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Query: UMLS:C0596263 (carcinogenesis)
 64,820 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Hyperplastic lesions of the oropharyngeal mucosa such as leukoplakia and oral lichen planus can eventually develop into squamous cell carcinomas (SCC) and provide an excellent model for multistage carcinogenesis. The development of carcinomas is assumed to be the result of the interaction of genetic factors, locally applied carcinogens and immunological unresponsiveness. Recently a novel gene termed mdm2 has been isolated that is found to be involved in transcriptional regulation and can inhibit p53 function by forming a complex with p53. In this study the immunohistochemical detection of the MDM2 protein in 186 paraffin embedded tissue sections of normal mucosa, premalignant, malignant and metastatic lesions of the oropharyngeal mucosa is reported for the first time. p53 protein expression was also investigated in the same tissue samples. The increase in the number of p53 and MDM2 positive biopsies was correlated with the dysplasia grade and the loss of differentiation in the premalignant and malignant lesions. In late stages of the disease the number of biopsies that expressed both p53 and MDM2 increased. Inactivation of p53 function in head and neck carcinogenesis may also be due to MDM2 binding. Detection of MDM2 protein expression by immunohistochemistry may be an important diagnostic tool in the future.
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PMID:Detection of p53 and MDM2 protein expression in head and neck carcinogenesis. 765 34

Mutations in the p53 tumor suppressor gene are commonly found in the major human cancers and the mutational spectrum in some cancer types is consistent with the genotoxic effects of the associated environmental risk factors. Thus far there is little information on p53 mutations in cancers of factory workers with a history of carcinogen exposure in the workplace. Occupational exposure to vinyl chloride causes liver angiosarcomas (ASL) and also increases the risk of several other cancers. Loss of p53 function in osteo- and fibrosarcomas can occur by two different mechanisms, p53 mutation and amplification of the MDM2 gene. We examined tumors from five vinyl chloride-exposed patients, four with ASL and one with hepatocellular carcinoma (HCC), for evidence of MDM2 proto-oncogene amplification or p53 mutation in exons 5-8. Amplification of MDM2 was not found, but in two of the angiosarcomas an A:T to T:A missense mutation was detected. p53 sequence analysis of vinyl chloride associated cancers may provide valuable information on the relationship between carcinogen exposure and DNA damage in cancer-related genes.
Carcinogenesis 1994 Jan
PMID:p53 mutations at A:T base pairs in angiosarcomas of vinyl chloride-exposed factory workers. 829 34

Oral cancer is a disease of the elderly and is closely connected with cigarette smoking and alcohol consumption. Since the successful introduction of multidisciplinary treatment, the survival rate has not changed. Because of the high mortality and potentially disfiguring treatment, today's efforts are aimed at eliminating risk factors, chemoprophylaxis, improvement in diagnostic procedures, and understanding of the genetic mechanisms of oral carcinogenesis. Immunohistochemical and molecular biology analysis of biopsy tissue and cell lines of preneoplastic and neoplastic lesions that originate from the oral mucosa have shown that alterations in tumour suppressor genes such as p53 and Rb gene may have an important role in oral carcinogenesis and may be potentially useful prognostic 'biomarkers' in oral carcinogenesis. Statistical analysis of immunohistochemical data from 216 patients did not identify significant or consistent differences of p53, MDM2, or RB expression with respect to stage of disease, malignant transformation, metastatic node involvement, recurrence, or survival. Nevertheless, p53 overexpression seems to correlate strongly with histological progression of the disease, which confirms the importance of p53 alterations in oral carcinogenesis. Overexpression of p53 is usually found in the less differentiated proliferating cells in benign and malignant oral lesions. Assessment of the proliferating activity is possible by immunohistochemical staining with monoclonal antibodies against proliferating nuclear antigen and Ki-67. Statistical analysis shows that overexpression of p53 combined with high proliferative activity predicts a less favourable course of disease in oral squamous cell carcinoma.
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PMID:Proliferative activity and loss of function of tumour suppressor genes as 'biomarkers' in diagnosis and prognosis of benign and preneoplastic oral lesions and oral squamous cell carcinoma. 976 52

Inactivation of wild-type p53 during gastric carcinogenesis is usually caused by mutations within exons 5-8 of the p53 gene leading to mutated, usually immunohistochemically detectable p53 proteins. However, functional inactivation of wild-type p53, mimicking mutational inactivation, may also result from binding to overexpressed MDM2 protein. While these two mechanisms of p53 inactivation are considered to be mutually exclusive, no data exist as to whether MDM2 overexpression occurs during gastric carcinogenesis. MDM2 protein overexpression was therefore studied in relation to p53 protein accumulation in gastric carcinogenesis. Forty-five paraffin-embedded gastrectomy specimens from early gastric carcinomas were examined for the presence of chronic active gastritis, chronic atrophic gastritis, subtypes of intestinal metaplasia, and dysplasia. The Lauren type was reassessed for all early carcinomas. p53 protein accumulation was examined using the monoclonal antibody DO-7. MDM2 protein overexpression was assessed with the monoclonal antibody SMP-14. Complete absence of nuclear p53 protein accumulation was observed in chronic active gastritis, chronic atrophic gastritis, and intestinal metaplasia, irrespective of the subtype. In gastric dysplasia (one mild, two moderate, one severe), only severe dysplasia was p53-positive. Intestinal-type (n = 20) and diffuse-type early gastric carcinoma (n = 25) were p53-positive in 70 and 52 per cent of the cases, respectively. MDM2 protein overexpression was not observed during gastric carcinogenesis, either in the p53-positive or in the p53-negative cases. In conclusion, it appears that functional inactivation of wild-type p53 by MDM2 protein overexpression plays no role in (early) gastric carcinogenesis.
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PMID:No evidence for functional inactivation of wild-type p53 protein by MDM2 overexpression in gastric carcinogenesis. 987 38

