Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P04637 (p53)
 77,613 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Using CM-1 antibody directed against the human p53 protein, high levels of mutant p53 protein expression were found in 12 out of 18 malignant choroidal melanomas. In contrast, we failed to observe elevated p53 expression, indicating the absence of p53 mutation in seven choroidal naevi, a potentially premalignant condition that can progress to form malignant melanoma. For two choroidal melanomas, we demonstrated that high levels of p53 protein were accompanied by exon 7 mutations. The mutations were found at codon 238, TGT-->TTT and codon 253, ACC-->AGC. These observations suggest that acquisition of abnormalities of the p53 gene may be an important step in the development of malignant melanoma.
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PMID:Increased expression and mutation of p53 in choroidal melanoma. 141 33

Paraffin-embedded materials obtained from 117 cases of endometrial hyperplasia and 84 cases of carcinoma were used for measurement of both ki-ras and p53 gene mutation and aromatase (ARO) and TGF-alpha immunostaining. The overall incidence of ki-ras mutations in the hyperplasia specimens (16%) was similar to the incidence detected in carcinomas (18%). None of 117 endometrial hyperplasias were found to have mutations in the p53 gene, whereas mutations were seen in 3 (13.3%) endometrial carcinomas. The intensity of both ARO and TGF-alpha immunostaining was increased in glands of both hyperplasia and carcinoma, and also in the interstitium of carcinoma. The positive sites of both ARO and TGF-alpha were almost the same, with an incidence below 40% in both hyperplasias and carcinomas. The cultured cells of endometrial carcinoma showed aromatase activity below MCF-7 cells, because testosterone was converted to estradiol (E2). TGF-alpha induced cell growth with at an optimal concentration. In HEC-59 cells, TGF-alpha increased both ARO-activity and mRNA. Some promoters on ARO-exon 1 in HEC-59 cells were different from those in BeWo cells. Progesterone inhibited the E2-induced excretion of pre TGF-alpha in endometrial carcinoma cells. These findings suggest that endometrial hyperplasia can be a premalignant condition of carcinoma, and can be initiated by both ki-ras codon 12 mutation and abnormal activity of ARO induced by TGF-alpha. In addition, HEC-59 cells may possess autocrine/paracrine properties involving ARO, E2 and TGF-alpha.
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PMID:[Aromatase activities of endometrial carcinomas and both basic and clinical analyses of endometrial hyperplasia as a premalignant disease]. 837 Oct 7

Mutations of the p53 tumour-suppressor gene are considered to be rare in human colorectal adenomas, a premalignant state of the digestive tract. We have analysed a series of 32 exophytic tumours of the colon and rectum for the presence of p53 protein. In 26 of the 28 pure adenomas, the presence of significant levels of p53 proteins was established by a sensitive two-point enzyme-linked immunosorbent assay. The detectability of p53 protein was frequently limited to PAb 1801, recognizing an N-terminal epitope. Immunoblotting of the fractions captured by the monoclonal antibodies revealed that PAb 421 reacted exclusively with a 53-kDa species, whereas an additional 48-kDa band was detected after incubation with PAb 1801. In the adenomas, the mutant conformation-specific PAb 240 was always negative and no mutations were detected on exons 5-8 in three large and highly dysplastic lesions, selected for their high p53 protein content. The remaining four of the 32 tumours presented foci of cancer. Three of these were shown to contain 'mutant' PAb 240-reactive p53, and gene mutations were identified in two by denaturing gradient gel electrophoresis and sequencing of the amplified products. Intense p53 nuclear immunohistochemical staining was associated with the malignant areas. We conclude that a novel mechanism affecting the regulation of p53 protein could occur in colorectal adenomas.
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PMID:Frequently elevated content of immunochemically defined wild-type p53 protein in colorectal adenomas. 837 77

In this study we evaluated the replication pattern and cell-cycle dynamics of cells from patients considered to have a premalignant condition (monoclonal gammopathy, or MGUS) and patients with multiple myeloma (MM), as well as healthy controls. We applied the fluorescence in situ hybridization (FISH) technique with the TP53, RB-1 and 21q22 loci on the patient's cells. Asynchrony was determined by the presence of one single and one set of double dots in the same cell. The rate of asynchronic replication was significantly higher in the cells from MM patients, with intermediate value in the cells from MGUS, while the lowest rate was in cells from controls. We suggest that these results may reflect the changes in gene replication and cell-cycle progression that occur in premalignant and malignant cells.
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PMID:Replication pattern in cancer: asynchronous replication in multiple myeloma and in monoclonal gammopathy. 997 21

