Frequent mutations of the p53 gene in cutaneous melanoma of the nodular type

Akslen, Lars A.; Monstad, Sissel E.; Larsen, Benedikte; Straume, Oddbjørn; Øgreid, D

doi:10.1002/(sici)1097-0215(19980220)79:1<91::aid-ijc17>3.0.co;2-k

Cited by 36 publications

(8 citation statements)

References 23 publications

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“…These results are consistent with a variety of data from other cell types, including normal human fibroblasts (38, 39), though importantly our results provide the first evidence that p53 status affects excision repair specifically in melanoma cells. Even though only 1% of primary melanomas and 5% of metastatic melanomas show mutations in the p53 gene (15, 16, 44), the common loss of ARF function in metastatic melanomas with deletion of the CDKN2A locus (17-19) suggests that p53-dependent processes may contribute to melanoma development. Since p53 regulates many components of the cellular response to DNA damage induced by UV irradiation, including DNA repair, cell cycle checkpoint, and apoptosis, it is not clear how its many diverse functions ultimately control cell fate in melanoma.…”

Section: Discussionmentioning

confidence: 99%

Similar Nucleotide Excision Repair Capacity in Melanocytes and Melanoma Cells

Gaddameedhi

Kemp

Reardon³

et al. 2010

Cancer Research

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Sunlight UV exposure produces DNA photoproducts in skin that are repaired solely by nucleotide excision repair in humans. A significant fraction of melanomas are thought to result from UV-induced DNA damage that escapes repair; however, little evidence is available about the functional capacity of normal human melanocytes, malignant melanoma cells, and metastatic melanoma cells to repair UV-induced photoproducts in DNA. In this study, we measured nucleotide excision repair in both normal melanocytes and a panel of melanoma cell lines. Our results show that in 11 of 12 melanoma cell lines tested, UV photoproduct repair occurred as efficiently as in primary melanocytes. Importantly, repair capacity was not affected by mutation in the N-RAS or B-RAF oncogenes, nor was a difference observed between a highly metastatic melanoma cell line (A375SM) or its parental line (A375P). Lastly, we found that although p53 status contributed to photoproduct removal efficiency, its role did not seem to be mediated by enhanced expression or activity of DNA binding protein DDB2. We concluded that melanoma cells retain capacity for nucleotide excision repair, the loss of which probably does not commonly contribute to melanoma progression. Cancer Res; 70(12); 4922-30. ©2010 AACR.

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Section: Discussionmentioning

confidence: 99%

Similar Nucleotide Excision Repair Capacity in Melanocytes and Melanoma Cells

Gaddameedhi

Kemp

Reardon³

et al. 2010

Cancer Research

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“…14 The p53 gene, which is the most commonly mutated gene in non-melanoma skin cancers, is not a prime target of inactivation in malignant melanoma but some p53 mutations have been reported. 15 In previous studies we reported CDKN2A mutations in a sub-set of sporadic primary melanomas, along with a high frequency of LOH. 8,16 In the current study on the same set of melanomas, we determined mutations and polymorphisms in the CDKN2A, CDKN2B, CDKN2C genes, CDK4 gene and the p53 gene.…”

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confidence: 87%

A single nucleotide polymorphism in the 3?untranslated region of theCDKN2A gene is common in sporadic primary melanomas but mutations in theCDKN2B,CDKN2C,CDK4 andp53 genes are rare

