Abnormalities of the p53 tumour suppressor gene in human pancreatic cancer

Barton, Claire; Staddon, S. L.; Hughes, Christine M.; Hall, Peter A.; O'Sullivan, Colette; Klöppel, Günter; Theis, B; Russell, Ryan C.; Neoptolemos, John P.; Williamson, Rcn

doi:10.1038/bjc.1991.467

Cited by 356 publications

(207 citation statements)

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“…Although there are sources of error in determination British Journal of Cancer (1997) 76 (1), [54][55][56][57][58][59] . Cancer Research Campaign 1997 of p53 -alterations, there is in general a correspondence between IHC results and the findings obtained using molecular biological techniques (Barton et al, 1991;Ruggeri et al, 1992;Kalthoff et al, 1993). The percentage of tumours with p53 alterations in the present study is within the range described in the literature (20-75%), as estimated by IHC (Barton et al, 1991;van den Berg et al, 1993) or molecular biological techniques (Kalthoff et al, 1993;Scarpa et al, 1993;Pellegata et al, 1994).…”

Section: Discussionmentioning

confidence: 68%

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Prognostic significance of Ki-67 antigen and p53 protein expression in pancreatic duct carcinoma: a study of the monoclonal antibodies MIB-1 and DO-7 in formalin-fixed paraffin-embedded tumour material

Linder

Parrado²,

Falkmer³

et al. 1997

Br J Cancer

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Summary Formalin-fixed paraffin-embedded material from 57 patients in whom curative resection of pancreatic carcinoma had been attempted was analysed by an immunohistochemical procedure to estimate proliferation and p53 protein expression. Using the monoclonal antibody (MAb) MIB-1, which recognizes a Ki-67 epitope, the proliferating cell index (PCI, percentage of immunoreactive tumour nuclei) and proliferating cell area (PCA, percentage of immunoreactive tumour nuclear area) were calculated using an interactive image analysis system and were compared with semiquantitative scoring of stainability. MAb DO-7, which recognizes both wild-and mutant-type p53 protein, was used to assess p53 expression in the same material. MIB-1 stainings were of high quality in 53 tumours. The median PCI was 29.7% (range 0.5-82.1%) and the median PCA was 10.6% (range 0.0-36.5%). There was a close correlation between PCI and PCA (P< 0.0001). PCI and PCA values were in conformity with the semiquantitative scoring (P < 0.0001). The p53 immunohistochemical stainings were successful in 48 tumours and the protein was expressed in 22 (46%). High PCI values (> 45%, n = 14) correlated with shorter survival time (P < 0.01). PCA (P < 0.05) and the expression of p53 protein (P < 0.001) were independent prognostic variables.Keywords: pancreatic carcinoma; Ki-67 antigen; p53; immunohistochemistry; prognosis Different epitopes of the Ki-67 antigen (Ki-67, Ki-S 1, Ki-S5, MIB-1-3) have been used to estimate proliferation in various tumours (Kelleher et al, 1994). The proliferating rate has often been described as a proliferating cell index (PCI) (Pinder et al, 1995) or has been scored subjectively (Railo et al, 1993;Lam et al, 1996). The PCI may be calculated with or without the use of interactive image analysis systems (Pinder et al, 1995;Lam et al, 1996).The more recently developed MIB antibodies exhibit a pattern of immunostaining in formalin-fixed paraffin-embedded material identical with that of Ki-67 antibodies in fresh or frozen material (McCormick et al, 1993) and correlate with other markers of proliferation (Weidner et al, 1994). Thus, expression of the Ki-67 antigen has been used in studies on archival tumour material and has been correlated with patient survival time (Railo et al, 1993;Pinder et al, 1995). p53 alterations may be detected at the protein level by immunohistochemical staining procedures (IHC) and at the DNA or RNA level by direct sequence studies (Bodner et al, 1992;Berrozpe et al, 1994). The presence of p53 abnormalities correlates in some tumours with short survival time (Isola et al, 1992;Martin et al, 1992;Hamelin et al, 1994). Only a few studies have been published on the prognostic value of p53 alterations in pancreatic carcinoma, and the results are contradictory (DiGiuseppe et al, 1994;Lundin et al, 1996). Received 29 August 1996Revised 17 December 1996 Accepted 3 January 1997Correspondence to: S LinderWe assessed the proliferating activity in pancreatic carcinoma using IHC on formalin-fixed paraffin-embedded material...

