Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P43146 (tumour suppressor)
 5,935 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The CDKN2 gene, encoding the cyclin dependent kinase inhibitor p16, is a tumour suppressor gene involved in melanoma and maps to chromosome band 9p22. Mutations or interstitial deletions of this gene have been found both in the germline of familial melanoma cases and somatically in melanoma cell lines. Previous mutation analyses of melanoma cell lines have indicated a high frequency of C:G to T:A transitions, with all of these mutations occurring at dipyrimidine sites. Including three melanoma cell lines carrying tandem CC to TT mutations, the spectrum of mutations so far reported indicates a possible role for u.v. radiation in the mutagenesis of this gene in some tumours. To further examine this hypothesis we have characterised mutations of the CDKN2 gene in 30 melanoma cell lines. Nineteen lines carried complete or partial homozygous deletions of the gene. Of the remaining cell lines, eight were shown by direct sequencing of PCR products from exon 1 and exon 2 to carry a total of nine different mutations of CDKN2. Two cell lines carried tandem CC to TT mutations and a high rate of C:G to T:A transitions was observed. This study provides further evidence for the role of u.v. light in the genesis of melanoma, with one target being the CDKN2 tumour suppressor gene.
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PMID:Evidence for u.v. induction of CDKN2 mutations in melanoma cell lines. 765 29

In the present study, we investigated the expression of the tumour suppressor protein p53 in 113 primary and 43 metastatic malignant melanomas by immunohistochemistry, and correlated the findings with clinicopathological parameters such as histological melanoma subtype, thickness of primary melanomas (Breslow thickness) and patient outcome. In primary melanomas, the polyclonal anti-p53 antibody CM-1 detected immunoreactivity in 70% of the lesions, predominantly in the cytoplasm. Signals were observed in this cellular compartment in 57% of the melanomas, whereas in 32% nuclear p53 over-expression was detected. Immunohistochemistry, using the monoclonal antibody DO-1, revealed lower staining frequencies. However, both antibodies showed congruent results in approximately 80% of the cases. Overall, immunoreactivity was observed in 73% of superficial spreading melanomas, but only in 52% of lentigo maligna melanomas. This difference (P < 0.001) was mainly due to a lower frequency of cytoplasmic immunoreactivity (P < 0.002). There was no difference with respect to cytoplasmic and nuclear immunoreactivity between thin (< 1 mm thickness) and thicker primary melanomas. Staining frequencies detected in metastatic lesions seemed to be lower than in primary tumours. In 103 primary melanomas, follow-up data for at least 5 years were available. In 71% (54 of 76) of the primary melanomas which did not recur, and in 78% (21 of 27) of tumours with subsequent metastases, p53 over-expression was detected by CM-1. However, this difference was not statistically significant. The results of the present study indicate that immunoreactivity to anti-p53 antibodies is a common observation in malignant melanomas, with staining signals predominantly found in the cytoplasm of cells.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Expression of p53 protein in malignant melanoma: clinicopathological and prognostic implications. 766 36

It is currently widely accepted that the tumour suppressor gene p53 is critically involved in the proliferation and differentiation of tumour cells including melanoma cells. In the present study, we examined 60 cases of primary melanoma to compare the expression of p53 protein with conventional prognostic markers for melanoma such as clinical and histological parameters. No correlation was found between the p53 protein and clinical factors except for the presence of a metastatic node and development to clinical stage II. However, the expression of p53 protein was significantly associated with tumour thickness over 1.5 mm, levels IV and V of invasion, the presence of ulceration, and high mitotic rate for 5-year survival rate. Although many questions still remain to be answered, our results and those of others for various other malignant tumours, implicate p53 in malignant transformation of pigment cells. Indeed, it could be a new marker for an unfavourable prognosis of malignant melanoma, even though the gene mutation in this highly lethal tumour has yet to be established.
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PMID:Expression of the p53 protein in malignant melanomas as a prognostic indicator. 776 85