It has been hypothesized that neoplastic progression develops as a consequence of an acquired genetic instability and the subsequent evolution of clonal populations with accumulated genetic errors. Accordingly, human cancers and some premalignant lesions contain multiple genetic abnormalities not present in the normal tissues from which the neoplasms arose. Barrett oesophagus (BE) is a premalignant condition which predisposes to oesophageal adenocarcinoma (EA) that can be biopsied prospectively over time because endoscopic surveillance is recommended for early detection of cancer. In addition, oesophagectomy specimens frequently contain the premalignant epithelium from which the cancer arose. Neoplastic progression in BE is associated with alterations in TP53 (also known as p53) and CDKN2A (also known as p16) and non-random losses of heterozygosity (LOH). Aneuploid or increased 4N populations occur in more than 90-95% of EAs, arise in premalignant epithelium and predict progression. We have previously shown in small numbers of patients that disruption of TP53 and CDKN2A typically occurs before aneuploidy and cancer. Here, we determine the evolutionary relationships of non-random LOH, TP53 and CDKN2A mutations, CDKN2A CpG-island methylation and ploidy during neoplastic progression. Diploid cell progenitors with somatic genetic or epigenetic abnormalities in TP53 and CDKN2A were capable of clonal expansion, spreading to large regions of oesophageal mucosa. The subsequent evolution of neoplastic progeny frequently involved bifurcations and LOH at 5q, 13q and 18q that occurred in no obligate order relative to each other, DNA-content aneuploidy or cancer. Our results indicate that clonal evolution is more complex than predicted by linear models.
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PMID:Evolution of neoplastic cell lineages in Barrett oesophagus. 1031 73

Chromosomal abnormalities, including mutations, deletions and allelic losses of different oncogenes and tumour suppressor genes have been discovered in the DNA of cancer cells and the application of molecular biological techniques now permits identification of these alterations in tumours. Although it has been possible to detect potentially important genetic alterations in tumour material for some years, it is now evident that many neoplasms shed tumour cells into sputum, urine, bile, pancreatic juice, faeces and blood of infected patients. Mutated DNA has also been detected free in the plasma of patients with cancer, and the DNA alternations in plasma are identical to those in the DNA of the primary cancer cells. Thus, the identification of DNA mutations in plasma, pancreatic juice and faeces might be a useful approach for the early detection and monitoring of patients with pancreatic cancer. The K-ras gene is mutated in over 90% of pancreatic cancer. These mutations are well defined, reliably detected by DNA application in assays and occur early in the genesis of pancreatic cancer. K-ras mutations can be detected in cancer tissue and pancreatic duct secretions. K-ras mutations have also been detected in stool of patients with pancreatic cancer. Invasive techniques for obtaining pancreatic juice or pancreatic tissue are undesirable and would certainly be inappropriate for cancer screening. Similarly, there is a lack of enthusiasm for developing diagnostic techniques that involve faecal extractions. Isolation of plasma DNA from pancreatic patients and detection of K-ras alterations with a PCR assay and subsequent product sequencing showed K-ras mutations in the plasma of 17 out of 21 patients (81%), and in cases in which both plasma and pancreatic tissue were available, DNA mutations were similar in plasma and tissue. Plasma DNA alterations were found 5-14 months before the clinical diagnosis of pancreatic cancer in 4 patients. K-ras mutations are also demonstrated in micro-dissected tissues taken from patients with pancreatic hyperplasia, with or without chronic pancreatitis. This has lead to the suggestion that pancreatic cell hyperplasia may be a premalignant condition although the demonstration of K-ras alterations in some cases of chronic pancreatitis has raised doubts about the sensitivity and specificity of K-ras testing for pancreatic cancer. However, the detection of K-ras mutations in plasma may still identify patients with or at risk of developing pancreatic cancer as it may only be in these patients that sufficient quantities of mutated DNA enter and can be detected in plasma. Thus, this non-invasive approach to early cancer detection may be applicable both to diagnosis of the symptomatic patient and for screening. A combined approach with other tumour markers such as p53 gene might increase the sensitivity of the test.
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PMID:Diagnosis of pancreatico-biliary malignancy: detection of gene mutations in plasma and stool. 1043