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Section: Discussionmentioning

confidence: 68%

“…Paraffin sections, frozen material and carcinoma cell lines have been investigated for p53 abnormalities in pancreatic carcinoma (Barton et al, 1991;Ruggeri et al, 1992;Berrozpe et al, 1994). IHC has shown the same p53 protein pattern in frozen sections as in paraffin ones in pancreatic carcinoma (van dem Berg et al, 1993).…”

Section: Discussionmentioning

confidence: 99%

Prognostic significance of Ki-67 antigen and p53 protein expression in pancreatic duct carcinoma: a study of the monoclonal antibodies MIB-1 and DO-7 in formalin-fixed paraffin-embedded tumour material

Linder

Parrado²,

Falkmer³

et al. 1997

Br J Cancer

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“…Common pancreatic ductal adenocarcinoma (PDC) is characterized by a relatively unique molecular fingerprint constituted by frequent alterations of the K-ras (Almoguera et al, 1988;Lemoine et al, 1992;), p53 (Barton et al, 1991;Kalthoff et al, 1993;Scarpa et al, 1993a), p16 INK4a and DPC4/Smad4 genes (Hahn et al, 1996). Numerous studies on K-ras and p53 have confirmed that they are mutated at high frequency in primary PDC (K-ras reviewed in Hruban et al, 1993 andScarpa et al, 1994a; for p53 see: Pellegata et al, 1994;Redston et al, 1994).…”

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confidence: 99%

Pancreatic tumours: molecular pathways implicated in ductal cancer are involved in ampullary but not in exocrine nonductal or endocrine tumorigenesis

et al. 2001

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Summary Alterations of K-ras, p53, p16 and DPC4/Smad4 characterize pancreatic ductal cancer (PDC). Reports of inactivation of these latter two genes in pancreatic endocrine tumours (PET) suggest that common molecular pathways are involved in the tumorigenesis of pancreatic exocrine and endocrine epithelia. We characterized 112 primary pancreatic tumours for alterations in p16 and DPC4 and immunohistochemical expression of DPC4. The cases included 34 PDC, 10 intraductal papillary-mucinous tumours (IPMT), 6 acinar carcinomas (PAC), 5 solid-pseudopapillary tumours (SPT), 16 ampulla of Vater cancers (AVC) and 41 PET. All tumours were also presently or previously analysed for K-ras and p53 mutations and allelic loss at 9p, 17p and 18q. Alterations in K-ras, p53, p16 and DPC4 were found in 82%, 53%, 38% and 9% of PDC, respectively and in 47%, 60%, 25% and 6% of AVC. Alterations in these genes were virtually absent in PET, PAC or SPT, while in IPMT only K-ras mutations were present (30%). Positive immunostaining confirmed the absence of DPC4 alterations in all IPMT, SPT, PAC and PET, while 47% of PDC and 38% of AVC were immunonegative. These data suggest that pancreatic exocrine and endocrine tumourigenesis involves different genetic targets and that among exocrine pancreatic neoplasms, only ductal and ampullary cancers share common molecular events.

