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)

Gastric dysplasia (high-grade, HGD, and low-grade, LGD) and normal mucosa were tested for anti-p53, anti-Ki-67 and anti-PCNA monoclonal antibodies on paraffin sections, and for relative AgNOR area and number on semithin Epon-Araldite sections. The proliferative compartment in normal mucosa was restricted to the middle layer corresponding to the neck-isthmus region. In LGD and HGD there was an expansion of this compartment to the lower and upper layers of mucosa, and in HGD in particular to the upper layer. p53 was always negative in LGD as well as in normal mucosa, while it was positive in 34 out of 51 cases of HGD. The most discriminant variables between LGD and HGD were relative AgNOR area and the percentages of MIB-1, p53 and PCNA. In p53-positive HGD the highest percentages of PCNA and MIB-1 were in the middle and upper layers (PCNA) or the upper layer (MIB-1), while in p53-negative HGD cases cell proliferation was maximal in the middle layer, although also present in the upper layer. The majority of cases of LGD did not demonstrate cell proliferation in the upper layer, but 5 cases behaved similarly to the p53-negative HGD cases. No significant correlations were found among percentages of MIB-1 and of PCNA and relative AgNOR area and number.
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PMID:Cell proliferation patterns and p53 expression in gastric dysplasia. 762 88

Our aim was to determine the sensitivity and specificity of p53 accumulation as a marker of malignant potential in Barrett's metaplasia (BM). One hundred eighty biopsies from 61 patients with BM were evaluated for p53 accumulation by immunohistochemistry. Of 25 patients with LGD, 9 had p53-positive biopsies, and of these 5 (56%) developed HGD/CA, whereas 16 had p53-negative biopsies and none (0%) developed HGD/CA after similar follow-up times (P = 0.0108). As a marker of malignant potential in BM, p53 accumulation has a sensitivity of 100%, specificity of 93%, and a predictive value of a positive test of 0.56, compared to sensitivity of 100%, specificity of 64%, and predictive value of a positive test of 0.2 for a histologic diagnosis of LGD. We conclude that: (1) p53 accumulation is more specific and has better predictive value for subsequent development of HGD/CA than histologic diagnosis of LGD. (2) Patients with LGD and p53-positive biopsies are more likely to develop HGD/CA; therefore, they should be followed up more closely than those with LGD and p53-negative biopsies.
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PMID:p53 Protein accumulation is a specific marker of malignant potential in Barrett's metaplasia. 912 34

We correlated p53 overexpression with allelic deletion of p53 in ulcerative colitis (UC) with high grade dysplasia (HGD, n=12) and carcinoma (CA, n=8). Sections were immunostained against p53 and epithelium was microdissected on consecutive sections with subsequent amplification for LOH of p53 (17p). Staining with anti-p53 was positive in HGD (9 of 12) and CA (7 of 8). Percent positive cells were less in HGD than in CA. LOH of p53 was present in HGD (5 of 12) and CA (5 of 7). Of cases with <10% of positive cells, including negative cases, 50% also showed LOH. These results suggest that most cases with prominent p53 overexpression but also significant numbers of cases with weak or negative expression have associated allelic p53 deletion. We conclude that i) immunohistochemical stains but not LOH for p53 correlate with progression of dysplasia to carcinoma, ii) p53 immunohistochemistry appears to more accurately predict biologic behavior of dysplasia and carcinoma in UC compared to allelic deletion studies alone. Further microdissection studies are necessary to evaluate the possibility of different carcinoma risk in patients with low percentage of p53 overexpression and associated LOH.
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PMID:Comparison of p53 immunoexpression with allelic loss of p53 in ulcerative colitis-associated dysplasia and carcinoma. 946 83

