Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0278883 (metastatic melanoma)
 6,224 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Nine metastatic melanoma cell lines and two melanocyte cell lines were analyzed for point mutations in highly conserved regions of the p53 gene. No mutations were detected in the two melanocytic cell lines and in eight melanoma cell lines. However, a C----T transition at codon 248, resulting in a substitution of tryptophan for arginine, was found in one melanoma cell line. On immunohistochemical staining, only this cell line showed reactivity for mouse monoclonal antibody 1801, which is immunoreactive with human p53 protein. The original paraffin-embedded specimen from which this mutant cell line was established was obtained, and sequence analysis detected the identical mutation in the p53 gene as that seen in the derived cell line. This is the first report indicating point mutations in the p53 gene in malignant melanocytic tissues.
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PMID:Mutational analysis of the human p53 gene in malignant melanoma. 192 72

Mutant p53 has been noted in a variety of human malignancies including carcinomas of lung, breast, and colon, which have also been reported to have frequent karyotype anomalies involving the locus of the p53 gene (17p13). Whereas chromosomal abnormalities of chromosomes 1, 6, and 7 have been noted previously in melanoma, frequent aberrations in chromosome 17 have not been reported previously. Due to the common mutation of this locus in so many types of neoplasms, a range of melanomas from different stages of tumor progression were examined immunohistochemically for expression of mutant p53, in order to assess its prevalence and consider the role of this oncogene in the biological progression of melanoma. Forty-five of 53 (85%) specimens from a range of primary and metastatic melanomas were found to have detectable evidence of p53 gene mutation, by virtue of the immunohistochemical detection of mutant p53 protein. Significantly increased prevalence of mutant p53 was found in metastatic melanoma, compared with primary tumors (P less than 0.05). These findings represent one of the highest incidences of this oncogenic mutation yet recorded in a human malignancy and support the concept that p53 may have a functional role in development of the metastatic tumor phenotype.
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PMID:Expression of mutant p53 in melanoma. 193 61

The WAF1 gene, located on chromosome 6p, encodes a M(r) 21,000 protein (p21) that can arrest cell growth by associating with and inhibiting cyclin-dependent kinase complexes that are necessary for cells to exit Gr. Transcriptional activation of WAF1 can be accomplished by increasing levels of p53 protein induced by various cellular stresses, including DNA damage. Metastatic melanomas are paradoxical in that most overexpress wild-type p53 protein, yet cell growth is not inhibited. Thus, it is possible that lack of growth suppression in melanomas is due, in part, to mutations in the WAF1 gene. Therefore, we examined the entire coding region of the WAF1 gene in 24 metastatic melanoma cell lines and three normal melanocyte lines by single-strand conformation polymorphism (SSCP) analysis and direct DNA sequencing. We similarly examined the DNA from lymphoblastoid cell lines, derived from nine individuals belonging to seven melanoma-prone families, in which haplotypes of markers on 6p cosegregate with melanoma for germline mutations in the WAF1 gene. Results indicate that (i) mutation of the WAF1 gene is an infrequent event in individuals with sporadic melanoma or predisposed to familial melanoma and (ii) the uncontrolled growth of melanoma cells is not due to mutation of the WAF1 gene. However, expression studies found a wide variation in the level of p21 protein in melanoma cells, suggesting that aberrant regulation of p21 may play a role in melanoma development. Moreover, there was no predictable relationship between p21 expression and p53 expression, indicating that other, p53-independent, pathways may be important for the regulation of p21 in melanoma cells.
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PMID:Mutations and defective expression of the WAF1 p21 tumour-suppressor gene in malignant melanomas. 749 59

We have examined melanocytic cells derived directly from fresh biopsy tissue for the presence of p53 mutations. Using selective media that permits growth of melanocytes and inhibits growth of fibroblasts and keratinocytes, we established short-term, primary cultures of melanocytes from skin biopsies of common acquired nevi, dysplastic nevi, and from metastatic melanoma. Using PCR-single-stranded conformational polymorphism analysis, we have detected p53 mutations in 2 of 11 benign compound nevi and 2 of 5 dysplastic nevi. All nevi positive for p53 mutations were derived from patients who previously had cutaneous moles and three of the four had a family and/or personal history of melanoma.
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PMID:Detection of p53 mutations in benign and dysplastic nevi. 767 Dec 35