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“…At least 75% of pancreatic carcinomas have mutations in codon 12 of the Ki-RAS oncogene (Almoguera et al, 1988;Shibata et al, 1990; Kalthoff et al, 1993), and more than 50% of pancreatic carcinomas express an altered p53 tumour-suppressor gene (Barton et al, 1991;Kalthoff et al, 1993). Deletions of cyclin kinase inhibitors pl6/MTS1 (Caldas et al, 1994) and pl5/MTS2 (Naumann et al, 1996) have been described, and a new tumour-suppressor gene, DPC4, has been found very recently (Hahn et al, 1996).…”

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confidence: 99%

Overexpression of p53 protein during pancreatitis

Maacke

Kessler²,

Schmiegel³

et al. 1997

Br J Cancer

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Summary Overexpression of p53 correlates with neoplasia in many cytological specimens. To test the specificity of overexpressed p53 as a tumour marker for the detection of pancreatic cancer, we analysed cytological specimens of pancreatic juice samples from patients with pancreatitis or pancreatic carcinoma (n = 42) for p53 protein overexpression. p53 protein overexpression was found in 59% of patients with pancreatitis and 67% of patients with pancreatic carcinoma. Thus, Kalthoff et al, 1993), and more than 50% of pancreatic carcinomas express an altered p53 tumour-suppressor gene (Barton et al, 1991;Kalthoff et al, 1993). Deletions of cyclin kinase inhibitors pl6/MTS1 (Caldas et al, 1994) and pl5/MTS2 (Naumann et al, 1996) have been described, and a new tumour-suppressor gene, DPC4, has been found very recently (Hahn et al, 1996). In spite of this progress at the molecular level, the clinical outcome of patients with pancreatic cancer is still very poor. Thus, detection of early stages of pancreatic cancer is still crucial for a better prognosis.For many cytological specimens, the detection of p53 overexpression by immunocytochemistry strongly correlates with neoplasia (Dowell et al, 1994). Our aim was to establish whether the detection of p53 overexpression in cytological specimens from pancreatic juice samples, collected during ERCP (endoscopic retrograde cholangiopancreaticography), may be useful in detecting early stages of pancreatic carcinoma.p53 protein overexpression was detected in nearly 60% of cytological specimens from patients with pancreatitis but without any sign of pancreatic cancer for up to 5 years (median follow-up) after ERCP. This indicates that, in the case of pancreatic disease, p53 protein overexpression does not correlate with neoplasia. However p53 seems to play an important role during pancreatitis, as apoptotic cell death has been observed during chronic disease. This is in line with the function of p53 as an inductor of apoptotic cell death (Lane, 1992 MATERIALS AND METHODS Preparation of cytological specimens by cytospin of pancreatic juicePancreatic juice samples were collected during diagnostic ERCP from a total of 42 patients. One group comprised 27 patients suffering from chronic pancreatitis. The other group had 15 patients with pancreatic ductal adenocarcinomas, the vast majority of which were in stage II and III. Sample preparation was performed exactly as described previously (Schmiegel et al, 1990). Median follow-up was 5 years in the group of pancreatitis patients. During this period, no pancreatic cancer cases were observed. Antibodies and immunoperoxidase studiesThe p53-specific monoclonal antibodies PAbl801, PAb240 and PAbl620 were obtained from Oncogene Sciences (Dianova, Hamburg). The polyclonal antiserum against recombinant human p53 (CM-1) was purchased from Medac (Hamburg). Immunoperoxidase studies were performed exactly as described previously (Kalthoff et al, 1993). Samples were scored positive when at least 5% of the cells from the investigated cytospin were...

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Abnormalities of the p53 tumour suppressor gene in human pancreatic cancer

Cited by 356 publications

References 24 publications

Prognostic significance of Ki-67 antigen and p53 protein expression in pancreatic duct carcinoma: a study of the monoclonal antibodies MIB-1 and DO-7 in formalin-fixed paraffin-embedded tumour material

Prognostic significance of Ki-67 antigen and p53 protein expression in pancreatic duct carcinoma: a study of the monoclonal antibodies MIB-1 and DO-7 in formalin-fixed paraffin-embedded tumour material

Pancreatic tumours: molecular pathways implicated in ductal cancer are involved in ampullary but not in exocrine nonductal or endocrine tumorigenesis

Overexpression of p53 protein during pancreatitis

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