Carcinoma in ulcerative colitis (UC) develops from dysplastic precursor lesions, which include flat dysplasia (FD) and polypoid dysplasias (PD). PD may present as single or multiple polypoid structures or as plaque-like lesions that, independent of histological grade, are an indication for colectomy. PDs are histologically similar to adenomas and may not be readily distinguished by light microscopy. It is not known whether FD and PD are different entities, or whether they represent etiologically similar lesions with different morphological expression. We microdissected 25 cases of UC with PD and 19 samples of FD with surrounding chronic colitis (CC) in UC. Loss of heterozygosity (LOH) at the von Hippel Lindau (vHL) gene locus and the putative tumor suppressor genes APC, INK4A (9p16), and p53 was studied. LOH of the vHL gene, INK4A (9p16), and APC was also studied in 11 sporadic adenomas of the colon. LOH at the vHL locus was present in 50% of the samples of PD and in 12% of the samples of FD. LOH was seen in CC close to PD and FD in 26% and 12% of cases, respectively. No adenoma showed LOH of the vHL gene markers studied. LOH in p53 was seen in PD in 16% cases and in FD in 42% cases and in CC close to PD and FD in 0% and 14% cases, respectively. LOH patterns between PD and FD of the markers for APC and 9p16 were not different. LOH in APC was seen in two of five cases of adenoma. We conclude that PD and FD share genetic alterations in APC and 9p16 genes. More frequent involvement of the VHL gene in PD and surrounding CC and involvement of p53 in HGD and CC in FD may represent genetic differences between the development of PD and FD and may be the cause of the different morphology. The infrequency of LOH at the vHL locus in adenomas versus PD may serve as a discriminator between adenomas and PD in diagnostically problematic cases.
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PMID:Loss of heterozygosity of the von Hippel Lindau gene locus in polypoid dysplasia but not flat dysplasia in ulcerative colitis or sporadic adenomas. 974 12

Increased protein expression of the G1 cyclins D1 and E is reported in invasive non-small cell lung carcinoma. However, during transformation of the bronchial epithelium, overexpression of these species occurs, and their relationship to aberrant expression of p53 and retinoblastoma (Rb) has not been described previously. To determine the expression of these cell cycle regulators during the development of invasive squamous cell carcinoma (SCC) of the lung, the immunohistochemical expression patterns in normal bronchial epithelium (n = 36), squamous metaplasia (SM; n = 28), and epithelial atypia (n = 34) were compared with that in low-grade dysplasia (LGD; n = 17), high-grade bronchial dysplasia (HGD; n = 30), and SCC (n = 36). Monoclonal anti-p53 Pab1801, polyclonal anti-cyclin D1 DCS6, monoclonal anti-cyclin E HE12, and monoclonal anti-Rb OP-66 antibodies were used. Cyclin D1 was not expressed in normal bronchial epithelium but was detected in 7% of SMs, 15% of atypias; 18% of LGDs, 47% of HGDs, and 42% of SCCs. Cyclin E was not detected in normal epithelium (n = 24), SM (n = 16), or LGD (n = 12), but it was found in 9% of atypias (2 of 22), 33% of HGDs (7 of 21), and 54% of SCCs (13 of 24). p53 was not expressed in normal epithelium, SM, and LGD, but it was overexpressed in 6% of atypias, 53% of HGDs, and 61% of SCCs. Abnormal Rb expression was found only in 2 of 36 cases of SCC. A total of 91% of HGDs and 92% of SCCs exhibited overexpression of at least one of the p53, cyclin D1, or cyclin E species. However, no link was observed between overexpression of p53 and the overexpressed G1 cyclins in preneoplastic lesions. Overexpression of cyclin D1, cyclin E, and p53 occurs frequently and independently in pulmonary SCC and is detected in lesions before the development of invasive carcinoma. In contrast, altered Rb expression is a late and infrequent event in squamous cell carcinogenesis.
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PMID:Overexpression of cyclins D1 and E is frequent in bronchial preneoplasia and precedes squamous cell carcinoma development. 1034 60

In order to evaluate the usefulness of p53 immunohistochemistry (IHC) in the diagnosis of ulcerative colitis-associated colorectal carcinoma (UCACRC), ordinary paraffin sections were examined in 61 cases with ulcerative colitis (UC) and 29 control cases without UC. Among the 61 cases with UC, 11 were complicated by carcinoma coexisting with dysplasia, three with dysplasia, and two cases with adenoma. There were a total of 38 dysplasias, including 33 low grade dysplasias (LGD) and five mixed low and high grade dysplasias (LGD + HGD). The results of p53 IHC were divided into diffuse, nested, scattered and sporadic patterns for 29 control cases. Diffuse and nested patterns were presumed to reflect mutant forms of p53 protein and were defined as overexpression of p53 protein. In non-neoplastic mucosa of UC, the frequency of p53 positive tubules was significantly higher in active phase (13.5-17.9%) than in resolving phase (3.9-6.5%) and in remission (0.7-2.4%), regardless of association with neoplasia. Eight of the 37 lesions of dysplasia (21. 6%) showed p53 overexpression: 12.5% in LGD and 80.0% in LGD + HGD. The rate of p53 overexpression was significantly higher in UCACRC (90.9%) than in non-neoplastic mucosa of UC (0%), LGD and sporadic colorectal carcinoma (54.5%), but it did not differ between UCACRC and LGD + HGD. Interestingly, the mucosa without dysplasia showed p53 overexpression in one case of UCACRC. The biopsy specimen taken 4 years before the diagnosis of carcinoma revealed p53 overexpression in another case with UCACRC. These results suggest that p53 abnormalities play an important role in UC-associated tumorigenesis in its relatively early phase. For the diagnosis of dysplasia and carcinoma in UC, p53 IHC seems to be useful.
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PMID:p53 immunohistochemistry of ulcerative colitis-associated with dysplasia and carcinoma. 1057 18

