The molecular pathology of melanoma has been an area of intense research activity and can be broadly divided into inherited mutations that confer increased susceptibility to melanoma and somatic alterations that occur in established tumours.

Approximately 10% of patients with a melanoma demonstrate a family history [3]. 20–40% of these families will have a mutation in CDKN2A, which is a locus that codes for two tumour suppressors (p16 and p14ARF) in separate overlapping reading frames. Mutations in CDK4 and BAP1 are also high-risk melanoma susceptibility loci.

Numerous studies have investigated recurrent somatic mutations in melanoma. Initial candidate screens identified somatic mutations in BRAF and NRAS as being common in cutaneous melanoma. BRAF, a serine-threonine kinase, is mutated in around 40% of melanomas and shows a mutational hotspot at codon 600, with BRAFV600E mutations (substitution of a valine for a glutamic acid) occurring in between 50 and 80% of BRAF mutated melanomas. Additional V600 mutations also occur (V600K, V600R, V600M) as well as mutations in codons 594, 597 and 601 (summarised in Table 2.3). Numerous studies have demonstrated that BRAFV600E has constitutive activity leading to increased signalling through the MAPK pathway with consequent effects a range of cellular properties, including differentiation, proliferation, survival and motility [4, 5]. Of note however, a larger proportion of melanocytic naevi (80%) harbour the same BRAF V600E mutations, demonstrating that this mutation is likely an early event during melanomagenesis, although not sufficient in and of itself [6].