The two gene products of the CDKN2A gene, p16 and p19ARF, have recently been linked to each of two major tumour suppressor pathways in human carcinogenesis, the RB1 pathway and the p53 pathway. p16 inhibits the phosphorylation of the retinoblastoma gene product by cyclin D-dependent kinases, whereas p19ARF targets MDM2, a p53 inhibitory protein, for degradation. A deletion of CDKN2A would therefore disturb both pathways. To explore the p53 pathway genes as a functional unit in diffuse large B cell non-Hodgkin's lymphomas (DLCL), we wanted to see whether there exists mutually exclusiveness of aberrations of CDKN2A, MDM2 and p53, since this has not been analysed previously. We investigated 37 DLCL for aberrations of p15, p16, p19ARF, MDM2, and p53 at the epigenetic, genetic and/or protein levels. Homozygous deletion of CDKN2A was detected in seven (19%) of 37 tumours, and another three cases were hypermethylated at the 5' CpG island of p16. No point mutations were found in CDKN2B or CDKN2A. Immunohistochemical staining of formalin-fixed, paraffin-embedded tissue for p16 confirmed these results, as all tumours with alterations of CDKN2A were p16 immunonegative. We found p53 mutations in eight (22%) cases and MDM2 overexpression in 16 (43%) tumours. Twenty-three (62%) tumours had alterations of one or more p53 pathway components (p53, p19ARF and MDM2). Furthermore, 7/9 (78%) p16-immunonegative tumours showed co-aberration of p53 and/or MDM2. The lack of correlation between these aberrations suggests that DLCL acquire additional growth advantage by inactivating both of these critical regulatory pathways.
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PMID:Aberrations of the p53 pathway components p53, MDM2 and CDKN2A appear independent in diffuse large B cell lymphoma. 1008 36

The overexpression of the oncogene product MDM2 is often observed in human breast cancer cells, especially in estrogen receptor (ER)-positive ones. To study the role of MDM2 protein in ER-positive breast cancer, we have established cell lines derived from MCF-7 which stably express increased and decreased levels of MDM2 by transfection of a mammalian expression vector containing human mdm2 cDNA in sense and antisense orientations, respectively. Interestingly, MDM2 overexpression in MCF-7 cells afforded a remarkable growth advantage under estradiol (E2)-supplemented condition. Then, we analyzed the expression of p53, which is an important regulator of growth and the cell cycle. Unexpectedly, the p53 accumulation induced by E2 was remarkably higher in MCF-7 cells stably overexpressing MDM2 than in the parent MCF-7 cells. On the other hand, reduction of MDM2 suppressed the E2-induced increase in p53 protein. Moreover, mdm2 antisense oligonucleotides prevented E2-induced accumulation of p53. In the steady state, the cellular levels of p53 were also correlated with those of MDM2. These interactions are not consistent with the well-known role of MDM2, which acts as a negative regulator for p53 by inhibiting its function and promoting its rapid degradation. These results suggest that MDM2 may regulate the expression of p53 in the steady state and in response to E2 in breast cancer cells, and imply a novel and important role of MDM2 during breast carcinogenesis.
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PMID:Overexpression of MDM2 in MCF-7 promotes both growth advantage and p53 accumulation in response to estradiol. 1018 92

Arbitrarily primed PCR (AP-PCR) fingerprinting method is easy and useful for analysis of genetic alterations in anonymous chromosomal regions. We applied this technology to analysis of DNA from human primary cancers and found amplification of a DNA fragment in a mediastinum fibrosarcoma. PCR-based analysis of radiation hybrid panels following cloning and nucleotide sequence determination of the fragment revealed that it was derived from a region of chromosome 12q13-q15. In this region, the MDM2 and IFNG genes were noted as known genes that could be involved in human carcinogenesis. Southern blot analysis of genomic DNA of the tumor revealed the amplification of the MDM2 gene together with the fragment locus, but not the IFNG gene. Our results demonstrated that detection of DNA alterations by AP-PCR fingerprinting without any previous knowledge of the genes and subsequent analysis of radiation hybrid panels could lead to easy identification of candidates for genes involved in carcinogenesis.
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PMID:Detection of DNA abnormalities by arbitrarily primed PCR fingerprinting: amplification of the MDM2 gene in a mediastinum fibrosarcoma. 1032 77

