Despite the large body of mutational data available for melanoma and epidemiological studies linking this cancer to ultraviolet radiation (UVR), the fundamental carcinogenic mechanisms involved in melanoma remain largely unknown. To this end, we systematically reviewed, extracted, and analyzed mutational data from the extant melanoma literature in an effort to gain more insight into its early pathogenic events. We searched PubMed (1966-January 2006) using the words "mutation" AND "melanoma" in the title or abstract. Out of 2,095 returned results, there were 203 eligible studies that were subsequently analyzed. We cataloged 8,201 somatic and cultured melanoma specimens and annotated 2,041 reported somatic sequence variants. The single BRAF c.1799T>A (p.Val600Glu) alteration is the most prevalent variant while other A:T>T:A transversions were uncommon. Four highly-recurrent, non-ultraviolet B (UVB) changes account for most of the NRAS and BRAF variants. CDKN2A, PTEN/MMAC1, and TP53 harbored statistically higher rates of UVB signature changes (64.2%, 52.4%, and 69.2%, respectively) than oncogenic loci (NRAS: 15.3% and BRAF: 2.4%). More specifically, cutaneous melanomas showed a significantly higher proportion of UVB signature mutations at both TP53 and CDKN2A when compared to non-skin cancers using data from their respective locus-specific databases. Superficial spreading and nodular melanomas had the highest rates of BRAF (53.4%) and NRAS (28.0%) mutations. In melanoma, there is sufficient mutational evidence to support a role for direct UVB participation, especially at TP53 and CDKN2A. For oncogenes, the role for UVB is less clear since functionally-activating changes are uncommon and are subject to sequence constraints.

Metastatic melanoma is notoriously one of the most difficult cancers to treat. Although many therapeutic regimens have been tested, very few achieve response rates greater than 25%. Given the rising incidence of melanoma and the paucity of effective treatments, there is much hope and excitement in leveraging recent genetic and molecular insights for therapeutic advantage. Over the past 30 years, elegant studies by many groups have helped decipher the complex genetic networks involved in melanoma proliferation, progression and survival, as well as several genes involved in melanocyte development and survival. Many of these oncogenic loci and pathways have become crucial targets for pharmacological development. In this article we review: (1) our current understanding of melanoma genetics within the context of signaling networks; (2) targeted therapies, including an extensive discussion of promising agents that act in the Bcl-2 signaling network; (3) future areas of research.

No abstract

No abstract

Melanoma therapy is moving away from combinatorial approaches and towards newer targeted strategies. With the identification of mutations in various RAS pathway genes, there are now tremendous opportunities to bring inhibitors of RAS signalling to the clinical arena.

No abstract

No abstract

Mohs surgical defects of the helix left to heal by second-intention have comparable long-term cosmetic outcomes to those repaired by FTSG. There was no significant difference in complications, and patients were highly satisfied with both repair options.