Kinase mutations in cancer

The RAS-RAF pathway regulates mitogenic signal transduction, and oncogenic RAS mutations are found in 15% of human cancers. In an Advanced Online Publication in Nature, Davies et al. describe results of a systematic genome-wide screen for mutations of genes in this pathway (9 June 2001, DOI:10.1038/nature00766). They found examples of somatic substitution mutations in the human BRAF gene in cancer cells. Analysis of over 500 cancer cell lines revealed a high mutation frequency in malignant melanomas, as well as mutations in a wide range of other tumor types. Mutant forms of the BRAF protein had elevated kinase activity, resulting in signalling and increased transforming capacity. Furthermore, Davies et al. found cancer cell lines that contain oncogenic mutations in both the RAS and BRAF genes, suggesting that tandem-activating mutations in more than one component of a signalling pathway may contribute to tumorigenesis.