Allelic losses on chromosome arm 10q and mutation of the PTEN ( MMAC1 ) tumour suppressor gene in primary and metastatic malignant melanomas

Reifenberger, Julia; Wolter, Marietta; Boström, Jan; Büschges, Rainer; Schulte, K.-W.; Megahed, Mosaad; Ruzicka, Thomas; Reifenberger, Guido

doi:10.1007/s004280050477

Cited by 75 publications

(56 citation statements)

References 35 publications

(53 reference statements)

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“…Applying denaturing gel electrophoresis, none of three primary melanomas with LOH but four of 61 melanoma metastases harboured mutations of the PTEN/MMAC1 gene (Birck et al, 2000). Reifenberger et al (2000) reported PTEN/MMAC1 mutations in four of 37 investigated metastases (11%) from which two had lost one PTEN/MMAC1 allele. Melanoma metastases seem to be affected by LOH at the PTEN/MMAC1 locus more frequently as was further reported for 33% of 21 cases; 19% of these specimens harboured mutations in the remaining allele (Celebi et al, 2000).…”

Section: Discussionmentioning

confidence: 93%

PTEN/MMAC1 expression in melanoma resection specimens

et al. 2002

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PTEN/MMAC1, a tumour suppressor gene located on chromosome 10q23.3, has been found to be deleted in several types of human malignancies. As the chromosomal region 10q22-qter commonly is affected by losses in melanomas, we addressed this gene as tumour suppressor candidate in melanomas. Investigating PTEN/MMAC1 expression at mRNA level by semiquantitative reverse transcription-polymerase chain reaction, we did not find a statistically significant down-regulation in melanoma resection specimens in comparison to acquired melanocytic nevi from which melanomas quite often are known to arise. Upon immunohistochemistry, PTEN/MMAC1 protein expression in melanomas was not lost. Sequencing the PTEN/ MMAC1 cDNAs in 26 melanoma resection specimens (21 primary melanomas, five metastases), we detected three point mutations and two nucleotide deletions which did not represent genetic polymorphisms. With respect to the predicted protein sequences, all three point mutations were silent whereas the two frame shifts at the extreme C-terminus resulted in a loss of the putative PDZ-targeting consensus sequence. As loss of this motif possibly impairs localization and function of PTEN/MMAC1 in the two corresponding primary tumours, alterations of this tumour suppressor protein may participate in some melanomas.

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Section: Discussionmentioning

confidence: 93%

PTEN/MMAC1 expression in melanoma resection specimens

et al. 2002

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“…11) and in melanoma cell lines (9-30% and 20-50%, respectively). However, absent or decreased PTEN protein expression occurs in 50% to 91% of primary melanomas (12).…”

Section: Introductionmentioning

confidence: 99%

Pten Deficiency in Melanocytes Results in Resistance to Hair Graying and Susceptibility to Carcinogen-Induced Melanomagenesis

Inoue-Narita¹,

Hamada

Sasaki

et al. 2008

Cancer Research

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Phosphate and tensin homologue deleted on chromosome 10 (PTEN) is a tumor suppressor gene inactivated in numerous sporadic cancers, including melanomas. To analyze Pten functions in melanocytes, we used the Cre-loxP system to delete Pten specifically in murine pigment-producing cells and generated DctCrePten flox/flox mice. Half of DctCrePten flox/flox mice died shortly after birth with enlargements of the cerebral cortex and hippocampus. Melanocytes were increased in the dermis of perinatal DctCrePten flox/flox mice. When the mutants were subjected to repeated depilations, melanocyte stem cells in the bulge of the hair follicle resisted exhaustion and the mice were protected against hair graying. Although spontaneous melanomas did not form in DctCrePten flox/flox mice, large nevi and melanomas developed after carcinogen exposure. DctCrePten flox/flox melanocytes were increased in size and exhibited heightened activation of Akt and extracellular signal-regulated kinases, increased expression of Bcl-2, and decreased expression of p27 Kip1 . Our results show that Pten is important for the maintenance of melanocyte stem cells and the suppression of melanomagenesis. [Cancer Res 2008;68(14):5760-8]

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“…However, whereas mutations and deletions of PTEN have been observed in up to 60% of melanoma cell lines, only about 10% of uncultured tumor material were found to harbor genetic alterations (10)(11)(12)(13)(14)(15)(16). These observations have led to speculations that PTEN inactivation may predominantly occur through a mechanism other than mutation for example by epigenetic silencing (17).…”

Section: Introductionmentioning

confidence: 99%

Epigenetic Silencing of the PTEN Gene in Melanoma

et al. 2006

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Phosphatase and tensin homologue deleted from chromosome 10 (PTEN) seems to be an important tumor suppressor gene in melanoma. Because the PTEN gene is only infrequently deleted or mutated, and because the PTEN protein is low to absent in a significant number of melanomas, we investigated alternative methods of epigenetic silencing. We did quantitative positional methylation analysis (pyrosequencing) on 37 sera from melanoma patients and on 21 pairs of corresponding sera and melanoma specimens in addition to Taqman reverse transcription-PCR. We report significant positional PTEN promoter methylation in 62% of circulating DNA isolated from sera of patients with metastatic melanoma. The percentage of methylation of a selected CpG island in blood showed a correlation with methylation levels in the corresponding melanoma tissue. Moreover, high percentages of PTEN methylation were associated with low PTEN transcription levels. Using the demethylation agent 5-aza-2 ¶-deoxycytidine, reduced methylation and a corresponding increase in PTEN protein were observed in BLM melanoma cells, leading to reduced AKT activity in an in vitro kinase assay. In summary, epigenetic PTEN silencing seems to be a relevant mechanism of inactivating this tumor suppressor gene in melanoma that may promote melanoma development by derepression of the AKT pathway.

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Allelic losses on chromosome arm 10q and mutation of the PTEN ( MMAC1 ) tumour suppressor gene in primary and metastatic malignant melanomas

Cited by 75 publications

References 35 publications

PTEN/MMAC1 expression in melanoma resection specimens

PTEN/MMAC1 expression in melanoma resection specimens

Pten Deficiency in Melanocytes Results in Resistance to Hair Graying and Susceptibility to Carcinogen-Induced Melanomagenesis

Epigenetic Silencing of the PTEN Gene in Melanoma

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