BRAF and NRAS mutational status are prognostically important in thick and locally advanced cutaneous melanoma

Abstract

The evolution in the understanding of kinase oncogene addiction as the driver of melanomagenic MAPK cascade activation has encouraged the molecular characterisation of melanoma on the basis of potentially druggable kinase mutations. Currently, the three best-characterised targets are <i>BRAF, KIT</i> and <i>NRAS</i>. Mutations in these genes largely occur in a mutually exclusive manner, with the former two kinases offering tantalising therapeutic opportunities, and are currently the subject of phase II and III trials. Notwithstanding the potential therapeutic opportunities offered by some of these mutations, there are conflicting data on the potential prognostic information conferred by the knowledge of the <i>NRAS</i> and <i>BRAF</i> mutational status. In this study, we have genotyped 192 cases of thick and/or metastatic melanoma, arising in a population exposed to a high degree of ambient UV radiation, and analysed the mutations in relation to the degree of cutaneous sun damage, and to clinical outcome. We report <i>BRAF</i> and<i>NRAS</i> mutations are associated with impaired and enhanced survival outcomes, respectively. Furthermore, this effect is mediated by a differential metastatic rate to locoregional sites, and subsequently upon distant sites.