The incidence of both esophageal adenocarcinoma and Barrett's esophagus, a premalignant condition predisposing to this cancer, is rising rapidly. There is growing evidence that both of these conditions are related to the reflux of acid and bile into the esophagus. This results in inflammation and cell damage which initiates a sequence of events termed the metaplasia-dysplasia-carcinoma sequence in which the squamous epithelium is replaced by columnar epithelium exhibiting increasing degrees of dysplasia and overt malignancy. This sequence of events is underpinned by changes in cell cycling, such as accumulation of p16 and p53 mutations and increased cyclin D1 activity. Progression along this pathway is characterized by changes in intercellular adhesion, in particular, loss of adenomatous polyposis coli, reduced cadherin expression and increased catenin phosphorylation resulting in its nuclear translocation. Herein, we detail these molecular defects and propose how they may interrelate in an ordered progression in the development of esophageal adenocarcinoma.
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PMID:Barrett's esophagus: disregulation of cell cycling and intercellular adhesion in the metaplasia-dysplasia-carcinoma sequence. 1067 68

Barrett esophagus is a premalignant condition that may progress to adenocarcinoma. The risk of developing cancer has been estimated to be approximately 1 in 250 patient-years of observation; however, there appear to be subsets of patients at much higher risk. Risk stratification has previously been determined by histological identification of dysplasia. Several new biomarkers are being tested to help clinicians better determine the risk of cancer development. Although none of these biomarkers has been proven in a prospective study to predict the onset of cancer, they have been correlated with cancer development. Most of these are factors that have been associated with cancer development in other organs. These include assessment of cell proliferation, expression of cyclooxygenase 2, growth factors and oncogenes, secretory factors, cell cycle proteins, adhesion molecules, and aneuploidy and other genetic abnormalities. In addition to their role as potential cancer biomarkers, these factors have increasingly been reported as surrogate markers to monitor the effectiveness of conservative treatments for Barrett esophagus. In this article, biological markers are reviewed for their relevance in Barrett esophagus. Although most biological markers need to be evaluated further and, for most, prospective follow-up studies are lacking, at present abnormal ploidy status, P16 and P53 gene abnormalities, or allelic losses are the most extensively documented.
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PMID:Biomarkers in Barrett esophagus. 1132 62

Although the risk of breast cancer for women in the United States is approximately 1 in 9, identification of risk factors and translation of that knowledge into strategies for prevention have been inhibited by poor understanding of disease pathogenesis. A few benign breast proliferations are associated with higher risks of breast cancer, but definition of a preneoplastic morphologic continuum is lacking. If progression from a premalignant state to malignancy is accompanied by genetic changes, then identification in benign breast disease lesions (BBD) of alterations similar to those found in breast cancer should strengthen the perception of BBD as a premalignant condition. Current testing for hereditary breast cancer susceptibility presumes that only women with invasive breast or ovarian cancer are gene carriers. Therefore, neither in situ breast cancer nor atypical hyperplasias are considered clinically as evidence of a breast-ovarian syndrome, nor are these diagnoses used to predict carrier status within at-risk families. This reflects lack of evidence that breast cancer develops along a recognized morphologic continuum from precursor lesions. New mutation screening procedures such as DNA microarrays can provide sensitivity, specificity, and high throughput that circumvent limitations imposed on the scope of molecular marker analyses applied to archival resources. We have studied a BRCA1-mutant individual with loss of the wild type BRCA1 allele in benign breast proliferations. Both her benign and malignant lesions showed molecularly identical TP53 mutations, indicating that significant genetic alterations can occur in BBD and supporting the clonal evolution from BBD to malignancy.
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PMID:Establishing a molecular continuum in breast cancer DNA microarrays and benign breast disease. 1177 52

Barrett's oesophagus is a premalignant condition whose incidence is rising dramatically. Molecular markers are urgently needed to identify Barrett's patients at the highest risk of cancer progression. To this end, we have used a rapid molecular technique, restriction site mutation (RSM), to detect low-frequency mutations in the p53 tumour suppressor gene in premalignant Barrett's tissues of cancer-free patients. In total, 38 endoscopically diagnosed Barrett's patients with a range of histological stages of Barrett's progression, plus four control patients without Barrett's oesophagus, were analysed for early p53 mutations. Tissue samples taken from these patients (93 samples in total) were analysed for the presence of low-frequency p53 mutations at hotspot codons: 175, 213, 248, 249, 282. In total, 13 of the 38 Barrett's patients were shown to possess a p53 mutation in at least one sample (no mutations in the four control patients). Although no statistically significant associations were found, p53 mutations reflected histological progression in Barrett's patients with p53 mutations found in 30% of metaplasia patients (P=0.4) and low-grade dysplasia patients (P=0.33) and 45% of high-grade dysplasia patients (P=0.15). Detected p53 mutations were mainly GC to AT transitions at CpG sites.
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PMID:Early p53 mutations in nondysplastic Barrett's tissue detected by the restriction site mutation (RSM) methodology. 1269 95


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