Mutations of theBRAFgene in human cancer, by Davieset al. (Nature2002; 417: 949-54)

Conflict of interest: none declared. It is now a decade since a multicentre, systematic, genome‐wide assessment of cancer‐associated pathways led to a major breakthrough in defining the molecular alterations associated with the development of sporadic cutaneous malignant melanoma (MM).1 Sporadic cancers occur because of the accumulation of mutations in essential genes that alter the normal functions of cell growth, differentiation and death.1 Large‐scale sequencing of growth‐associated genes in the RAS–RAF–MEK–ERK–MAPK pathway in a variety of cancers identified a high frequency (66%) of activating mutations of the BRAF kinase gene in human MMs.1 Through functional studies in cell‐lines, Davies et al.1 realized that what has come to be known as the BRAF V600E mutation2 led to the development of autonomous overactivity in the mitogen‐activated protein kinase (MAPK) pathway, presumably leading to increased cell growth.1 They correctly predicted that this discovery would lead to new therapeutic options.1 Soon many other studies characterizing the BRAF V600E mutation followed. Somatic mutations in the BRAF gene are particularly linked to intermittent ultraviolet radiation (UVR) exposure.2 3 Of these mutations, 92% occur in a single codon (BRAF V600E).2 However, as BRAF V600E is found in up to 82% of benign naevi (and never in congenital naevi), factors other than UVR induction of BRAF V600E mutations are needed for tumorigenesis.3