcriptase-polymerase chain reaction (RT-PCR). All six pancreatic cancer cell lines had p53 mutations, with the concomitant loss of the other normal allele, encoding wild-type p53. Frequent homozygous deletions were found in p16 and p15, but the RB gene was expressed. Four of the five hepatoma cell lines had p53 mutations with loss of the normal allele and aberrant RB. There were no deletions of p16 and p15 in any of the hepatoma cell lines. These findings suggest that alterations in the p53, p16, and p15 genes are common in human pancreatic cancer cell lines, while p53 or RB mutations are common in hepatoma cell lines. Alterations of these tumor suppressor genes may thus be important features in organ-specific carcinogenesis.
The aim of this study was to investigate mutations of the K-ras oncogene and the p53 tumor suppressor gene in pancreatic juice and to evaluate our method for the diagnosis of intraductal papillary rnucinous tumors (IPMT). Pancreatic juice was collected endoscopically from 12 patients with IPMT who underwent surgical resection (eight carcinomas and four adenomas) and eight cases without evident pancreatic diseases. DNA was extracted and both genes were examined by polymerase chain reaction single-strand conformation polymorphism (PCR-SSCP) analysis and direct sequencing. In addition, surgically resected specimens were analyzed for both genes by the same methods, and p53 overexpression was investigated immunohistochernically. K-ras point mutations were detected in pancreatic juice from all 12 patients (loo%) and p53 mutations were detected in five of 12 (42%). They were detected not only in carcinoma but also in adenoma and there was no difference between the mutations detected in pancreatic juice and surgical specimens. No mutations were found in any cases without pancreatic diseases. These findings suggest that alterations of K-ras and p53 gene are common events in the development of IPMT and that genetic analysis of them in pancreatic juice can be a useful tool for the clinical diagnosis of IPMT before surgery.
Objective: IgG4-related sclerosing cholangitis (IgG4-SC) is recognized as a benign steroid-responsive disease; however, little is known about the risk of development of cancer in patients with IgG4-SC and about how to counter this risk. Design: We conducted a retrospective review of the data of 924 patients with IgG4-SC selected from a Japanese nationwide survey. The incidence, type of malignancy, and risk of malignancy in these patients were examined. Then, the standardized incidence ratio (SIR) of cancer in patients with IgG4-SC was calculated. Results: Relapse was recognized in 19.7% (182/924) of patients, and cancer development was noted in 15% (139/924) of patients. Multivariate analysis identified only relapse as an independent risk factor for the development of cancer. In most of these patients with pancreato-biliary cancer, the cancer developed within 8 years after the diagnosis of IgG4-SC. The SIR for cancer after the diagnosis of IgG4-SC was 12.68 (95% confidence interval [CI] 6.89-8.79). The SIRs of cancers involving the biliary system and pancreas were 27.35 and 18.43, respectively. The cumulative survival rate was significantly better in the group that received maintenance steroid treatment (MST) than in the group that did not; thus, MST influenced the prognosis of these patients. Conclusion: Among the cancers, the risk of pancreatic and biliary cancers is the highest in these patients. Because of the elevated cancer risk, surveillance after the diagnosis and management to prevent relapse are important in patients with IgG4-SC to reduce the risk of development of cancer.K Kubota et al.IgG4-related sclerosing cholangitis and cancer 557
Proteolytic enzymes in human pure pancreatic juice (PPJ), which was collected by cannulating the main pancreatic duct using endoscopy, were investigated by two-dimensional zymography (2-DZ). 2-DZ was carried out by combining isoelectric focusing (IEF) in the first dimension with sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) in the second dimension, using gels containing casein or gelatin as a substrate for the proteolytic enzymes. After electrophoresis, the gels were incubated in Triton X-100 followed by incubation at 37 degrees C in Tris buffer (pH 8.5) containing CaCl2. By staining the gels with Coomassie Brilliant Blue (CBB R-250), proteolytic enzymes were detected as clear spots and zones against a blue background. Proteinase inhibitors, such as a cysteine proteinase inhibitor (E-64), a metalloproteinase inhibitor (EDTA), and a serine proteinase inhibitor (Pefabloc SC), were added to PPJ in order to determine the types of proteinases. In patients with pancreatic cancer, spots of molecular weight (Mr) 70,000 and isoelectric points (pI) 5.3-5.5 were clearly detected on the gels containing casein and gelatin, while these spots were not detected in the PPJ from healthy subjects. The proteolytic activities of these spots were strongly inhibited by EDTA and Pefabloc SC but not E-64. These results suggest that the spots of Mr 70,000 and pI 5.3-5.5 in PPJ of pancreatic cancer might be matrix metalloproteinase 2, which is a candidate for tumor-associated proteinase. 2-DZ proved to be a tool for analysis of proteolytic enzymes in PPJ and for the clinical diagnosis of pancreatic cancer.
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