Recent advances in our understanding of the genetics of melanoma have shed light on the causes, behavior and possible therapeutic interventions.

Genetic studies of the rare families with strong predisposition to melanoma have identified candidate polymorphisms in several high penetrance genes including CDKN2A,CDK4 and BAP-1. To date however these have not revealed insights into the biology of pathogenesis of most melanoma nor candidate therapeutic targets. Low and intermediate germline susceptibility genes have been identified and include among others MC1R and MITF.

The study of somatic mutations has revolutionised the treatment of melanoma with the identification of the BRaf mutations and the development of B Raf inhibitors. NGS sequencing has shown that melanoma is a highly mutagenic cancer, with a high proportion of mutations being attributed to UV radiation. A major challenge is the identification of driver mutations in a sea of passenger mutations, and hence identify suitable targets for melanoma. The V600E mutation is the most common in melanoma. Rarer mutations have been identified in the BRaf gene, and in genes encoding MAPK pathway proteins including NRas and MEK. Rarer mutations are seen in the PI3-K-PTen-AKT pathway. The CKIT amplification is seen a 6-8% of melanomas with a preponderance in acral and mucosal melanomas.The role of these and other mutations in the behavior and in the response and resistance to existing and future treatments will be discussed.