The significance of p53 mutations and DNA aneuploidy in carcinoma cells has been investigated on the basis of a multi-step development theory of carcinogenesis. It has, however, not been determined whether these alterations can be used as diagnostic markers for the early detection of bronchial squamous cell carcinoma (BSqCC). To address this problem, we topographically investigated p53 alterations and DNA aneuploidy in 24 X-ray-negative, early BSqCC patients with various preneoplastic lesions and in 25 non-carcinoma patients with preneoplastic lesions. Bronchial lesions (n=88) were morphologically classified as hyperplasia (HP, n=5), squamous metaplasia (SM, n=23), low-grade dysplasia (LGD, n=14), high-grade dysplasia (HGD, n=11), intraepithelial carcinoma including 'carcinoma in situ' (CIS) (IEC, n=15), and microinvasive carcinoma (MIC, n=20). Immunohistochemistry for the p53 protein and image cytometry for DNA ploidy detection were performed in serial sections of each lesion. Overexpression of p53 protein was detected in 36, 73, and 65% of the HGD, IEC, and MIC lesions, respectively. Aneuploid DNA profiles were found only in carcinoma lesions, 33% in IEC and 85% in MIC. The topographical analysis revealed two types of early BSqCCs, one with adjacent preneoplastic lesions (sequential type, n=8) and another without such lesions (de novo type, n=16). The p53 protein was frequently overexpressed in both types (sequential type, 79%; de novo type, 62%). In the sequential type, however, the p53 protein was overexpressed in HGD lesions that were directly adjacent to p53-overexpressing carcinoma lesions without exception. The present topographical study suggests that p53 mutations play an important role in the carcinogenesis of BSqCC and that p53-overexpressing HGD lesions in sequential types should be regarded as 'truly' preneoplastic lesions that actually develop into carcinomas. In addition, our study demonstrated that DNA aneuploidy might occur at times after p53 alteration with increasing frequency, as invasive growth begins. Such combination analysis of p53 immunohistochemistry and nuclear DNA ploidy in routine histology may contribute to estimates of malignant potential in preneoplastic and intraepithelial squamous lesions and provide additional information for early detection of BSqCC.
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PMID:Topographical analysis of p53 expression and DNA ploidy in early bronchial squamous cell carcinoma and preneoplastic lesions. 1171 32

Precursor lesions in the GIT include flat dysplasias, adenomas, dysplasia superimposed on nonneoplastic polyps, endocrine cell dysplasia, ACF, and condyloma accuminatum. Interobserver variability can be a problem in reporting dysplasia, and ancillary techniques including flow cytometry, image analysis, proliferation markers, and examination for p53 expression can help in this task. Squamous dysplasia seen in the esophagus and anus is graded on either a two-tiered or three-tiered system largely based on the extent of mucosal involvement. Glandular dysplasia is morphologically similar whether seen as an adenomatous polyp or within the setting of Barrett's esophagus, atrophic gastritis, or idiopathic inflammatory bowel disease. The distinction between LGD and HGD in glandular mucosa is based on the severity of cytologic and architectural distortion. Type I dysplasia is the classic adenomatous pattern seen most commonly and recognized by the presence of elongate hyperchromatic stratified nuclei. Type II, the nonadenomatous variant, contains vesicular nuclei and alteration in nuclear size and shape. Nonantral endocrine dysplasia in the stomach is seen in the setting of corporal predominant atrophic chronic gastritis and Zollinger-Ellison syndrome with Multiple Endocrine Neoplasia syndrome type I. Condyloma accuminatum is a HPV-related lesion most commonly seen in men practicing anal intercourse. Superimposed squamous dysplasia can be seen with HGD most frequently in the HIV-positive population. Recognition of the different classification systems of dysplasia, the most frequent settings in which these lesions are found, and their natural history is important for all practicing gastroenterologists and pathologists.
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PMID:Histologic precursors of gastrointestinal tract malignancy. 1213 10