p73, a member of the p53 family at 1p36.3, has been demonstrated to be expressed monoallelically and induce apoptosis or G1 arrest of the cell cycle. To explore the candidacy of p73 as a suppressor in bladder tumorigenesis, we examined expression level, allelic origin, and mutation of p73 mRNA in 45 primary bladder carcinomas. Quantitative PCR analysis showed no allelic loss of the gene but showed various levels of mRNA expression in both carcinoma and noncancerous tissues. Elevated expression of p73 was frequently observed in carcinoma tissues [18 (40.0%) of 45] and showed a strong correlation with tumor stage or grade. Allotyping analysis using a StyI polymorphism detected biallelic expression in 12 (52.2%) of 23 heterozygous carcinomas but none in 4 noncancerous tissues. Tumor-specific biallelic expression was also identified from one matched set. In addition, 8 (66.7%) of these 12 expressed high levels of p73 mRNA, whereas only 2 (18.2%) of 11 monoallelic expressors showed high expression, which suggests that the increased expression of p73 might be caused by the transcriptional activation of a silent allele in carcinomas. Single-strand conformational polymorphism analysis of the entire coding region of p73 revealed no mutation, whereas 12 (26.7%) of the same set showed p53 alterations. No relationship between expression of p73 and p53 mutation or expression of p21Waf1 or MDM2 was identified. Taken together, our data argue that p73 does not play a role as a tumor suppressor in bladder carcinogenesis and suggest that the activation of a silent allele may contribute to the progression of bladder tumors.
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PMID:Elevated and biallelic expression of p73 is associated withprogression of human bladder cancer. 1038 32

Sequencing of p53 exons 5-8 was carried out on 51 initial superficial bladder tumors selected on the basis of high grade and/or p53 overexpression (immunohistochemistry without antigen retrieval). Fourteen point mutations in 13 tumors and one 21 bp deletion in another tumor were identified. In addition, a germ-line mutation corresponding to a previously described polymorphism was detected in exon 6, in two tumors. Mostly G-->A transitions (10) were found. Only three occurred at CpG sites, suggesting a major role for exogenous carcinogens in bladder tumorigenesis. Immunostaining for p53 and MDM2, using antigen retrieval, was carried out on the same tumors. A correlation was found between the percentage of p53-positive cells and the presence of p53 mutations (P = 0.005). No correlation was found between overexpression of p53 and MDM2 in this selected cohort of mostly high grade tumors. The presence of p53 mutations was also analyzed as a function of the smoking habits of the patients. A significant association was found between the presence of p53 point mutations and the number of years of smoking (P = 0.043). All patients with tumors carrying missense or nonsense p53 mutations had smoked for >/=30 years and if former smokers, had stopped for </=5 years. However, no correlation was found between the presence of p53 point mutations and the number of cigarettes smoked. The deletion mutation was the only one present in a tumor from a non-smoker. The data suggest that duration of exposure to carcinogens is the most critical factor in p53 mutagenesis in bladder cancer.
Carcinogenesis 2000 Jan
PMID:P53 point mutations in initial superficial bladder cancer occur only in tumors from current or recent cigarette smokers. 1060 40

Data are non-existent regarding coincidental alterations in the expression of p53 and its downstream target genes MDM2 and p21(Waf1/Cip1) in gastric carcinogenesis. An immunohistochemical study was therefore performed to examine the interrelationships of p53, MDM2, and p21(Waf1/Cip1) expression in a series of Caucasian early gastric carcinomas and precursor lesions. In normal gastric mucosa, chronic gastritis, and intestinal metaplasia, the surface cells expressed p21(Waf1/Cip1) in the absence of detectable nuclear p53 and MDM2 protein. Nuclear p53 protein accumulation was found in 60 per cent of the carcinomas, with significant differences in staining characteristics between the Lauren types in the absence of detectable MDM2 protein ( p< 0.005). Nearly 80 per cent of the carcinomas expressed p21(Waf1/Cip1), irrespective of Lauren type. Stratification of the carcinomas according to histological grade and growth pattern did not result in significant differences in p53 and p21(Waf1/Cip1) expression. Finally, no significant correlation was found between overall p53 and p21(Waf1/Cip1) expression in early gastric carcinomas. It is concluded that p21(Waf1/Cip1) expression in the non-neoplastic mucosa most likely relates to cell senescence and/or terminal differentiation, perhaps even in a p53-independent manner. In view of p53/MDM2 homeostasis, the differences in p53 staining characteristics between intestinal and diffuse-type carcinomas probably result, at least in part, from a difference in the prevalence of p53 gene mutations. Moreover, p53-independent induction of p21(Waf1/Cip1) expression apparently occurs in a considerable proportion of early carcinomas. Finally, in contrast to other carcinomas, p21(Waf1/Cip1) expression is not significantly correlated with histological grade in gastric carcinomas, suggesting possible defects downstream of p21(Waf1/Cip1) as an underlying cause for this apparent discrepancy.
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PMID:p21(Waf1/Cip1) expression and the p53/MDM2 feedback loop in gastric carcinogenesis. 1062 47


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