Lack of allelic deletion and point mutation as mechanisms of p53 activation in human malignant melanoma

Castresana, Javier S.; Rubio, Mari-Paz; Seizinger, Bernd R.; Vázquez, J. J.; Idoate, Miguel A.; Sober, Arthur J.; Barnhill, Raymond L.

doi:10.1002/ijc.2910550407

Cited by 94 publications

(65 citation statements)

References 15 publications

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“…These findings sharply contrast with the situation in human melanoma, in which p53 mutations are not commonly detected (Volkenandt et al, 1991;Castresana et al, 1993;Weiss et al, 1993;Lübbe et al, 1994;Albino et al, 1994;Florenes et al, 1994;Montano et al, 1994;Sparrow et al, 1995;Hartmann et al, 1996;Papp et al, 1996), with frequencies ranging from 0 to 6% in tumour samples (Castresana et al, 1993;Florenes et al, 1994;Lübbe et al, 1994;Papp et al, 1996). However, mutations in the N-ras gene have been shown to occur in at least 15% of melanomas (van Elsas et al, 1996) and occur more frequently in tumours from sun-exposed body sites compared with tumours from intermittently or unexposed sites, implicating sun exposure in the aetiology of these melanomas (van Elsas et al, 1996).…”

contrasting

confidence: 78%

“…21% vs 0-6% in tumours (Castresana et al, 1993;Florenes et al, 1994;Lübbe et al, 1994;Papp et al, 1996) and 27% vs 11-25% in cell lines (Volkenandt et al, 1991;Weiss et al, 1993;Albino et al, 1994;Papp et al, 1996). One report describes p53 mutations in exons 7 and 8 in 15% of the tumours studied (Akslen et al, 1998).…”

Section: P53 Mutation Frequencies In Skin Cancermentioning

confidence: 99%

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p53 mutations in human cutaneous melanoma correlate with sun exposure but are not always involved in melanomagenesis

et al. 1999

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SummaryIn melanoma, the relationship between sun exposure and the origin of mutations in either the N-ras oncogene or the p53 tumoursuppressor gene is not as clear as in other types of skin cancer. We have previously shown that mutations in the N-ras gene occur more frequently in melanomas originating from sun-exposed body sites, indicating that these mutations are UV induced. To investigate whether sun exposure also affects p53 in melanoma, we analysed 81 melanoma specimens for mutations in the p53 gene. The mutation frequency is higher than thus far reported: 17 specimens (21%) harbour one or more p53 mutations. Strikingly, 17 out of 22 mutations in p53 are of the C:G to T:A or CC:GG to TT:AA transitional type, strongly suggesting an aetiology involving UV exposure. Interestingly, the p53 mutation frequency in metastases was much lower than in primary tumours. In the case of metastases, a role for sun exposure was indicated by the finding that the mutations are present exclusively in skin metastases and not in internal metastases. Together with a relatively frequent occurrence of silent third-base pair mutations in primary melanomas, this indicates that the p53 mutations, at least in these tumours, have not contributed to melanomagenesis and may have originated after establishment of the primary tumour.

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contrasting

confidence: 78%

Section: P53 Mutation Frequencies In Skin Cancermentioning

confidence: 99%

p53 mutations in human cutaneous melanoma correlate with sun exposure but are not always involved in melanomagenesis

et al. 1999

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“…However, some melanomas which were immunopositive for p21 WAF1 contained foci within the tumour which were strongly immunopositive for p53 but which were p21 WAF1 negative. Because p21 WAF1 is mutated infrequently in melanoma (Vidal et al, 1995), it is likely that p53 was mutated in these clones, and suggests that when the TP53 gene becomes mutated (albeit at a low frequency) in cutaneous melanoma it occurs as a late event during melanoma progression (Castresana et al, 1993;Albino et al, 1994;Florenes et al, 1994;Lubbe et al, 1994;Montano et al, 1994).…”