The aim of this study was to clarify the mechanism of malignant transformation of gastric hyperplastic polyps, focusing on phenotypic expression, cell proliferation, and p53 overexpression. Twenty-two lesions of gastric hyperplastic polyps with neoplastic foci were selected for this study. The phenotypes were divided into 3 types (G, gastric; incomp I, incomplete intestinal; and comp I, complete intestinal), according to immunohistochemical stains (human gastric mucin [HGM], MUC2, and CD10). The cell proliferative activity by Ki-67 and overexpression of p53 protein were also examined. Eleven of these lesions contained carcinoma components (CA, category 5 by the Vienna classification), 6 of which were accompanied by low-grade dysplasia (LGD, category 3) and 4 of which were accompanied by high-grade dysplasia (HGD, category 4). Another 2 were composed only of HGD, and the remaining 9 were composed of both LGD and HGD components. As a result, 15 LGD, 15 HGD, and 11 CA components were recognized. The 15 LGD components were classified as 1 G type and 14 incomp I type. All hyperplastic components expressed HGM, 5 (22.7%) of which were accompanied by focal intestinal metaplasia demonstrated by MUC2 expression, whereas intestinalization frequently occurred in neoplastic components (93% of LGD, 53% of HGD, and 64% of CA components). The labeling index was 22.2% in hyperplastic, 42.2% in LGD, 55.7% in HGD, and 53.9% in CA components. p53 protein overexpression was recognized in none of hyperplastic, in 40% of the LGD, in 60% of the HGD, and in 45% of the CA components. These results suggest the importance of the dysplasia-carcinoma sequence in malignant transformation of hyperplastic polyps. Interestingly, intestinalization frequently occurs during neoplastic transformation, although it is not common in the surrounding hyperplastic components.
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PMID:Malignant transformation of gastric hyperplastic polyps: alteration of phenotypes, proliferative activity, and p53 expression. 1239 75

This article provides a framework for clinicians who are attempting the difficult task of interpreting the Barrett's biomarker literature with the goal of improving care for their patients. Although many articles. including more that 60 proposed biomarkers, have been published on this subject, only a few describe phase 3 and 4 studies that are of interest to the clinical gastroenterologist (Table 1). For year, dysplasia grade has been the sole means of risk stratification for patients with BE, and it likely will continue to be used in the foreseeable future. The current authors believe that dysplasia classification can be valuable using the team management approach and quality controls described previously. Significant problems, however, have emerged in phase 2 through 4 studies of dysplasia that make it imperative for the Barrett's field to incorporate additional biomarkers as they are validated. These problems include poor reproducibility of dysplasia interpretations, poor predictive value for negative, indefinite, and low-grade dysplasia, and inconsistent results for HGD in different centers, all of which makes it virtually impossible to develop national guidelines for surveillance. Some studies have even suggested that endoscopic biopsy surveillance using dysplasia may not be worthwhile. Currently, flow cytometric tetraploidy and aneuploidy have progressed furthest in biomarker validation (see Table 1). With proper handling, endoscopic biopsy specimens can be shipped to reference laboratories that have the instruments, computer analytic methods, and expertise to reproducibly detect tetraploidy and aneuploidy. The results of phase 4 studies indicate that flow cytometry appears to be useful in detecting a subset of patients who do not have HGD and yet have an increased risk of progression to cancer that cannot be identified by dysplasia grade. For many reasons, the authors anticipate that the number of validated biomarkers will increase substantially in the future. Biopsy repositories are now readily available for phase 3 studies that can evaluate and compare biomarkers. There are initiatives for multi-institutional Barrett's Centers of Excellence that could provide rapid progress in biomarker evaluation. In addition to new candidate biomarkers, the human genome project has provided high-throughput methodologies and methods for computer analysis of data, which can provide the volume and quality control required for clinically useful biomarkers. Currently, 17p (p53) LOH has progressed the furthest among molecular biomarkers. The authors do not recommend its routine clinical use at the present time, however. Finally, it is likely that clinicians will want to follow the results of clinical treatment-response studies and epidemiologic studies that evaluate relationship between clinical interventions or environmental risk and protective factors and surrogate endpoints, especially if the endpoints are progessing well along the phases of biomarker validation. These studies are likely to be of clinical interest because they may becoming the basis for randomized clinical trials to prevent cancer in BE.
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PMID:Biomarkers in Barrett's esophagus. 1291 66


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