In the last decade, significant progress has been made in our understanding of the genetic alterations in melanocytic tumors. The most exciting finding is the discovery of oncogenic BRAF mutations in both malignant melanoma and melanocytic nevi. This finding indicates that activation of the mitogen-activated protein kinase pathway may be a critical initiating step of melanocytic neoplasia, and that the fundamental difference between melanoma and nevi may lie in the inhibitory machinery for this oncogenic signaling. In addition, different genetic alterations identified in melanomas at different sites and with different levels of sun exposure have been shown, indicating that there are several distinct genetic pathways in the development of melanoma. Different patterns of genetic alterations have also been identified among different kinds of melanocytic nevi. While acquired nevi and small congenital nevi show a high frequency of BRAF mutations regardless of their anatomic localization, the mutations were rare in medium-sized congenital nevi and giant congenital nevi. Spitz nevi show no BRAF mutations, while a subset of cases show HRAS mutations, often associated with a copy number increase of chromosome 11p. The clear differences in genetic aberration patterns have significant clinical implications in the diagnosis and treatment of melanocytic tumors.
"All reported NRAS gene mutations occur in exon 2 or exon 3, with 65% of mutations occurring in exon 3 at codon 61. The most frequent amino acid substitutions are Q61K and Q61R (Takata and Saida, 2006). These substitutions result in a constitutively active NRAS protein, unable to cleave guanosine triphosphate. "
[Show abstract][Hide abstract] ABSTRACT: Congenital melanocytic nevus (CMN) is a particular melanocytic in utero proliferation characterized by an increased risk of melanoma transformation during infancy or adulthood. NRAS and BRAF mutations have consistently been reported in CMN samples, but until recently results have been contradictory. We therefore studied a series of large and giant CMN and compared them to small and medium CMN using Sanger sequencing, pyrosequencing, high resolution melting analysis and mutation enrichment by an enhanced version of ice-COLD-PCR. Large-giant CMN displayed NRAS mutations in 94.7% of cases (18/19). At that point, the role of additional mutations in CMN pathogenesis had to be asked. We therefore performed exome-sequencing on 5 specimens of large-giant nevi. The results showed that NRAS mutation was the sole recurrent somatic event found in such melanocytic proliferations. The genetic profile of small-medium CMN was significantly different with 70% of cases bearing NRAS mutations and 30% showing BRAF mutations. These findings strongly suggest that NRAS mutations are sufficient to drive melanocytic benign proliferations in utero.Journal of Investigative Dermatology accepted article preview online, 15 October 2013; doi:10.1038/jid.2013.429.
"All reported NRAS gene mutations occur in exon 2 and exon 3 (known before as exon 1 and exon 2). Approximately 65% of the mutations occur at codon 61 in exon 3, where the most frequent amino acids substitutions are Q61K and Q61R . The replacement of the glutamine residue (Q61) with lysine (K) or arginine (R) results in an aberrant protein that is unable to cleave GTP, and thus the protein remains constitutively active. "
[Show abstract][Hide abstract] ABSTRACT: Despite recent advances, the biology underlying nevogenesis remains unclear. Activating mutations in NRAS, HRAS, BRAF, and GNAQ have been identified in benign nevi. Their presence roughly correlates with congenital, Spitz, acquired, and blue nevi, respectively. These mutations are likely to play a critical role in driving nevogenesis. While each mutation is able to activate the MAP kinase pathway, they also interact with a host of different proteins in other pathways. The different melanocytic developmental pathways activated by each mutation cause the cells to migrate, proliferate, and differentiate to different extents within the skin. This causes each mutation to give rise to a characteristic growth pattern. The exact location and differentiation state of the cell of origin for benign moles remains to be discovered. Further research is necessary to fully understand nevus development given that most of the same developmental pathways are also present in melanoma.
Dermatology Research and Practice 04/2011; 2011(6):463184. DOI:10.1155/2011/463184
"Thus, in medaka, the absence of dysfunctional p53 is not a precondition for malignant melanoma development in general. The role of p53 deficiency for melanoma needs to be elucidated further in both models, as p53 itself is rarely mutated in human melanoma development (for review see Levy et al., 2006; Takata and Saida, 2006). Xmrk as a receptor tyrosine kinase is strategically placed at the top of several growth-promoting signaling pathways. "
[Show abstract][Hide abstract] ABSTRACT: Melanoma is a tumor with a very low cure rate once metastasized. Although many genes important for melanoma induction, transformation, and metastasis have been identified, the process of melanomagenesis is only partly understood. Melanoma mediators are easiest to investigate in cell culture models, but animal models are required to evaluate their importance in the context of the whole organism. Here, we describe a transgenic melanoma model in medaka. The oncogenic receptor tyrosine kinase, Xmrk, responsible for melanoma formation in Xiphophorus, was stably expressed under the control of a pigment cell-specific promoter. The transgenic fish developed pigment cell tumors with a penetrance of 100%. The model was used for monitoring the in vivo relevance of several apoptosis and differentiation genes, and for induction of melanoma-relevant signal transduction pathways. We found that Stat5 activation, and Mitf and Bcl-2 levels correlated with a more aggressive stage of the malignancy. Interestingly, different types of pigment cell tumors occurred depending on the genetic background, namely invasive melanoma, uveal melanoma, or exophytic and less aggressive pigment cell tumors called xanthoerythrophoroma. Furthermore, on p53 mutant background, the expression of xmrk led to the appearance of giant focal pigment cell tumors, whereas tumor onset was unchanged compared with wild-type medaka.
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