Alterations in the function of p53, a tumor suppressor gene, have been postulated as a principal underlying mechanism involved in the loss of cell cycle control in human malignancies. Because p53 dysfunction is generally associated with protein overexpression, immunocytochemistry is a valuable technique for the analysis of p53's functional status. We tested the hypothesis that loss of p53 function is a critical event in the early development and progression of human malignant melanoma and can lead to alterations in cell proliferation. We performed an immunocytochemical study in archival fixed, embedded specimens that included 102 melanocytic lesions ranging from benign nevi to metastatic melanoma. In addition to p53, we assessed the p53-associated protein, mdm-2, and markers of cell cycle status (the MIB-1-defined cell proliferation marker; proliferating cell nuclear antigen; and statin, a 57-kDa nuclear protein expressed preferentially by G0 cells). Tumor expression of all nuclear proteins was scored in a semiquantitative fashion related to the fraction of positive tumor nuclei. The overall incidence of significant p53 overexpression was low (8% of primary and 14% of metastatic melanomas). Analysis demonstrated strong correlation between increasing p53 expression in primary versus metastatic lesions (chi 2 analysis, P = 0.001). Correlation was found between increased MIB-1-defined cell proliferation and p53 overexpression in primary melanomas (P = 0.02). Detectable mdm-2 expression was significantly correlated with p53 overexpression (P = 0.02). Comparison of statin and proliferating cell nuclear antigen indices demonstrated inverse correlation (chi 2 , P = 0.03) in the combined groups, but within the metastatic group there was a subset of cases strongly expressing the two markers.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:p53 and mdm-2 expression in malignant melanoma: an immunocytochemical study of expression of p53, mdm-2, and markers of cell proliferation in primary versus metastatic tumors. 767 73

Recent studies on the role of the p53 gene in human melanoma have largely been contradictory. To further assess p53 expression in melanoma, we have studied p53 immunoreactivity in 87 cases of primary, recurrent, and metastatic melanoma. Routine immunostaining was performed on paraffin sections with the monoclonal antibody PAb1801 and a streptavidin-biotin method. All specimens were blindly and independently assessed by two observers for number of melanoma cells with granular nuclear staining. Seven melanomas (8%) exhibited from 1 to 50% positive cells and another eight cases (9%) showed p53 immunoreactivity in < 1% of cells. All of the melanomas found to be positive for p53 with one exception (< 1.50 mm) were either thicker than 1.50 mm, recurrent, or metastatic. We conclude that these findings provide little evidence for significant p53 alteration in the initiation and development of melanoma.
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PMID:p53 expression in cutaneous malignant melanoma: an immunohistochemical study of 87 cases of primary, recurrent, and metastatic melanoma. 793 17

p53, A tumor suppressor gene, has been documented as the most frequently mutated gene in human cancers including non-melanoma skin tumors. It has been controversial whether the p53 gene mutation plays a major role for melanoma genesis. To examine the role of p53 in human malignant melanoma carcinogenesis, we performed immunohistochemical analysis using anti-p53 antibodies (CM-1 and DO-7) in microwaved paraffin sections. When cases having more than 1% reactive cells were regarded as positive, immunohistochemical analysis revealed that in primary melanomas 14 of 51 (27%) were positive with CM-1 or 15 of 51 (29%) were positive with DO-7. Tumor thickness of primary melanomas in p53 positive cases was significantly thicker than that in p53 negative cases. In metastatic melanomas, 35 of 41 (85%) lymph node metastases were positive with either antibody and in skin metastases 16 of 28 (57%) lesions with CM-1 or 18 of 28 (64%) lesions with DO-7 were positive. The mean percentages of reactive cells were 2.3% in primary lesions and 4.9% in metastases. The incidence of positivity was significantly higher in metastases than primary lesions. In 10 cases examined, with both primary and metastatic melanoma, 3 cases were negative in both lesions and 1 case was positive in both lesions, while 6 cases were negative in the primary lesions and positive only in metastatic lesions. Four Spitz nevi, 6 dysplastic nevi and 11 common nevi were all negative. These data suggest that the expression of p53 protein may be a late event in melanoma progression.
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PMID:Expression of p53 protein in melanoma progression. 881 40