Following reports of linkage to chromosome 9p in families with malignant melanoma, we have been studying a series of UK families. Six families were selected with three or more cases of malignant melanoma. We have used a total of twelve markers mapping in the interval 9p13-p23 and constructed a set of haplotypes to study the inheritance of the disease chromosome. Of the six families, three were consistent with linkage to the short arm of 9, although their limited size precluded confirmation of linkage. One family was clearly unlinked, one family was either unlinked, or contains a sporadic case, or delimits the location of the melanoma gene, and one family was essentially uninformative. This is strong evidence for genetic heterogeneity in families with the malignant melanoma phenotype. We have also sequenced exon 2 of the recently identified candidate tumour suppressor gene, p16, in six individuals and found no evidence for germline mutations in this region of the p16 gene in our families with inherited malignant melanoma.
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PMID:Genetic heterogeneity in familial malignant melanoma. 788 19

Melanoma may cluster in families with 'family cancer syndromes' in which there is a predisposition to a variety of different tumours. Other families seem vulnerable to melanoma alone. In the majority of these families, the propensity to melanoma is associated with the presence of abnormal melanocytic naevi, the so-called atypical mole syndrome (AMS) phenotype. However, in a smaller number of families, individuals are susceptible to melanoma but have normal naevi. There appears, therefore, to be clinical (and probably genetic) heterogeneity. Segregation analysis does not support a predisposition by single dominant gene as an explanation for the AMS/melanoma syndrome. To date, a single gene which is clearly important for susceptibility to melanoma has not been identified. Karyotypic studies of melanoma tumours have pointed to chromosomes 1, 6, 7, 9 and 10 as possible sites for melanoma related genes. Loss of heterozygosity studies have suggested that chromosome 9 may carry a tumour suppressor gene important in familial disease, and linkage studies appear to confirm this. It is not yet clear, however, what percentage of familial melanoma is attributable to this gene. A more longstanding suggestion that a gene on chromosome 1 may be important has not been confirmed, but a chromosome/gene may be responsible for susceptibility in a small subset of melanoma families. Even within AMS families, there is a lack of concordance between the AMS phenotype and susceptibility to melanoma. This might be explained either by the effects of modifying genes, or the environment.
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PMID:Genetics of melanoma. 798 47

Karyotypic analysis, loss of somatic heterozygosity, microcell fusion and cDNA transfection studies have provided compelling evidence that at least one tumour suppressor gene for melanoma resides on chromosome 6. In an attempt to further define the regions to which these putative suppressor genes map, we have carried out loss of heterozygosity (LOH) studies on DNA from 25 fresh melanoma tumours for 9 simple tandem repeat (STR) polymorphism markers spanning chromosome 6. Four samples displayed LOH or homozygosity for all markers studied, indicating that they had lost one homologue of chromosome 6. An additional 3 samples showed LOH for all markers on 6q. Furthermore, 30 melanoma cell lines, for which there were no matching somatic DNA samples, were analyzed for hemizygosity of markers on 6q. One cell line had a homozygous deletion of all markers tested and a further 12 cell lines displayed only one allele for 3 or 4 contiguous markers, indicating that most, if not all of these samples were hemizygous for the region of 6q distal to D6S87. Overall, the rate of LOH on 6q in the 55 melanoma DNAs was 35%, and there were no losses of markers on 6p without concomitant loss of markers on 6q. Two of 5 samples derived from primary melanomas showed LOH, which indicates that LOH for the melanoma suppressor gene on 6q, which maps to a region that contains the SOD2 locus, is a frequent and early event in melanoma tumorigenesis.
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PMID:Simple tandem repeat allelic deletions confirm the preferential loss of distal chromosome 6q in melanoma. 802 82