Section: Discussionmentioning

confidence: 99%

Prognostic significance of allelic losses in primary melanoma

et al. 1998

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Loss of genetic material, including loss of loci on chromosome arms 6q, 9p, and 10q, occurs frequently in cutaneous melanoma but infrequently in benign melanocytic nevi or other melanocytic lesions, suggesting that these genetic alterations are important in the development and progression of melanoma. To examine whether allelic loss is of prognostic importance in melanoma, disease-free survival was related to loss of heterozygosity on 6q, 9p and 10q in 83 individuals with sporadic primary cutaneous melanoma. Loss of chromosome arms 6q and 10q were each signi®cantly associated with a poorer clinical outcome (P=0.013 and P=0.001 respectively). In a subgroup of 41 subjects whose primary tumours were allelotyped, the fractional allelic loss (FAL) at 39 autosomal arms also signi®cantly correlated with disease-free survival (P=0.013), with an increase in FAL associated with a poorer outcome; this association remained signi®cant when controlled for tumour thickness (P=0.035). In addition, a greater proportion of cells were immunopositive for Ki67 antigen, p53 and p21 WAF1 protein in the primary melanomas than in the benign melanocytic nevi, however, only p53 overexpression was signi®cantly associated with improved survival (P=0.041).

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“…This abnormal expression of wild-type p53 protein was also found in normal cells of a patient from a family with a history of cancer (Barnes et al, 1992) and, more recently, a new case of Li-Fraumeni was reported in which no mutation in the coding sequence of the p53 gene was detected (Birch et al, 1994). In all cases, stabilization of the p53 protein depends on factors other than p53 gene mutation, such as (1) binding to other molecules of cellular (mdm2 gene product) or viral origin blocking p53 in an inactive conformation; and/or (2) (Lang et al, 1994), melanomas (Castresana et al, 1993) and testis cancer (Peng et al, 1993), and that nuclear exclusion of p53 might also be one way of inactivating p53 in breast cancer (Moll et al, 1992). Nuclear exclusion of wild-type p53 is suggested in a study showing its cytoplasmic accumulation in colorectal cancers (Bosari et al, 1995) with a higher prevalence in advanced tumours (Sun et al, 1992).…”

Section: Discussionmentioning

confidence: 99%

“…However, the literature concerning the prognostic value ofp53 immunoreactivity is controversial, as the results of IHC assays cannot be accepted as evidence of p53 gene mutation (Battifora et al, 1994). In addition, there is no clear picture concerning the significance of wild-type overexpression observed in several studies on colorectal adenomas (Pignatelli et al, 1992;Pignatelli et al, 1992;Tominaga et al, 1993) and demonstrated in anaplastic astrocytomas (Lang et al, 1994), breast cancer (Moll et al, 1992), melanomas (Castresana et al, 1993), testis cancer (Peng et al, 1993) and hepatic tumours of childhood (Kennedy et al, 1994 Primer 11 Sense Intron 6 5'-GTC TCC CCA AGG CGC ACT GG-3' Primer 12…”

Section: Materials and Methods Materialsmentioning

confidence: 99%

Overexpression of p53 mRNA in colorectal cancer and its relationship to p53 gene mutation

el-Mahdani

Vaillant²,

Guiguet³

et al. 1997

Br J Cancer

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We analysed the frequency of p53 mRNA overexpression in a series of 109 primary colorectal carcinomas and its association with p53 gene mutation, which has been correlated with short survival. Sixty-nine of the 109 cases (63%) demonstrated p53 mRNA overexpression, without any correlation with stage or site of disease. Comparison with p53 gene mutation indicated that, besides cases in which p53 gene mutation and p53 mRNA overexpression were either both present (40 cases) or both absent (36 cases), there were also cases in which p53 mRNA was overexpressed in the absence of any mutation (29 cases) and those with a mutant gene in which the mRNA was not overexpressed (four cases). Moreover, the mutant p53 tumours exhibited an increase of p53 mRNA expression, which was significantly higher in tumours expressing the mutated allele alone than in tumours expressing both wild- and mutated-type alleles. These data (1) show that p53 mRNA overexpression is a frequent event in colorectal tumours and is not predictive of the status of the gene, i.e. whether or not a mutation is present; (2) provide further evidence that p53 protein overexpression does not only result from an increase in the half-life of mutated p53 and suggest that inactivation of the p53 function in colorectal cancers involves at least two distinct mechanisms, including p53 overexpression and/or mutation; and (3) suggest that p53 mRNA overexpression is an early event, since it is not correlated with Dukes stage.

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Lack of allelic deletion and point mutation as mechanisms of p53 activation in human malignant melanoma

Cited by 94 publications

References 15 publications

p53 mutations in human cutaneous melanoma correlate with sun exposure but are not always involved in melanomagenesis

p53 mutations in human cutaneous melanoma correlate with sun exposure but are not always involved in melanomagenesis

Prognostic significance of allelic losses in primary melanoma

Overexpression of p53 mRNA in colorectal cancer and its relationship to p53 gene mutation

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