An inverse correlation between the nm23 RNA level and tumour progression of melanocytes has been reported. To elucidate whether the expression of nm23 gene product in malignant melanoma is also inversely correlated with metastatic potential, conventional prognostic parameters or the tumour suppressor protein p53, immunohisto-chemical studies using a monoclonal antibody against nm23-H1 protein were performed on 138 benign and malignant melanocytic tumours. The expression of nm23 protein was compared with that of p53 protein and conventional clinicopathological prognostic factors. The nm23 protein level in benign melanocytes and metastatic melanoma cells was also studied by Western blot analysis. No significant difference regarding the protein was observed between naevi and melanomas, either at histological or protein levels. The expression correlated with local recurrence within 1 year after surgery, level of invasion and tumour thickness, but no parallels were observed between the nm23 and p53 proteins, suggesting that gene is regulated by independent mechanisms, although located on the same chromosome. There was no inverse correlation between the nm23 protein and melanoma metastasis which suggested that the nm23 protein does not appear to be lost during melanoma metastasis.
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PMID:Expression of metastasis suppressor gene product, nm23 protein, is not inversely correlated with the tumour progression in human malignant melanomas. 897 56

p21(WAF1/CIP1) (p21) is an inhibitor of cyclin-dependent kinases recently identified as the downstream effector of wild-type p53-mediated cell cycle arrest. The gene coding for p21 may function as a negative regulator of melanoma growth, progression, and metastasis. Using immunohistochemistry and Western blotting, we investigated the expression of p21 in human melanocytic proliferations. Immunohistochemical staining was performed on 13 common acquired nevi, 12 dysplastic nevi, 23 primary malignant melanomas, and 12 metastatic melanomas. Common acquired nevi showed minimal p21 staining (1.8+/-0.3%, mean+/-SEM). The percentage of positive nuclei was slightly elevated in dysplastic nevi (8.9+/-1.7%). Both primary malignant melanoma (29+/-3%) and metastatic melanoma (33+/-5%) demonstrated a significantly increased number of p21-positive nuclei compared to benign lesions (p<0.001). p21 was strongly expressed even in actively proliferating lesions as confirmed by MIB-1 labelling, and although the majority of p21-positive cells likely represent a non-proliferating population, staining was occasionally observed in cells undergoing mitosis, suggesting abnormal function of this cell cycle inhibitor in malignant melanoma. Overexpression of p21 in metastatic melanoma compared to common acquired nevi was confirmed by Western blot analysis of human tumor samples. These findings suggest that increased p21 expression relative to benign nevi is not sufficient to control melanoma growth in vivo.
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PMID:Overexpression of the cyclin-dependent kinase inhibitor p21(WAF1/CIP1) in human cutaneous malignant melanoma. 919 78

On the basis of reports linking mutant p53 (mp53) to decreased expression of the angiogenesis inhibitor thrombospondin-1 (TSP-1) and increased angiogenesis, we compared primary and metastatic melanoma tumor specimens to determine if these factors were associated with metastatic progression. Western blotting, immunohistochemistry (IHC), and image analysis (IA) techniques were employed to evaluate the relationship between p53 status and TSP-1 expression in Zaz and M14 melanoma cell lines, and among p53, TSP-1, and angiogenesis in primary and metastatic melanomas. Zaz cells expressed wild-type p53 (WT p53) and high levels of TSP-1, while the M14 cells expressed mp53 and low TSP-1 levels. Examination of clinical melanoma specimens (N = 99) revealed an incidence of mp53 of 48%. Specimens with WT p53 (N = 46) expressed significantly higher mean levels of TSP-1 (41 +/- 27 vs. 21 +/- 24; p = 0.0004), and lower microvessel counts per 200x field (25 +/- 17 vs. 40 +/- 20; p = 0.0001) than tumors expressing mp53 (N = 42). A significantly higher incidence of mp53 expression was seen in metastatic tumors (64%, 37/58) than in primary tumors (27%, 11/41)(p < 0.0005). Primary tumors specimens had higher levels of TSP-1 (40 +/- 27 vs. 25 +/- 25; p = 0.0054) and lower microvessel counts (26 +/- 18 vs. 39 +/- 20, p = 0.0013) than metastatic tumors. These data suggest that acquisition of mp53, decreased TSP-1, and increased microvessel infiltration may be interrelated and associated with the metastatic phenotype in malignant melanoma.
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PMID:Mutant p53 correlates with reduced expression of thrombospondin-1, increased angiogenesis, and metastatic progression in melanoma. 961 39


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