A gene for familial melanoma (MLM) has been mapped to 9p22-p13 by linkage analysis using simple tandem repeat polymorphisms (STRPs) at the IFNA and D9S126 loci. This localization is consistent with the finding of homozygous deletions of these markers in DNA from two melanoma cell lines, which suggest that the locus has the properties of a tumour suppressor gene. In an attempt to further define the position of the MLM locus we have typed 10 STRPs from the short arm of chromosome 9 in 15 Australian melanoma kindreds. Extended haplotype analysis of these markers and identification of recombinants in our pedigrees indicate that the MLM gene is flanked on the centromeric side by D9S169 and on the telomeric side by D9S156. These results limit the location of the MLM locus to an interval of about 16 centimorgans.
Melanoma Res 1994 Feb
PMID:Haplotype analysis limits the position of the familial melanoma locus on 9p to the D9S169-D9S156 interval. 803 15

The expression of the tumour suppressor gene p53 was analyzed in a variety of human solid tumours by immunohistochemistry and direct DNA sequencing. Positive nuclear staining using a panel of anti-p53 antibodies was used to select tumours for further genetic analysis. Using PCR amplification followed by immobilization onto magnetic beads and direct sequencing, we sequenced exons 5-9 of the p53 gene from 9 melanomas, 8 nasopharyngeal carcinomas, 16 sporadic breast carcinomas and 11 patients from familial breast cancer families. No sequence alterations of the p53 gene were detected in either the melanoma or nasopharyngeal tumours and only 19% of the primary breast carcinomas showed a variant band indicative of a mutation. Our results indicate firstly that p53 mutations are not generally involved in the tumour types studied and secondly the data emphasize the disparity encountered when attempting to correlate p53 immunohistochemical positivity with mutations within the p53 gene.
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PMID:p53 protein detected by immunohistochemical staining is not always mutant. 808 13

Various lines of evidence including linkage analysis, frequent homozygous and heterozygous deletions in melanoma DNAs, and the finding of a patient with multiple primary melanomas who harbours a 5p/9p translocation involving loss of several 9p markers, have indicated that the 9p22-p13 region harbours a gene important for the development of melanoma (MLM). We have used eight short tandem repeat polymorphism (STRP) markers mapping to this region to look for allelic losses in DNA from melanoma biopsies and cell lines. Heterozygous losses were found in 8/14 (57%) fresh melanoma biopsy DNAs with the smallest region of overlap (SRO) being between IFNA and D9S169. In addition, when DNA from 30 melanoma cell lines was studied, four cell lines (13%) were found to be homozygously deleted for various 9p markers. Two of these cell lines define the borders of overlapping homozygous deletions within a 4cM region of 9p21 between IFNA and D9S171. Moreover, a further 14 melanoma cell lines were hemizygous for the IFNA/D9S171/D9S126 region. These data support the hypothesis that the MLM gene acts as a tumour suppressor, and provide a refinement of its localization on 9p.
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PMID:Refined localization of the melanoma (MLM) gene on chromosome 9p by analysis of allelic deletions. 810 24

Recent studies have implicated chromosome 9p21-22 as a location for a gene involved in cutaneous melanoma (CM). Deletion mapping in 35 matched tumour-constitutional DNA pairs from metastatic melanomas (including one melanoma cell line) and one dysplastic naevus has been performed using six short tandem repeat polymorphic (STRP) markers (D9S157-D9S162-IFNA-D9S171-DS9126-D9S10 4 ) which span approximately 19 cM across the 9p21-22 region. Both heterozygous and homozygous deletions were observed across the region in melanomas from both sporadic and familial cases. Overall 57% (20/35) of the samples displayed some form of loss. A deletion map identifies two areas of common loss either side of the interferon gene cluster. Familial CM has previously been shown to link to the more proximal of these regions. The deleted region distal to IFNA has not been previously described in melanoma. The results imply the involvement of more than one tumour suppressor gene on 9p in CM.
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PMID:Loss of heterozygosity and homozygous deletions on 9p21-22 in melanoma. 815 96


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