Kumar¹,

Smeds²,

Berggren³

et al. 2001

Int. J. Cancer

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Ten patients with advanced B-cell lymphoma were treated with a single locoregional injection of CD3CD19 bispecific and costimulating CD28 monospecific antibodies to activate tumor-infiltrating T-lymphocytes. Antibodies were administered at 4 different dose levels (30 g, 270 g, 810 g, 1,600 g of each antibody) either by intratumoral or intralym-phatic injection. Most patients developed responses within different compartments of the immune systems (T cells, NK cells) subsequent to the antibody application. Comparative studies in 2 patients of which treated as well as untreated lymph nodes were available revealed the up-regulation of T-cell activation markers induced by the antibody injection. Additionally, in 1 patient the induction of apoptosis of lym-phoma B cells in the antibody-treated lymph node was observed. Specificity analyses of peripheral blood T cells by means of IFN-ELISpot measurement indicated the recruitment of idiotype-specific T cells, as in 1 out of 3 investigated patients an increased T-cell response toward autologous id-iotype peptides could be demonstrated. We conclude that a single injection of CD3CD19 bispecific antibodies is capable to induce an activation of autologous T lymphocytes if simultaneous costimulatory signaling by CD28 antibodies is provided. Furthermore, our data suggest that at least in some patients lymphoma-specific T cells can be recruited by this immunotherapeutic approach toward B-cell lymphoma. Among the immunotherapeutic approaches toward malignant diseases of B-cell origin, strategies aiming at the activation of T lymphocytes are most promising as these are known to be highly specialized effector cells of the cellular immune system mediating key functions such as cytotoxicity, cytokine production, regulation of other effector cells, and immunological memory. The central role of T lymphocytes in the regulation of the immune system is the rationale for the therapeutic use of professional antigen-presenting cells (APC), namely dendritic cells (DC), that can process and present tumor-associated antigens (TAA) and thus are able to activate tumor-specific T lymphocytes. 1 APC-based approaches for the induction of anti-tumoral T-cell responses are therefore being tested in clinical studies in several human malignancies including B-cell lymphomas and myeloma. 2,3 Tumor-specific T-cell activation by non-cellular immunothera-peutic agents avoids the requirement to generate autologous DC ex vivo for every individual patient. In this view, CD3-based bispe-cific antibodies (CD3anti-TAA) may be used alternatively or in addition to vaccination protocols with DC as they can stimulate T cells in a tumor-specific manner as well. 4 As the application of CD3anti-TAA bispecific antibodies alone will result in an insufficient activation or even apoptosis of the effector cells, 5 the additional stimulation of the effector T cells is an indispensable demand. To address this problem, we used locoregional (i.e., intratumoral) injections of CD3CD19 bispecific antibodies targeting the B-cell anti...

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“…ARF blocks murine double minute 2-induced degradation of p53, whereas p16 INK4a and p15 INK4b inhibit cyclin-dependent kinases 4 and 6 , leading to RB-hypophosphorylation and cell cycle arrest. Although ARF loss is the most common lesion of the ARF–murine double minute 2–p53 pathway in melanoma, mutational inactivation of p53 is observed in 10–30% of melanomas (Albino et al , 1994; Sparrow et al , 1995; Akslen et al , 1998; Zerp et al , 1999). …”

Section: Introductionmentioning

confidence: 99%

Somatic p16INK4a loss accelerates melanomagenesis

et al. 2010

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Loss of p16INK4a–RB and ARF–p53 tumor suppressor pathways, as well as activation of RAS–RAF signaling, is seen in a majority of human melanomas. Although heterozygous germline mutations of p16INK4a are associated with familial melanoma, most melanomas result from somatic genetic events: often p16INK4a loss and N-RAS or B-RAF mutational activation, with a minority possessing alternative genetic alterations such as activating mutations in K-RAS and/or p53 inactivation. To generate a murine model of melanoma featuring some of these somatic genetic events, we engineered a novel conditional p16INK4a-null allele and combined this allele with a melanocyte-specific, inducible CRE recombinase strain, a conditional p53-null allele and a loxP-stop-loxP activatable oncogenic K-Ras allele. We found potent synergy between melanocyte-specific activation of K-Ras and loss of p16INK4a and/or p53 in melanomagenesis. Mice harboring melanocyte-specific activated K-Ras and loss of p16INK4a and/or p53 developed invasive, unpigmented and nonmetastatic melanomas with short latency and high penetrance. In addition, the capacity of these somatic genetic events to rapidly induce melanomas in adult mice suggests that melanocytes remain susceptible to transformation throughout adulthood.

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Frequent mutations of the p53 gene in cutaneous melanoma of the nodular type

Cited by 36 publications

References 23 publications

Similar Nucleotide Excision Repair Capacity in Melanocytes and Melanoma Cells

Similar Nucleotide Excision Repair Capacity in Melanocytes and Melanoma Cells

A single nucleotide polymorphism in the 3?untranslated region of theCDKN2A gene is common in sporadic primary melanomas but mutations in theCDKN2B,CDKN2C,CDK4 andp53 genes are rare

Somatic p16INK4a loss accelerates melanomagenesis

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